Importance and review of drug metabolite synthesis

Zafer Şahin; Pınar Sinem Omurtag Özgen; Sevim Rollas

doi:10.26650/IstanbulJPharm.2023.1033045

Review

Importance and review of drug metabolite synthesis

Year 2023, Volume: 53 Issue: 2, 251 - 269, 30.08.2023

Zafer Şahin , Pınar Sinem Omurtag Özgen Sevim Rollas

https://doi.org/10.26650/IstanbulJPharm.2023.1033045

Abstract

Phase I and Phase II metabolic reactions are involved in the pharmacokinetic properties of drugs after administration. These reactions mainly aim to make drugs more polar and eliminate them safely. However, some of these metabolites have the potential to exhibit a toxicological effect. Industry and/or academia have to consider these metabolites in terms of their pharmacodynamic and pharmacokinetic properties. These metabolites are not only residual intermediates from the synthetic process of the main drug but also unique structures produced by metabolic enzymes in the human organism. Thus, metabolite synthesis by synthetic or semi-synthetic methods is a key feature in the pharmaceutical industry. In this review, synthetic methods of the metabolites from all known metabolic pathways are reviewed from the literature. It was observed that both synthetic and semi-synthetic methods require more attention as they are as important and complex as drug synthesis. Moreover, it showed that there was much more research available for Phase I than Phase II in the literature.

Keywords

Drug metabolite, metabolism, synthesis, oxidation, Phase I, Phase II

References

Adamczyk, M., & Fino, J. R. (1996). Synthesis of procainamide me-tabolites, N-acetyl desethylprocainamide, and desethylprocain-amide. Organic Preparations and Procedures International, 28(4), 470-474. doi:Doi 10.1080/00304949609356555 google scholar
Althuis, T. H., & Hess, H. J. (1977). Synthesis and identification of the major metabolites of prazosin formed in dog and rat. Journal of Medicinal Chemistry, 20(1), 146-149. doi:10.1021/jm00211a031 google scholar
Arewang, C. J., Lahmann, M., Oscarson, S., & Tiden, A. K. (2007). Synthesis of urine drug metabolites: glucuronic acid glycosides of phenol intermediates. Carbohydrate Research, 342(7), 970-974. doi:10.1016/j.carres.2007.01.014 google scholar
Argikar, U. A. (2012). Unusual glucuronides. Drug Metabolism & Disposition, 40(7), 1239-1251. doi:10.1124/dmd.112.045096 google scholar
Asha, S., & Vidyavathi, M. (2009). Cunninghamella--a microbial model for drug metabolism studies--a review. Biotechnology Ad-vances, 27(1), 16-29. doi:10.1016/j.biotechadv.2008.07.005 google scholar
Bailey, M. J., & Dickinson, R. G. (2003). Acyl glucuronide reactiv-ity in perspective: biological consequences. Chemico-Biological Interactions, 145(2), 117-137. doi:10.1016/s0009-2797(03)00020-6 google scholar
Baillie, T. A., Cayen, M. N., Fouda, H., Gerson, R. J., Green, J. D., Grossman, S. J., . . . Shipley, L. A. (2002). Drug metabolites in safety testing. Toxicology and Applied Pharmacology, 182(3), 188-196. doi:10.1006/taap.2002.9440 google scholar
Baldwin, B. C., Robinson, D., & Williams, R. T. (1960). Studies in detoxi-cation. 82. The fate of benzoic acid in some domestic and other birds. The Biochemical Journal, 76(3), 595-600. doi:10.1042/bj0760595 google scholar
Boerner, U. (1975). The metabolism of morphine and heroin in man. Drug Metabolism Reviews, 4(1), 39-73. doi:10.3109/03602537508993748 google scholar
Bradshaw, P. R., Athersuch, T. J., Stachulski, A. V., & Wilson, I. D. (2020). Acyl glucuronide reactivity in perspective. Drug Discovery Today, 25(9), 1639-1650. doi:10.1016/j.drudis.2020.07.009 google scholar
Brown, D. D., Axelrod, J., & Tomchick, R. (1959). Enzymatic N-Methylation of Histamine. Nature, 183(4662), 680-680. doi:10.1038/183680a0 google scholar
Cai, X., Sha, M., Guo, C., & Pan, R. M. (2012). Synthesis of Tertiary Amine N-oxides—A Review. Asian Journal of Chemistry, 24(9), 3781-3784. google scholar
Caswell, J. M., O’Neill, M., Taylor, S. J., & Moody, T. S. (2013). Engi-neering and application of P450 monooxygenases in pharma-ceutical and metabolite synthesis. Current Opinion in Chemical Biology, 17(2), 271-275. doi:10.1016/j.cbpa.2013.01.028 google scholar
Cece-Esensencan, E. N., Fontaine, F., Plasencia, G., Teppner, M., Brink, A., Pahler, A., & Zamora, I. (2016). Enhancing throughput of glutation ad-duct formation studies and structural identification using software as-sisted-workflow based on high-resolution mass spectrometry (HRMS) data. SM Analytical and Bioanalytical Techniques, 1(1002), 1-12. google scholar
Chung, K. T., Fulk, G. E., & Egan, M. (1978). Reduction of azo dyes by intestinal anaerobes. Applied and Environmental Microbiology, 35(3), 558-562. doi:10.1128/AEM.35.3.558-562.1978 google scholar
Constanzer, M. L., Chavez-Eng, C. M., Fu, I., Woolf, E. J., & Matusze-wski, B. K. (2005). Determination of dextromethorphan and its metabolite dextrorphan in human urine using high performance liquid chromatography with atmospheric pressure chemical ionization tandem mass spectrometry: a study of selectivity of a tandem mass spectrometric assay. Journal of Chromatography B, 816(1-2), 297-308. doi:10.1016/j.jchromb.2004.11.049 google scholar
Cornelissen, S., Julsing, M. K., Schmid, A., & Buhler, B. (2012). Com-parison of microbial hosts and expression systems for mamma-lian CYP1A1 catalysis. Journal of Industrial Microbiology & Biotech-nology, 39(2), 275-287. doi:10.1007/s10295-011-1026-4 google scholar
Correia, M. S. P., Rao, M., Ballet, C., & Globisch, D. (2019). Coupled Enzymatic Treatment and Mass Spectrometric Analysis for Iden-tification of Glucuronidated Metabolites in Human Samples. google scholar
Chembiochem, 20(13), 1678-1683. doi:10.1002/cbic.201900065 Çoruh, I. (2012). Synthesis and evaluation of cytotoxic activities of some 1,4-disubstituted thiosemicarbazides, 2,5-disubstituted-1,3,4-thiadiazoles and 1,2,4-triazole-5-thiones derived from ben-zilic acid hydrazide. Marmara Pharmaceutcal Journal, 1(16), 56-63. doi:10.12991/201216421 google scholar
Cusack, K. P., Koolman, H. F., Lange, U. E., Peltier, H. M., Piel, I., & Va-sudevan, A. (2013). Emerging technologies for metabolite gener-ation and structural diversification. Bioorganic & Medicinal Chem-istry Letters, 23(20), 5471-5483. doi:10.1016/j.bmcl.2013.08.003 google scholar
Dahlin, D. C., & Nelson, S. D. (1982). Synthesis, decomposition ki-netics, and preliminary toxicological studies of pure N-acetyl-p-benzoquinone imine, a proposed toxic metabolite of acetamino-phen. Journal of Medicinal Chemistry, 25(8), 885-886. doi:10.1021/ jm00350a001 google scholar
de Paula, N. C., Araujo Cordeiro, K. C., de Melo Souza, P. L., Noguei-ra, D. F., da Silva e Sousa, D. B., Costa, M. B., . . . de Oliveira, V. (2015). Biosynthesis of human diazepam and clonazepam metabo-lites. Bioorganic & Medicinal Chemistry Letters, 25(5), 1026-1029. doi:10.1016/j.bmcl.2015.01.025 google scholar
Di Nardo, G., & Gilardi, G. (2012). Optimization of the bacterial cy-tochrome P450 BM3 system for the production of human drug metabolites. International Journal of Molecular Sciences, 13(12), 15901-15924. doi:10.3390/ijms131215901 google scholar
Doddaga, S., & Peddakonda, R. (2013). Chloroquine-N-oxide, a ma-jor oxidative degradation product of chloroquine: identification, synthesis and characterization. Journal of Pharmaceutical and Bio-medical Analysis, 81-82, 118-125. doi:10.1016/j.jpba.2013.04.004 google scholar
Dutkiewicz, G., Chidan Kumar, C. S., Yathirajan, H. S., Mayekar, A. N., & Kubicki, M. (2009). 3-Methyl-1,2,4-triazolo[3,4-a]phthalazine monohydrate. Acta crystallographica. Section E, Structure reports online, 65(11), o2694. doi:10.1107/S1600536809040677 google scholar
Fang, T., Wang, Y., Ma, Y., Su, W., Bai, Y., & Zhao, P. (2006). A rapid LC/ MS/MS quantitation assay for naringin and its two metabolites in rats plasma. Journal of Pharmaceutical and Biomedical Analysis, 40(2), 454-459. doi:10.1016/j.jpba.2005.07.031 google scholar
Feely, J., Kavanagh, P. V., McNamara, S. M., & O’Brien, J. E. (1999). Simple preparation of the major urinary metabolites of flunitraz-epam and nitrazepam. Irish Journal of Medical Science, 168(1), 8-9. doi:10.1007/BF02939571 google scholar
Fessner, N. D., Srdic, M., Weber, H., Schmid, C., Schonauer, D., Schwaneberg, U., & Glieder, A. (2020). Preparative-Scale Produc-tion of Testosterone Metabolites by Human Liver Cytochrome P450 Enzyme 3A4. Advanced Synthesis & Catalysis, 362(13), 27252738. doi:10.1002/adsc.202000251 google scholar
Flores, J. R., Nevado, J. J. B., Salcedo, A. M. C., & Diaz, M. P. C. (2004). Non-aqueous capillary zone electrophoresis method for the analysis of paroxetine, tamoxifen, and their main metabolites in urine. Analytica Chimica Acta, 512(2), 287-295. doi:10.1016/j. aca.2004.02.048 google scholar
Fodi, T., Ignacz, G., Decsi, B., Beni, Z., Turos, G. I., Kupai, J., . . . Balogh, G. T. (2018). Biomimetic Synthesis of Drug Metabolites in Batch and Continuous-Flow Reactors. Chemistry, 24(37), 9385-9392. doi:10.1002/chem.201800892 google scholar
Food Drug Administration (FDA). (2008). Guidance for industry: safety testing of drug metabolites Retrieved from http://www. fda.gov/CDER/GUIDANCE/fnl.pdf google scholar
Foster, A. B., Griggs, L. J., Howe, I., Jarman, M., Leung, C. S., Manson, D., & Rowlands, M. G. (1984). Metabolism of aminoglutethimide in humans. Identification of four new urinary metabolites. Drug Metabolism & Disposition, 12(4), 511-516. google scholar
Foster, B. C., Thomas, B. H., Zamecnik, J., Dawson, B. A., Wilson, D. L., Duhaime, R., . . . Lodge, B. A. (1991). Aromatic Hydroxylation and Sul-fation of Phenazopyridine by Cunninghamella-Echinulata. Canadian Journal of Microbiology, 37(7), 504-508. doi:10.1139/m91-085 google scholar
Foti, R. S., & Dalvie, D. K. (2016). Cytochrome P450 and non-cy-tochrome P450 oxidative metabolism: Contributions to the 266 pharmacokinetics, safety, and efficacy of xenobiotics. Drug Me-tabolism and Disposition, 44(8), 1229-1245. doi.org/10.1124/ dmd.116.071753 google scholar
Fox, H. H., & Gibas, J. T. (1953). Synthetic Tuberculostats. VIII. Acyl Derivatives of Isonicotinyl Hydrazine. The Journal of Organic Chemistry, 18(10), 1375-1379. doi:10.1021/jo50016a018 google scholar
Frere, J. M., & Verly, W. G. (1971). O-methylation of noradrenaline and demethylation in rat blood. Biochimica et Biophysica Acta (BBA) - Enzymology, 235(1), 85-88. doi:10.1016/0005-2744(71)90035-0 google scholar
Fura, A., Shu, Y. Z., Zhu, M., Hanson, R. L., Roongta, V., & Hum-phreys, W. G. (2004). Discovering Drugs through Biological Trans-formation: Role of Pharmacologically Active Metabolites in Drug Discovery. Journal of Medicinal Chemistry, 47(18), 4339-4351. doi:10.1021/jm040066v google scholar
Gao, C., & Zheng, T. (2019). Drug metabolite synthesis by immobi-lized human FMO3 and whole cell catalysts. Microbial Cell Facto-ries, 18(1), 133. doi:10.1186/s12934-019-1189-7 google scholar
Geier, M., Bachler, T., Hanlon, S. P., Eggimann, F. K., Kittelmann, M., Weber, H., . . . Winkler, M. (2015). Human FMO2-based microbial whole-cell catalysts for drug metabolite synthesis. Microbial Cell Factories, 14(1), 82. doi:10.1186/s12934-015-0262-0 google scholar
Genovino, J., Sames, D., Hamann, L. G., & Toure, B. B. (2016). Ac-cessing Drug Metabolites via Transition-Metal Catalyzed C-H Oxidation: The Liver as Synthetic Inspiration. Angewandte Che-mie International Edition, 55(46), 14218-14238. doi:10.1002/ anie.201602644 google scholar
Gill, R., Law, B., & Gibbs, J. P. (1986). High-performance liquid chro-matography systems for the separation of benzodiazepines and their metabolites. Journal of Chromatography A, 356(1), 37-46. doi:10.1016/s0021-9673(00)91465-1 google scholar
Gomez de Santos, P., Cervantes, F. V., Tieves, F., Plou, F. J., Hollmann, F., & Alcalde, M. (2019). Benchmarking of laboratory evolved un-specific peroxygenases for the synthesis of human drug metabo-lites. Tetrahedron, 75(13), 1827-1831. doi:10.1016/j.tet.2019.02.013 google scholar
Gu, G., Black, M., Cookson, C., Fiorella, A., Li, Y., Gorman, S. H., & Bakhtiar, R. (2018). Validation of an LC-MS/MS method for simul-taneous quantification of venlafaxine and its five metabolites in rat plasma and its application in a pharmacokinetic study. Journal of Chromatography B, 1087-1088, 29-35. doi:10.1016/j. jchromb.2018.04.033 google scholar
Hanlon, S. P., Camattari, A., Abad, S., Glieder, A., Kittelmann, M., Lutz, S., . . . Winkler, M. (2012). Expression of recombinant human flavin monooxygenase and moclobemide-N-oxide synthesis on multi-mg scale. Chemical communications, 48(48), 6001-6003. doi:10.1039/c2cc17878h google scholar
Helfer, A. G., Michely, J. A., Weber, A. A., Meyer, M. R., & Maurer, H. H. (2015). Orbitrap technology for comprehensive metabolite-based liquid chromatographic-high resolution-tandem mass spectrometric urine drug screening - exemplified for cardiovas-cular drugs. Analytica Chimica Acta, 891, 221-233. doi:10.1016/j. aca.2015.08.018 google scholar
Hoshino, J., Park, E. J., Kondratyuk, T. P., Marler, L., Pezzuto, J. M., van Breemen, R. B., . . . Cushman, M. (2010). Selective synthesis and bi-ological evaluation of sulfate-conjugated resveratrol metabolites. Journal of Medicinal Chemistry, 53(13), 5033-5043. doi:10.1021/ jm100274c google scholar
Huber, C., Bartha, B., Harpaintner, R., & Schroder, P. (2009). Me-tabolism of acetaminophen (paracetamol) in plants--two inde-pendent pathways result in the formation of a glutathione and a glucose conjugate. Environmental Science and Pollution Research International, 16(2), 206-213. doi:10.1007/s11356-008-0095-z google scholar
Hutt, A. J., & Caldwell, J. (1990). Amino acid conjugation. In G. J. Mulder (Ed.), Conjugation Reactions In Drug Metabolism: An Inte-grated Approach (pp. 273-305). London: CRC Press. google scholar
Ishigai, M., Langridge, J. I., & Bordoli, R. S. (2001). A new approach for dynamics of enzyme-catalyzed glutathione conjugation by electrospray quadrupole/time-of-flight mass spectrometry. Ana-lytical Biochemistry, 298(1), 83-92. doi:10.1006/abio.2001.5339 google scholar
Ishihara, K., Hamada, H., Hirata, T., & Nakajima, N. (2003). Biotrans-formation using plant cultured cells. Journal of Molecular Catalysis B-Enzymatic, 23(2-6), 145-170. doi:10.1016/S1381-1177(03)00080-8 google scholar
Jaworski, T. J., Sardessai, M. S., Aravagiri, M., Lin, G., Shi, Y. Y., Hawes, E. M., . . . Midha, K. K. (1993). Synthesis of the N-oxides of pheno-thiazine antipsychotic agents. Journal of Pharmaceutical Sciences, 82(3), 330-333. doi:10.1002/jps.2600820323 google scholar
Kaspersen, F. M., & Van Boeckel, C. A. (1987). A review of the meth-ods of chemical synthesis of sulphate and glucuronide conjugates. Xenobiotica, 17(12), 1451-1471. doi:10.3109/00498258709044005 google scholar
Ketterer, B., & Mulder, G. J. (1990). Glutathione conjugation. In G. J. Mulder (Ed.), Conjugation Reactions In Drug Metabolism: An Inte-grated Approach (pp. 307-364). London: CRC Press. google scholar
King, A. M., Mullin, L. G., Wilson, I. D., Coen, M., Rainville, P. D., Plumb, R. S., . . . Trengove, R. (2019). Development of a rapid profil-ing method for the analysis of polar analytes in urine using HILIC-MS and ion mobility enabled HILIC-MS. Metabolomics, 15(2), 17. doi:10.1007/s11306-019-1474-9 google scholar
Klencsar, B., Sanchez, C., Balcaen, L., Todoli, J., Lynen, F., & Van-haecke, F. (2018). Comparative evaluation of ICP sample in-troduction systems to be used in the metabolite profiling of chlorine-containing pharmaceuticals via HPLC-ICP-MS. Jour-nal of Pharmaceutical and Biomedical Analysis, 153, 135-144. doi:10.1016/j.jpba.2018.02.031 google scholar
Kostiainen, R., Kotiaho, T., Kuuranne, T., & Auriola, S. (2003). Liquid chromatography/atmospheric pressure ionization-mass spec-trometry in drug metabolism studies. Journal of Mass Spectrom-etry, 38(4), 357-372. doi:10.1002/jms.481 google scholar
Krebsfaenger, N. (2007). Species Comparison of Metabolism in Microsomes and Hepatocytes. In Preclinical Development Hand-book (pp. 919-935). google scholar
Kucukguzel, S. G., Kucukguzel, I., Oral, B., Sezen, S., & Rollas, S. (2005). Detection of nimesulide metabolites in rat plasma and hepatic subcellular fractions by HPLC-UV/DAD and LC-MS/MS studies. European Journal of Drug Metabolism and Pharmacokinet-ics, 30(1-2), 127-134. doi:10.1007/BF03226418 google scholar
Kuo, F., Gillespie, T. A., Kulanthaivel, P., Lantz, R. J., Ma, T. W., Nelson, D. L., . . . Zmijewski, M. (2004). Synthesis and biological activity of some known and putative duloxetine metabolites. Bioorganic & Medicinal Chemistry Letters, 14(13), 3481-3486. doi:10.1016/j. bmcl.2004.04.066 google scholar
Li, S., Klencsar, B., Balcaen, L., Cuyckens, F., Lynen, F., & Vanhaecke, F. (2018). A pre-column derivatization method allowing quantita-tive metabolite profiling of carboxyl and phenolic hydroxyl group containing pharmaceuticals in human plasma via liquid chroma-tography-inductively coupled plasma-tandem mass spectrom-etry (LC-ICP-MS/MS). Journal of Analytical Atomic Spectrometry, 33(2), 274-282. doi:10.1039/c7ja00385d google scholar
Lombardino, J. G. (1981). Synthesis and antiinflammatory activity of metabolites of piroxicam. Journal of Medicinal Chemistry, 24(1), 39-42. doi:10.1021/jm00133a009 google scholar
Low, L. K., & Castagnoli, J. R. N. (1991). Metabolic changes of drug and related organic compounds. In C. O. Wilson, O. Gisvold, J. H. Block, & J. M. Beale (Eds.), Wilson and Gisvold’s Textbook of Organic Medicinal and Pharmaceutical Chemistry. Philadelphia: Lippincott Williams & Wilkins. google scholar
Lu, J., Shang, X., Zhong, W., Xu, Y., Shi, R., & Wang, X. (2020). New insights of CYP1A in endogenous metabolism: a focus on single nucleotide polymorphisms and diseases. Acta Pharmaceutica Si-nica B, 10(1), 91-104. doi:10.1016/j.apsb.2019.11.016 google scholar
Luo, H., Hawes, E. M., McKay, G., & Midha, K. K. (1992). Synthesis and characterization of quaternary ammonium-linked gluc-uronide metabolites of drugs with an aliphatic tertiary amine group. Journal of Pharmaceutical Sciences, 81(11), 1079-1083. doi:10.1002/jps.2600811107 google scholar
Mackichan, J. J. (1980). Simultaneous Liquid-Chromatographic Analysis for Carbamazepine and Carbamazepine 10,11-Epoxide in Plasma and Saliva by Use of Double Internal Standardization. Journal of Chromatography B, 181(3-4), 373-383. doi:Doi 10.1016/ S0378-4347(00)81140-8 google scholar
Michely, J. A., & Maurer, H. H. (2018). A multi-analyte approach to help in assessing the severity of acute poisonings - Development and validation of a fast LC-MS/MS quantification approach for 45 drugs and their relevant metabolites with one-point calibration. Drug Testing and Analysis, 10(1), 164-176. doi:10.1002/dta.2257 google scholar
Moody, J. D., Freeman, J. P., Fu, P. P., & Cerniglia, C. E. (2002). Bio-transformation of mirtazapine by Cunninghamella elegans. Drug Metabolism & Disposition, 30(11), 1274-1279. doi:10.1124/ dmd.30.11.1274 google scholar
Mulder, G. J. C., Micheal W. H. , & Burchell, B. (1990). Glucuronida-tion, Conjugation Reactions. In G. J. Mulder (Ed.), Conjugation Re-actions In Drug Metabolism: An Integrated Approach (pp. 51-105). London: Taylor Francis. google scholar
Nelson, S. D., Garland, W. A., Breck, G. D., & Trager, W. F. (1977). Quantification of lidocaine and several metabolites utilizing chemical-ionization mass spectrometry and stable isotope labeling. Journal of Pharmaceutical Sciences, 66(8), 1180-1190. doi:10.1002/jps.2600660834 google scholar
Nobilis, M., Vybiralova, Z., Sladkova, K., Lisa, M., Holcapek, M., & Kvetina, J. (2006). High-performance liquid-chromatographic determination of 5-aminosalicylic acid and its metabolites in blood plasma. Journal of Chromatography A, 1119(1-2), 299-308. doi:10.1016/j.chroma.2006.01.058 google scholar
Obach, R. S. (2013). Pharmacologically active drug metabolites: impact on drug discovery and pharmacotherapy. Pharmacologi-cal Reviews, 65(2), 578-640. doi:10.1124/pr.111.005439 google scholar
Otey, C. R., Bandara, G., Lalonde, J., Takahashi, K., & Arnold, F. H. (2006). Preparation of human metabolites of propranolol using laboratory-evolved bacterial cytochromes P450. Biotechnology & Bioengineering, 93(3), 494-499. doi:10.1002/bit.20744 google scholar
Patrick, K. S., Kilts, C. D., & Breese, G. R. (1981). Synthesis and phar-macology of hydroxylated metabolites of methylphenidate. Journal of Medicinal Chemistry, 24(10), 1237-1240. doi:10.1021/ jm00142a021 google scholar
Petsalo, A., Turpeinen, M., Pelkonen, O., & Tolonen, A. (2008). Analysis of nine drugs and their cytochrome P450-specific probe metabolites from urine by liquid chromatography-tandem mass spectrometry utilizing sub 2 microm particle size column. Jour-nal of Chromatography A, 1215(1-2), 107-115. doi:10.1016/j.chro-ma.2008.10.122 google scholar
Pohland, A., Boaz, H. E., & Sullivan, H. R. (1971). Synthesis and iden-tification of metabolites resulting from the biotransformation of DL-methadone in man and in the rat. Journal of Medicinal Chem-istry, 14(3), 194-197. doi:10.1021/jm00285a004 google scholar
Protti, M., Marasca, C., Cirrincione, M., Cavalli, A., Mandrioli, R., & Mercolini, L. (2020). Assessment of capillary volumetric blood mi-crosampling for the analysis of central nervous system drugs and metabolites. Analyst, 145(17), 5744-5753. doi:10.1039/d0an01039a google scholar
Pryde, J., & Williams, R. T. (1933). The biochemistry and physiol-ogy of glucuronic acid: The structure of glucuronic acid of animal origin. The Biochemical Journal, 27(4), 1197-1204. doi:10.1042/ bj0271197 google scholar
Rasheed, A., Kumar, C. K. A., Shama, S. N., & Mishra, A. (2011). Syn-thesis and Pharmacological Evaluation of Tyrosine and Glycine Prodrugs of Aceclofenac. Jordan Journal of Pharmaceutical Sci-ences, 4(3), 198-208. google scholar
Reddy, G. M., Mukkanti, K., Bhaskar, B. V., & Reddy, P. P. (2008). Syn-thesis of Metabolites and Related Substances of Rabeprazole, an Anti-Ulcerative Drug. Synthetic Communications, 39(2), 278-290. doi:10.1080/00397910802372541 google scholar
Reddy, G. M.,Mukkanti,K.,Kumar,T.L., Babu,J.M.,&Reddy,P.P.(2008). Synthesis and Characterization of Metabolites and Potential Im-purities of Lansoprazole, an Antiulcerative Drug. Synthetic Com-munications, 38(20), 3477-3489. doi:10.1080/00397910802162934 google scholar
Ren, J. L., Zhang, A. H., Kong, L., & Wang, X. J. (2018). Advances in mass spectrometry-based metabolomics for investigation of metabolites. RSC Advances, 8(40), 22335-22350. doi:10.1039/ c8ra01574k google scholar
• Rice, K. C. (1977). A rapid, high-yield conversion of codeine to morphine. Journal of Medicinal Chemistry, 20(1), 164-165. doi:10.1021/jm00211a036 google scholar
• Rinnofner, C., Kerschbaumer, B., Weber, H., Glieder, A., & Winkler, M. (2019). Cytochrome P450 mediated hydroxylation of ibupro-fen using Pichia pastoris as biocatalyst. Biocatalysis and Agricul-tural Biotechnology, 17, 525-528. doi:10.1016/j.bcab.2018.12.022 google scholar
Rollas, S. (2007). In Vivo Metabolism in Preclinical Drug Develop-ment. In S. C. Gad (Ed.), Preclinical Development Handbook (pp. 829-851): John Wiley & Sons, Inc. google scholar
Rollas, S. (2010). Reduction of aromatic and heteroaromatic azo compounds with hydrazine hydrate. Marmara Pharmaceutcal Journal, 1(14), 41-46. doi:10.12991/201014458 google scholar
Sang, S., Lambert, J. D., Ho, C. T., & Yang, C. S. (2011). The chem-istry and biotransformation of tea constituents. Pharmacological Research, 64(2), 87-99. doi:10.1016/j.phrs.2011.02.007 google scholar
Sawayama, A. M., Chen, M. M., Kulanthaivel, P., Kuo, M. S., Hemmer-le, H., & Arnold, F. H. (2009). A panel of cytochrome P450 BM3 vari-ants to produce drug metabolites and diversify lead compounds. Chemistry, 15(43), 11723-11729. doi:10.1002/chem.200900643 google scholar
Schaber, G., Wiatr, G., Wachsmuth, H., Dachtler, M., Albert, K., Gaertner, I., & Breyer-Pfaff, U. (2001). Isolation and identification of clozapine metabolites in patient urine. Drug Metabolism & Dispo-sition, 29(6), 923-931. google scholar
Schroer, K., Kittelmann, M., & Lutz, S. (2010). Recombinant human cytochrome P450 monooxygenases for drug metabolite synthe-sis. Biotechnology & Bioengineering, 106(5), 699-706. doi:10.1002/ bit.22775 google scholar
Sidelmann, U. G., Christiansen, E., Krogh, L., Cornett, C., Tjornelund, J., & Hansen, S. H. (1997). Purification and 1H NMR spectroscopic characterization of phase II metabolites of tolfenamic acid. Drug Metabolism & Disposition, 25(6), 725-731. google scholar
Sinha, S. K., Praveen, B., Shrivastava, P. K., & Shrivastava, S. K. (2012). Synthesis, characterization and biological evaluation of some glutathione inducing amino acid conjugates ofvalproic acid with reduced hepatotoxicity. Asian Pacific Journal of Tropical Disease, 2, 218-222. doi:10.1016/s2222-1808(12)60155-8 google scholar
Smith, D. A., & Obach, R. S. (2005). Seeing through the mist: abundance versus percentage. Commentary on metabolites in safety testing. Drug Metabolism & Disposition, 33(10), 1409-1417. doi:10.1124/dmd.105.005041 google scholar
Stachulski, A. V., & Meng, X. (2013). Glucuronides from metabo-lites to medicines: a survey of the in vivo generation, chemical synthesis and properties of glucuronides. Natural Product Reports, 30(6), 806-848. doi:10.1039/c3np70003h google scholar
Stalder, R., & Roth, G. P. (2013). Preparative microfluidic electrosyn-thesis of drug metabolites. ACS Medicinal Chemistry Letters, 4(11), 1119-1123. doi:10.1021/ml400316p google scholar
Steinbrecht, S., Kiebist, J., König, R., Thiessen, M., Schmidtke, K.-U., Kammerer, S., . . . Scheibner, K. (2020). Synthesis of cyclophospha-268 _________________________________mide metabolites by a peroxygenase from Marasmius rotula for toxicological studies on human cancer cells. AMB Express, 10(1), 128. doi:10.1186/s13568-020-01064-w. (Accession No. 32683510) google scholar
Strachan, R. G., Meisinger, M. A. P., Ruyle, W. V., Hirschmann, R., & Shen, T. Y. (1964). Synthesis of Indomethacin Metabolites. Journal of Medicinal Chemistry, 7(6), 799-800. doi:10.1021/jm00336a026 google scholar
Sun, H., Moore, C., Dansette, P. M., Kumar, S., Halpert, J. R., & Yost, G. S. (2009). Dehydrogenation of the Indoline-Containing Drug 4-Chloro-N-(2-methyl-1-indolinyl)-3-sulfamoylbenzamide (In-dapamide) by CYP3A4: Correlation with in Silico Predictions. Drug Metabolism and Disposition, 37(3), 672-684. doi:10.1124/ dmd.108.022707 google scholar
Sun, L., Huang, H.-H., Liu, L., & Zhong, D.-F. (2004). Transforma-tion of Verapamil by Cunninghamella blakesleeana. Applied and Environmental Microbiology, 70(5), 2722-2727. doi:10.1128/ AEM.70.5.2722-2727.2004 google scholar
Sundell, J., Bienvenu, E., Birgersson, S., Abelo, A., Ashton, M., & Hoffmann, K. J. (2019). Simultaneous quantification of four first line antitubercular drugs and metabolites in human plasma by hydrophilic interaction chromatography and tandem mass spectrometry. Journal of Chromatography B, 1105, 129-135. doi:10.1016/j.jchromb.2018.10.027 google scholar
Turgeon, J., Pare, J. R., Lalande, M., Grech-Belanger, O., & Belanger, P. M. (1992). Isolation and structural characterization by spectro-scopic methods of two glucuronide metabolites of mexiletine after N-oxidation and deamination. Drug Metab Dispos, 20(5), 762-769. google scholar
Uldam, H. K., Juhl, M., Pedersen, H., & Dalgaard, L. (2011). Biosyn-thesis and identification of an N-oxide/N-glucuronide metabo-lite and first synthesis of an N-O-glucuronide metabolite of Lu AA21004. Drug Metabolism & Disposition, 39(12), 2264-2274. doi:10.1124/dmd.111.040428 google scholar
Vail, R. B., Homann, M. J., Hanna, I., & Zaks, A. (2005). Preparative synthesis of drug metabolites using human cytochrome P450s 3A4, 2C9 and 1A2 with NADPH-P450 reductase expressed in Escherichia coli. Journal of Industrial Microbiology and Biotechnol-ogy, 32(2), 67-74. doi:10.1007/s10295-004-0202-1 google scholar
Valero, E., Lozano, M. I., Varon, R., & Garcia-Carmona, F. (2003). Enzymatic synthesis of 3’-hydroxyacetaminophen catalyzed by tyrosinase. Biotechnology Progress, 19(6), 1632-1638. doi:10.1021/ bp034075t google scholar
Wang, Z., Sun, W., Lin, Z. F., Sun, R., Huang, C. K., Ye, W. J., . . . Chen, R. J. (2019). A UHPLC-MS/MS method coupled with liquid-liquid extraction for the quantitation of phenacetin, omeprazole, meto-prolol, midazolam and their metabolites in rat plasma and its ap-plication to the study of four CYP450 activities. Journal of Phar-maceutical and Biomedical Analysis, 163, 204-210. doi:10.1016/j. jpba.2018.10.012 google scholar
Weis, R., Winkler, M., Schittmayer, M., Kambourakis, S., Vink, M., Ro-zzell, J. D., & Glieder, A. (2009). A Diversified Library of Bacterial and Fungal Bifunctional Cytochrome P450 Enzymes for Drug Metabo-lite Synthesis. Advanced Synthesis & Catalysis, 351(13), 2140-2146. doi:10.1002/adsc.200900190 google scholar
Wheals, B. B., & Jane, I. (1977). Analysis of drugs and their metabo-lites by high-performance liquid chromatography. A review. Ana-lyst, 102(1218), 625-644. doi:10.1039/an9770200625 google scholar
Williams, R. T. (1938). Studies in detoxication. II. (a) The conju-gation of isomeric 3-menthanols with glucuronic acid and the asymmetric conjugation of dl-menthol and dl-isomenthol in the rabbit. (b) d-isoMenthylglucuronide, a new conjugated glucuron-ic acid. The Biochemical Journal, 32(10), 1849-1855. doi:10.1042/ bj0321849 google scholar
Williams, R. T. (1943). Studies in detoxication: 13. The biosynthesis of aminophenyl- and sulphonamidoaminophenylglucuronides in the rabbit and their action on haemoglobin in vitro. Biochemi-cal Journal, 37(3), 329-333. google scholar
Winkler, M., Geier, M., Hanlon, S. P., Nidetzky, B., & Glieder, A. (2018). Human Enzymes for Organic Synthesis. Angewandte Che-mie International Edition, 57(41), 13406-13423. doi:https://doi. org/10.1002/anie.201800678 google scholar
Wu, Y, Wang, R, Yang, H., & Sui, F. (2019). UPLC-Q-TOF-MS and UPLC-MS/MS methods for metabolism profiles and pharmacokinetics of major compounds in Xuanmai Ganjie Granules. Biomedical Chroma-tography, 33(3), e4449. doi:https://doi.org/10.1002/bmc.4449 google scholar
Xing, J., Zang, M., Zhang, H., & Zhu, M. (2015). The application of high-resolution mass spectrometry-based data-mining tools in tandem to metabolite profiling of a triple drug combination in humans. Analytica Chimica Acta, 897, 34-44. doi:10.1016/j. aca.2015.09.034 google scholar
Yoshimura, H., Oguri, K., & Tsukamoto, H. (1968). Metabolism of drugs. LX. The synthesis of codeine and morphine glucuronides. Chemical and Pharmaceutical Bulletin, (Tokyo), 16(11), 2114-2119. doi:10.1248/cpb.16.2114 google scholar
Youssif, S. (2001). Recent trends in the chemistry of pyridine N-oxides. J Arkivoc, 1, 242-268. google scholar
Zhang, D., Freeman, J. R., Sutherland, J. B., Walker, A. E., Yang, Y., & Cerniglia, C. E. (1996). Biotransformation of chlorpromazine and methdilazine by Cunninghamella elegans. Applied and Environ-mental Microbiology, 62(3), 798-803. doi:10.1128/AEM.62.3.798-803.1996 google scholar
Schroer, K., Kittelmann, M., & Lutz, S. (2010). Recombinant human cytochrome R450 monooxygenases for drug metabolite synthe-sis. Biotechnology & Bioengineering, 106(5), 699-706. google scholar

Year 2023, Volume: 53 Issue: 2, 251 - 269, 30.08.2023

Zafer Şahin , Pınar Sinem Omurtag Özgen Sevim Rollas

https://doi.org/10.26650/IstanbulJPharm.2023.1033045

Abstract

References

Adamczyk, M., & Fino, J. R. (1996). Synthesis of procainamide me-tabolites, N-acetyl desethylprocainamide, and desethylprocain-amide. Organic Preparations and Procedures International, 28(4), 470-474. doi:Doi 10.1080/00304949609356555 google scholar
Althuis, T. H., & Hess, H. J. (1977). Synthesis and identification of the major metabolites of prazosin formed in dog and rat. Journal of Medicinal Chemistry, 20(1), 146-149. doi:10.1021/jm00211a031 google scholar
Arewang, C. J., Lahmann, M., Oscarson, S., & Tiden, A. K. (2007). Synthesis of urine drug metabolites: glucuronic acid glycosides of phenol intermediates. Carbohydrate Research, 342(7), 970-974. doi:10.1016/j.carres.2007.01.014 google scholar
Argikar, U. A. (2012). Unusual glucuronides. Drug Metabolism & Disposition, 40(7), 1239-1251. doi:10.1124/dmd.112.045096 google scholar
Asha, S., & Vidyavathi, M. (2009). Cunninghamella--a microbial model for drug metabolism studies--a review. Biotechnology Ad-vances, 27(1), 16-29. doi:10.1016/j.biotechadv.2008.07.005 google scholar
Bailey, M. J., & Dickinson, R. G. (2003). Acyl glucuronide reactiv-ity in perspective: biological consequences. Chemico-Biological Interactions, 145(2), 117-137. doi:10.1016/s0009-2797(03)00020-6 google scholar
Baillie, T. A., Cayen, M. N., Fouda, H., Gerson, R. J., Green, J. D., Grossman, S. J., . . . Shipley, L. A. (2002). Drug metabolites in safety testing. Toxicology and Applied Pharmacology, 182(3), 188-196. doi:10.1006/taap.2002.9440 google scholar
Baldwin, B. C., Robinson, D., & Williams, R. T. (1960). Studies in detoxi-cation. 82. The fate of benzoic acid in some domestic and other birds. The Biochemical Journal, 76(3), 595-600. doi:10.1042/bj0760595 google scholar
Boerner, U. (1975). The metabolism of morphine and heroin in man. Drug Metabolism Reviews, 4(1), 39-73. doi:10.3109/03602537508993748 google scholar
Bradshaw, P. R., Athersuch, T. J., Stachulski, A. V., & Wilson, I. D. (2020). Acyl glucuronide reactivity in perspective. Drug Discovery Today, 25(9), 1639-1650. doi:10.1016/j.drudis.2020.07.009 google scholar
Brown, D. D., Axelrod, J., & Tomchick, R. (1959). Enzymatic N-Methylation of Histamine. Nature, 183(4662), 680-680. doi:10.1038/183680a0 google scholar
Cai, X., Sha, M., Guo, C., & Pan, R. M. (2012). Synthesis of Tertiary Amine N-oxides—A Review. Asian Journal of Chemistry, 24(9), 3781-3784. google scholar
Caswell, J. M., O’Neill, M., Taylor, S. J., & Moody, T. S. (2013). Engi-neering and application of P450 monooxygenases in pharma-ceutical and metabolite synthesis. Current Opinion in Chemical Biology, 17(2), 271-275. doi:10.1016/j.cbpa.2013.01.028 google scholar
Cece-Esensencan, E. N., Fontaine, F., Plasencia, G., Teppner, M., Brink, A., Pahler, A., & Zamora, I. (2016). Enhancing throughput of glutation ad-duct formation studies and structural identification using software as-sisted-workflow based on high-resolution mass spectrometry (HRMS) data. SM Analytical and Bioanalytical Techniques, 1(1002), 1-12. google scholar
Chung, K. T., Fulk, G. E., & Egan, M. (1978). Reduction of azo dyes by intestinal anaerobes. Applied and Environmental Microbiology, 35(3), 558-562. doi:10.1128/AEM.35.3.558-562.1978 google scholar
Constanzer, M. L., Chavez-Eng, C. M., Fu, I., Woolf, E. J., & Matusze-wski, B. K. (2005). Determination of dextromethorphan and its metabolite dextrorphan in human urine using high performance liquid chromatography with atmospheric pressure chemical ionization tandem mass spectrometry: a study of selectivity of a tandem mass spectrometric assay. Journal of Chromatography B, 816(1-2), 297-308. doi:10.1016/j.jchromb.2004.11.049 google scholar
Cornelissen, S., Julsing, M. K., Schmid, A., & Buhler, B. (2012). Com-parison of microbial hosts and expression systems for mamma-lian CYP1A1 catalysis. Journal of Industrial Microbiology & Biotech-nology, 39(2), 275-287. doi:10.1007/s10295-011-1026-4 google scholar
Correia, M. S. P., Rao, M., Ballet, C., & Globisch, D. (2019). Coupled Enzymatic Treatment and Mass Spectrometric Analysis for Iden-tification of Glucuronidated Metabolites in Human Samples. google scholar
Chembiochem, 20(13), 1678-1683. doi:10.1002/cbic.201900065 Çoruh, I. (2012). Synthesis and evaluation of cytotoxic activities of some 1,4-disubstituted thiosemicarbazides, 2,5-disubstituted-1,3,4-thiadiazoles and 1,2,4-triazole-5-thiones derived from ben-zilic acid hydrazide. Marmara Pharmaceutcal Journal, 1(16), 56-63. doi:10.12991/201216421 google scholar
Cusack, K. P., Koolman, H. F., Lange, U. E., Peltier, H. M., Piel, I., & Va-sudevan, A. (2013). Emerging technologies for metabolite gener-ation and structural diversification. Bioorganic & Medicinal Chem-istry Letters, 23(20), 5471-5483. doi:10.1016/j.bmcl.2013.08.003 google scholar
Dahlin, D. C., & Nelson, S. D. (1982). Synthesis, decomposition ki-netics, and preliminary toxicological studies of pure N-acetyl-p-benzoquinone imine, a proposed toxic metabolite of acetamino-phen. Journal of Medicinal Chemistry, 25(8), 885-886. doi:10.1021/ jm00350a001 google scholar
de Paula, N. C., Araujo Cordeiro, K. C., de Melo Souza, P. L., Noguei-ra, D. F., da Silva e Sousa, D. B., Costa, M. B., . . . de Oliveira, V. (2015). Biosynthesis of human diazepam and clonazepam metabo-lites. Bioorganic & Medicinal Chemistry Letters, 25(5), 1026-1029. doi:10.1016/j.bmcl.2015.01.025 google scholar
Di Nardo, G., & Gilardi, G. (2012). Optimization of the bacterial cy-tochrome P450 BM3 system for the production of human drug metabolites. International Journal of Molecular Sciences, 13(12), 15901-15924. doi:10.3390/ijms131215901 google scholar
Doddaga, S., & Peddakonda, R. (2013). Chloroquine-N-oxide, a ma-jor oxidative degradation product of chloroquine: identification, synthesis and characterization. Journal of Pharmaceutical and Bio-medical Analysis, 81-82, 118-125. doi:10.1016/j.jpba.2013.04.004 google scholar
Dutkiewicz, G., Chidan Kumar, C. S., Yathirajan, H. S., Mayekar, A. N., & Kubicki, M. (2009). 3-Methyl-1,2,4-triazolo[3,4-a]phthalazine monohydrate. Acta crystallographica. Section E, Structure reports online, 65(11), o2694. doi:10.1107/S1600536809040677 google scholar
Fang, T., Wang, Y., Ma, Y., Su, W., Bai, Y., & Zhao, P. (2006). A rapid LC/ MS/MS quantitation assay for naringin and its two metabolites in rats plasma. Journal of Pharmaceutical and Biomedical Analysis, 40(2), 454-459. doi:10.1016/j.jpba.2005.07.031 google scholar
Feely, J., Kavanagh, P. V., McNamara, S. M., & O’Brien, J. E. (1999). Simple preparation of the major urinary metabolites of flunitraz-epam and nitrazepam. Irish Journal of Medical Science, 168(1), 8-9. doi:10.1007/BF02939571 google scholar
Fessner, N. D., Srdic, M., Weber, H., Schmid, C., Schonauer, D., Schwaneberg, U., & Glieder, A. (2020). Preparative-Scale Produc-tion of Testosterone Metabolites by Human Liver Cytochrome P450 Enzyme 3A4. Advanced Synthesis & Catalysis, 362(13), 27252738. doi:10.1002/adsc.202000251 google scholar
Flores, J. R., Nevado, J. J. B., Salcedo, A. M. C., & Diaz, M. P. C. (2004). Non-aqueous capillary zone electrophoresis method for the analysis of paroxetine, tamoxifen, and their main metabolites in urine. Analytica Chimica Acta, 512(2), 287-295. doi:10.1016/j. aca.2004.02.048 google scholar
Fodi, T., Ignacz, G., Decsi, B., Beni, Z., Turos, G. I., Kupai, J., . . . Balogh, G. T. (2018). Biomimetic Synthesis of Drug Metabolites in Batch and Continuous-Flow Reactors. Chemistry, 24(37), 9385-9392. doi:10.1002/chem.201800892 google scholar
Food Drug Administration (FDA). (2008). Guidance for industry: safety testing of drug metabolites Retrieved from http://www. fda.gov/CDER/GUIDANCE/fnl.pdf google scholar
Foster, A. B., Griggs, L. J., Howe, I., Jarman, M., Leung, C. S., Manson, D., & Rowlands, M. G. (1984). Metabolism of aminoglutethimide in humans. Identification of four new urinary metabolites. Drug Metabolism & Disposition, 12(4), 511-516. google scholar
Foster, B. C., Thomas, B. H., Zamecnik, J., Dawson, B. A., Wilson, D. L., Duhaime, R., . . . Lodge, B. A. (1991). Aromatic Hydroxylation and Sul-fation of Phenazopyridine by Cunninghamella-Echinulata. Canadian Journal of Microbiology, 37(7), 504-508. doi:10.1139/m91-085 google scholar
Foti, R. S., & Dalvie, D. K. (2016). Cytochrome P450 and non-cy-tochrome P450 oxidative metabolism: Contributions to the 266 pharmacokinetics, safety, and efficacy of xenobiotics. Drug Me-tabolism and Disposition, 44(8), 1229-1245. doi.org/10.1124/ dmd.116.071753 google scholar
Fox, H. H., & Gibas, J. T. (1953). Synthetic Tuberculostats. VIII. Acyl Derivatives of Isonicotinyl Hydrazine. The Journal of Organic Chemistry, 18(10), 1375-1379. doi:10.1021/jo50016a018 google scholar
Frere, J. M., & Verly, W. G. (1971). O-methylation of noradrenaline and demethylation in rat blood. Biochimica et Biophysica Acta (BBA) - Enzymology, 235(1), 85-88. doi:10.1016/0005-2744(71)90035-0 google scholar
Fura, A., Shu, Y. Z., Zhu, M., Hanson, R. L., Roongta, V., & Hum-phreys, W. G. (2004). Discovering Drugs through Biological Trans-formation: Role of Pharmacologically Active Metabolites in Drug Discovery. Journal of Medicinal Chemistry, 47(18), 4339-4351. doi:10.1021/jm040066v google scholar
Gao, C., & Zheng, T. (2019). Drug metabolite synthesis by immobi-lized human FMO3 and whole cell catalysts. Microbial Cell Facto-ries, 18(1), 133. doi:10.1186/s12934-019-1189-7 google scholar
Geier, M., Bachler, T., Hanlon, S. P., Eggimann, F. K., Kittelmann, M., Weber, H., . . . Winkler, M. (2015). Human FMO2-based microbial whole-cell catalysts for drug metabolite synthesis. Microbial Cell Factories, 14(1), 82. doi:10.1186/s12934-015-0262-0 google scholar
Genovino, J., Sames, D., Hamann, L. G., & Toure, B. B. (2016). Ac-cessing Drug Metabolites via Transition-Metal Catalyzed C-H Oxidation: The Liver as Synthetic Inspiration. Angewandte Che-mie International Edition, 55(46), 14218-14238. doi:10.1002/ anie.201602644 google scholar
Gill, R., Law, B., & Gibbs, J. P. (1986). High-performance liquid chro-matography systems for the separation of benzodiazepines and their metabolites. Journal of Chromatography A, 356(1), 37-46. doi:10.1016/s0021-9673(00)91465-1 google scholar
Gomez de Santos, P., Cervantes, F. V., Tieves, F., Plou, F. J., Hollmann, F., & Alcalde, M. (2019). Benchmarking of laboratory evolved un-specific peroxygenases for the synthesis of human drug metabo-lites. Tetrahedron, 75(13), 1827-1831. doi:10.1016/j.tet.2019.02.013 google scholar
Gu, G., Black, M., Cookson, C., Fiorella, A., Li, Y., Gorman, S. H., & Bakhtiar, R. (2018). Validation of an LC-MS/MS method for simul-taneous quantification of venlafaxine and its five metabolites in rat plasma and its application in a pharmacokinetic study. Journal of Chromatography B, 1087-1088, 29-35. doi:10.1016/j. jchromb.2018.04.033 google scholar
Hanlon, S. P., Camattari, A., Abad, S., Glieder, A., Kittelmann, M., Lutz, S., . . . Winkler, M. (2012). Expression of recombinant human flavin monooxygenase and moclobemide-N-oxide synthesis on multi-mg scale. Chemical communications, 48(48), 6001-6003. doi:10.1039/c2cc17878h google scholar
Helfer, A. G., Michely, J. A., Weber, A. A., Meyer, M. R., & Maurer, H. H. (2015). Orbitrap technology for comprehensive metabolite-based liquid chromatographic-high resolution-tandem mass spectrometric urine drug screening - exemplified for cardiovas-cular drugs. Analytica Chimica Acta, 891, 221-233. doi:10.1016/j. aca.2015.08.018 google scholar
Hoshino, J., Park, E. J., Kondratyuk, T. P., Marler, L., Pezzuto, J. M., van Breemen, R. B., . . . Cushman, M. (2010). Selective synthesis and bi-ological evaluation of sulfate-conjugated resveratrol metabolites. Journal of Medicinal Chemistry, 53(13), 5033-5043. doi:10.1021/ jm100274c google scholar
Huber, C., Bartha, B., Harpaintner, R., & Schroder, P. (2009). Me-tabolism of acetaminophen (paracetamol) in plants--two inde-pendent pathways result in the formation of a glutathione and a glucose conjugate. Environmental Science and Pollution Research International, 16(2), 206-213. doi:10.1007/s11356-008-0095-z google scholar
Hutt, A. J., & Caldwell, J. (1990). Amino acid conjugation. In G. J. Mulder (Ed.), Conjugation Reactions In Drug Metabolism: An Inte-grated Approach (pp. 273-305). London: CRC Press. google scholar
Ishigai, M., Langridge, J. I., & Bordoli, R. S. (2001). A new approach for dynamics of enzyme-catalyzed glutathione conjugation by electrospray quadrupole/time-of-flight mass spectrometry. Ana-lytical Biochemistry, 298(1), 83-92. doi:10.1006/abio.2001.5339 google scholar
Ishihara, K., Hamada, H., Hirata, T., & Nakajima, N. (2003). Biotrans-formation using plant cultured cells. Journal of Molecular Catalysis B-Enzymatic, 23(2-6), 145-170. doi:10.1016/S1381-1177(03)00080-8 google scholar
Jaworski, T. J., Sardessai, M. S., Aravagiri, M., Lin, G., Shi, Y. Y., Hawes, E. M., . . . Midha, K. K. (1993). Synthesis of the N-oxides of pheno-thiazine antipsychotic agents. Journal of Pharmaceutical Sciences, 82(3), 330-333. doi:10.1002/jps.2600820323 google scholar
Kaspersen, F. M., & Van Boeckel, C. A. (1987). A review of the meth-ods of chemical synthesis of sulphate and glucuronide conjugates. Xenobiotica, 17(12), 1451-1471. doi:10.3109/00498258709044005 google scholar
Ketterer, B., & Mulder, G. J. (1990). Glutathione conjugation. In G. J. Mulder (Ed.), Conjugation Reactions In Drug Metabolism: An Inte-grated Approach (pp. 307-364). London: CRC Press. google scholar
King, A. M., Mullin, L. G., Wilson, I. D., Coen, M., Rainville, P. D., Plumb, R. S., . . . Trengove, R. (2019). Development of a rapid profil-ing method for the analysis of polar analytes in urine using HILIC-MS and ion mobility enabled HILIC-MS. Metabolomics, 15(2), 17. doi:10.1007/s11306-019-1474-9 google scholar
Klencsar, B., Sanchez, C., Balcaen, L., Todoli, J., Lynen, F., & Van-haecke, F. (2018). Comparative evaluation of ICP sample in-troduction systems to be used in the metabolite profiling of chlorine-containing pharmaceuticals via HPLC-ICP-MS. Jour-nal of Pharmaceutical and Biomedical Analysis, 153, 135-144. doi:10.1016/j.jpba.2018.02.031 google scholar
Kostiainen, R., Kotiaho, T., Kuuranne, T., & Auriola, S. (2003). Liquid chromatography/atmospheric pressure ionization-mass spec-trometry in drug metabolism studies. Journal of Mass Spectrom-etry, 38(4), 357-372. doi:10.1002/jms.481 google scholar
Krebsfaenger, N. (2007). Species Comparison of Metabolism in Microsomes and Hepatocytes. In Preclinical Development Hand-book (pp. 919-935). google scholar
Kucukguzel, S. G., Kucukguzel, I., Oral, B., Sezen, S., & Rollas, S. (2005). Detection of nimesulide metabolites in rat plasma and hepatic subcellular fractions by HPLC-UV/DAD and LC-MS/MS studies. European Journal of Drug Metabolism and Pharmacokinet-ics, 30(1-2), 127-134. doi:10.1007/BF03226418 google scholar
Kuo, F., Gillespie, T. A., Kulanthaivel, P., Lantz, R. J., Ma, T. W., Nelson, D. L., . . . Zmijewski, M. (2004). Synthesis and biological activity of some known and putative duloxetine metabolites. Bioorganic & Medicinal Chemistry Letters, 14(13), 3481-3486. doi:10.1016/j. bmcl.2004.04.066 google scholar
Li, S., Klencsar, B., Balcaen, L., Cuyckens, F., Lynen, F., & Vanhaecke, F. (2018). A pre-column derivatization method allowing quantita-tive metabolite profiling of carboxyl and phenolic hydroxyl group containing pharmaceuticals in human plasma via liquid chroma-tography-inductively coupled plasma-tandem mass spectrom-etry (LC-ICP-MS/MS). Journal of Analytical Atomic Spectrometry, 33(2), 274-282. doi:10.1039/c7ja00385d google scholar
Lombardino, J. G. (1981). Synthesis and antiinflammatory activity of metabolites of piroxicam. Journal of Medicinal Chemistry, 24(1), 39-42. doi:10.1021/jm00133a009 google scholar
Low, L. K., & Castagnoli, J. R. N. (1991). Metabolic changes of drug and related organic compounds. In C. O. Wilson, O. Gisvold, J. H. Block, & J. M. Beale (Eds.), Wilson and Gisvold’s Textbook of Organic Medicinal and Pharmaceutical Chemistry. Philadelphia: Lippincott Williams & Wilkins. google scholar
Lu, J., Shang, X., Zhong, W., Xu, Y., Shi, R., & Wang, X. (2020). New insights of CYP1A in endogenous metabolism: a focus on single nucleotide polymorphisms and diseases. Acta Pharmaceutica Si-nica B, 10(1), 91-104. doi:10.1016/j.apsb.2019.11.016 google scholar
Luo, H., Hawes, E. M., McKay, G., & Midha, K. K. (1992). Synthesis and characterization of quaternary ammonium-linked gluc-uronide metabolites of drugs with an aliphatic tertiary amine group. Journal of Pharmaceutical Sciences, 81(11), 1079-1083. doi:10.1002/jps.2600811107 google scholar
Mackichan, J. J. (1980). Simultaneous Liquid-Chromatographic Analysis for Carbamazepine and Carbamazepine 10,11-Epoxide in Plasma and Saliva by Use of Double Internal Standardization. Journal of Chromatography B, 181(3-4), 373-383. doi:Doi 10.1016/ S0378-4347(00)81140-8 google scholar
Michely, J. A., & Maurer, H. H. (2018). A multi-analyte approach to help in assessing the severity of acute poisonings - Development and validation of a fast LC-MS/MS quantification approach for 45 drugs and their relevant metabolites with one-point calibration. Drug Testing and Analysis, 10(1), 164-176. doi:10.1002/dta.2257 google scholar
Moody, J. D., Freeman, J. P., Fu, P. P., & Cerniglia, C. E. (2002). Bio-transformation of mirtazapine by Cunninghamella elegans. Drug Metabolism & Disposition, 30(11), 1274-1279. doi:10.1124/ dmd.30.11.1274 google scholar
Mulder, G. J. C., Micheal W. H. , & Burchell, B. (1990). Glucuronida-tion, Conjugation Reactions. In G. J. Mulder (Ed.), Conjugation Re-actions In Drug Metabolism: An Integrated Approach (pp. 51-105). London: Taylor Francis. google scholar
Nelson, S. D., Garland, W. A., Breck, G. D., & Trager, W. F. (1977). Quantification of lidocaine and several metabolites utilizing chemical-ionization mass spectrometry and stable isotope labeling. Journal of Pharmaceutical Sciences, 66(8), 1180-1190. doi:10.1002/jps.2600660834 google scholar
Nobilis, M., Vybiralova, Z., Sladkova, K., Lisa, M., Holcapek, M., & Kvetina, J. (2006). High-performance liquid-chromatographic determination of 5-aminosalicylic acid and its metabolites in blood plasma. Journal of Chromatography A, 1119(1-2), 299-308. doi:10.1016/j.chroma.2006.01.058 google scholar
Obach, R. S. (2013). Pharmacologically active drug metabolites: impact on drug discovery and pharmacotherapy. Pharmacologi-cal Reviews, 65(2), 578-640. doi:10.1124/pr.111.005439 google scholar
Otey, C. R., Bandara, G., Lalonde, J., Takahashi, K., & Arnold, F. H. (2006). Preparation of human metabolites of propranolol using laboratory-evolved bacterial cytochromes P450. Biotechnology & Bioengineering, 93(3), 494-499. doi:10.1002/bit.20744 google scholar
Patrick, K. S., Kilts, C. D., & Breese, G. R. (1981). Synthesis and phar-macology of hydroxylated metabolites of methylphenidate. Journal of Medicinal Chemistry, 24(10), 1237-1240. doi:10.1021/ jm00142a021 google scholar
Petsalo, A., Turpeinen, M., Pelkonen, O., & Tolonen, A. (2008). Analysis of nine drugs and their cytochrome P450-specific probe metabolites from urine by liquid chromatography-tandem mass spectrometry utilizing sub 2 microm particle size column. Jour-nal of Chromatography A, 1215(1-2), 107-115. doi:10.1016/j.chro-ma.2008.10.122 google scholar
Pohland, A., Boaz, H. E., & Sullivan, H. R. (1971). Synthesis and iden-tification of metabolites resulting from the biotransformation of DL-methadone in man and in the rat. Journal of Medicinal Chem-istry, 14(3), 194-197. doi:10.1021/jm00285a004 google scholar
Protti, M., Marasca, C., Cirrincione, M., Cavalli, A., Mandrioli, R., & Mercolini, L. (2020). Assessment of capillary volumetric blood mi-crosampling for the analysis of central nervous system drugs and metabolites. Analyst, 145(17), 5744-5753. doi:10.1039/d0an01039a google scholar
Pryde, J., & Williams, R. T. (1933). The biochemistry and physiol-ogy of glucuronic acid: The structure of glucuronic acid of animal origin. The Biochemical Journal, 27(4), 1197-1204. doi:10.1042/ bj0271197 google scholar
Rasheed, A., Kumar, C. K. A., Shama, S. N., & Mishra, A. (2011). Syn-thesis and Pharmacological Evaluation of Tyrosine and Glycine Prodrugs of Aceclofenac. Jordan Journal of Pharmaceutical Sci-ences, 4(3), 198-208. google scholar
Reddy, G. M., Mukkanti, K., Bhaskar, B. V., & Reddy, P. P. (2008). Syn-thesis of Metabolites and Related Substances of Rabeprazole, an Anti-Ulcerative Drug. Synthetic Communications, 39(2), 278-290. doi:10.1080/00397910802372541 google scholar
Reddy, G. M.,Mukkanti,K.,Kumar,T.L., Babu,J.M.,&Reddy,P.P.(2008). Synthesis and Characterization of Metabolites and Potential Im-purities of Lansoprazole, an Antiulcerative Drug. Synthetic Com-munications, 38(20), 3477-3489. doi:10.1080/00397910802162934 google scholar
Ren, J. L., Zhang, A. H., Kong, L., & Wang, X. J. (2018). Advances in mass spectrometry-based metabolomics for investigation of metabolites. RSC Advances, 8(40), 22335-22350. doi:10.1039/ c8ra01574k google scholar
• Rice, K. C. (1977). A rapid, high-yield conversion of codeine to morphine. Journal of Medicinal Chemistry, 20(1), 164-165. doi:10.1021/jm00211a036 google scholar
• Rinnofner, C., Kerschbaumer, B., Weber, H., Glieder, A., & Winkler, M. (2019). Cytochrome P450 mediated hydroxylation of ibupro-fen using Pichia pastoris as biocatalyst. Biocatalysis and Agricul-tural Biotechnology, 17, 525-528. doi:10.1016/j.bcab.2018.12.022 google scholar
Rollas, S. (2007). In Vivo Metabolism in Preclinical Drug Develop-ment. In S. C. Gad (Ed.), Preclinical Development Handbook (pp. 829-851): John Wiley & Sons, Inc. google scholar
Rollas, S. (2010). Reduction of aromatic and heteroaromatic azo compounds with hydrazine hydrate. Marmara Pharmaceutcal Journal, 1(14), 41-46. doi:10.12991/201014458 google scholar
Sang, S., Lambert, J. D., Ho, C. T., & Yang, C. S. (2011). The chem-istry and biotransformation of tea constituents. Pharmacological Research, 64(2), 87-99. doi:10.1016/j.phrs.2011.02.007 google scholar
Sawayama, A. M., Chen, M. M., Kulanthaivel, P., Kuo, M. S., Hemmer-le, H., & Arnold, F. H. (2009). A panel of cytochrome P450 BM3 vari-ants to produce drug metabolites and diversify lead compounds. Chemistry, 15(43), 11723-11729. doi:10.1002/chem.200900643 google scholar
Schaber, G., Wiatr, G., Wachsmuth, H., Dachtler, M., Albert, K., Gaertner, I., & Breyer-Pfaff, U. (2001). Isolation and identification of clozapine metabolites in patient urine. Drug Metabolism & Dispo-sition, 29(6), 923-931. google scholar
Schroer, K., Kittelmann, M., & Lutz, S. (2010). Recombinant human cytochrome P450 monooxygenases for drug metabolite synthe-sis. Biotechnology & Bioengineering, 106(5), 699-706. doi:10.1002/ bit.22775 google scholar
Sidelmann, U. G., Christiansen, E., Krogh, L., Cornett, C., Tjornelund, J., & Hansen, S. H. (1997). Purification and 1H NMR spectroscopic characterization of phase II metabolites of tolfenamic acid. Drug Metabolism & Disposition, 25(6), 725-731. google scholar
Sinha, S. K., Praveen, B., Shrivastava, P. K., & Shrivastava, S. K. (2012). Synthesis, characterization and biological evaluation of some glutathione inducing amino acid conjugates ofvalproic acid with reduced hepatotoxicity. Asian Pacific Journal of Tropical Disease, 2, 218-222. doi:10.1016/s2222-1808(12)60155-8 google scholar
Smith, D. A., & Obach, R. S. (2005). Seeing through the mist: abundance versus percentage. Commentary on metabolites in safety testing. Drug Metabolism & Disposition, 33(10), 1409-1417. doi:10.1124/dmd.105.005041 google scholar
Stachulski, A. V., & Meng, X. (2013). Glucuronides from metabo-lites to medicines: a survey of the in vivo generation, chemical synthesis and properties of glucuronides. Natural Product Reports, 30(6), 806-848. doi:10.1039/c3np70003h google scholar
Stalder, R., & Roth, G. P. (2013). Preparative microfluidic electrosyn-thesis of drug metabolites. ACS Medicinal Chemistry Letters, 4(11), 1119-1123. doi:10.1021/ml400316p google scholar
Steinbrecht, S., Kiebist, J., König, R., Thiessen, M., Schmidtke, K.-U., Kammerer, S., . . . Scheibner, K. (2020). Synthesis of cyclophospha-268 _________________________________mide metabolites by a peroxygenase from Marasmius rotula for toxicological studies on human cancer cells. AMB Express, 10(1), 128. doi:10.1186/s13568-020-01064-w. (Accession No. 32683510) google scholar
Strachan, R. G., Meisinger, M. A. P., Ruyle, W. V., Hirschmann, R., & Shen, T. Y. (1964). Synthesis of Indomethacin Metabolites. Journal of Medicinal Chemistry, 7(6), 799-800. doi:10.1021/jm00336a026 google scholar
Sun, H., Moore, C., Dansette, P. M., Kumar, S., Halpert, J. R., & Yost, G. S. (2009). Dehydrogenation of the Indoline-Containing Drug 4-Chloro-N-(2-methyl-1-indolinyl)-3-sulfamoylbenzamide (In-dapamide) by CYP3A4: Correlation with in Silico Predictions. Drug Metabolism and Disposition, 37(3), 672-684. doi:10.1124/ dmd.108.022707 google scholar
Sun, L., Huang, H.-H., Liu, L., & Zhong, D.-F. (2004). Transforma-tion of Verapamil by Cunninghamella blakesleeana. Applied and Environmental Microbiology, 70(5), 2722-2727. doi:10.1128/ AEM.70.5.2722-2727.2004 google scholar
Sundell, J., Bienvenu, E., Birgersson, S., Abelo, A., Ashton, M., & Hoffmann, K. J. (2019). Simultaneous quantification of four first line antitubercular drugs and metabolites in human plasma by hydrophilic interaction chromatography and tandem mass spectrometry. Journal of Chromatography B, 1105, 129-135. doi:10.1016/j.jchromb.2018.10.027 google scholar
Turgeon, J., Pare, J. R., Lalande, M., Grech-Belanger, O., & Belanger, P. M. (1992). Isolation and structural characterization by spectro-scopic methods of two glucuronide metabolites of mexiletine after N-oxidation and deamination. Drug Metab Dispos, 20(5), 762-769. google scholar
Uldam, H. K., Juhl, M., Pedersen, H., & Dalgaard, L. (2011). Biosyn-thesis and identification of an N-oxide/N-glucuronide metabo-lite and first synthesis of an N-O-glucuronide metabolite of Lu AA21004. Drug Metabolism & Disposition, 39(12), 2264-2274. doi:10.1124/dmd.111.040428 google scholar
Vail, R. B., Homann, M. J., Hanna, I., & Zaks, A. (2005). Preparative synthesis of drug metabolites using human cytochrome P450s 3A4, 2C9 and 1A2 with NADPH-P450 reductase expressed in Escherichia coli. Journal of Industrial Microbiology and Biotechnol-ogy, 32(2), 67-74. doi:10.1007/s10295-004-0202-1 google scholar
Valero, E., Lozano, M. I., Varon, R., & Garcia-Carmona, F. (2003). Enzymatic synthesis of 3’-hydroxyacetaminophen catalyzed by tyrosinase. Biotechnology Progress, 19(6), 1632-1638. doi:10.1021/ bp034075t google scholar
Wang, Z., Sun, W., Lin, Z. F., Sun, R., Huang, C. K., Ye, W. J., . . . Chen, R. J. (2019). A UHPLC-MS/MS method coupled with liquid-liquid extraction for the quantitation of phenacetin, omeprazole, meto-prolol, midazolam and their metabolites in rat plasma and its ap-plication to the study of four CYP450 activities. Journal of Phar-maceutical and Biomedical Analysis, 163, 204-210. doi:10.1016/j. jpba.2018.10.012 google scholar
Weis, R., Winkler, M., Schittmayer, M., Kambourakis, S., Vink, M., Ro-zzell, J. D., & Glieder, A. (2009). A Diversified Library of Bacterial and Fungal Bifunctional Cytochrome P450 Enzymes for Drug Metabo-lite Synthesis. Advanced Synthesis & Catalysis, 351(13), 2140-2146. doi:10.1002/adsc.200900190 google scholar
Wheals, B. B., & Jane, I. (1977). Analysis of drugs and their metabo-lites by high-performance liquid chromatography. A review. Ana-lyst, 102(1218), 625-644. doi:10.1039/an9770200625 google scholar
Williams, R. T. (1938). Studies in detoxication. II. (a) The conju-gation of isomeric 3-menthanols with glucuronic acid and the asymmetric conjugation of dl-menthol and dl-isomenthol in the rabbit. (b) d-isoMenthylglucuronide, a new conjugated glucuron-ic acid. The Biochemical Journal, 32(10), 1849-1855. doi:10.1042/ bj0321849 google scholar
Williams, R. T. (1943). Studies in detoxication: 13. The biosynthesis of aminophenyl- and sulphonamidoaminophenylglucuronides in the rabbit and their action on haemoglobin in vitro. Biochemi-cal Journal, 37(3), 329-333. google scholar
Winkler, M., Geier, M., Hanlon, S. P., Nidetzky, B., & Glieder, A. (2018). Human Enzymes for Organic Synthesis. Angewandte Che-mie International Edition, 57(41), 13406-13423. doi:https://doi. org/10.1002/anie.201800678 google scholar
Wu, Y, Wang, R, Yang, H., & Sui, F. (2019). UPLC-Q-TOF-MS and UPLC-MS/MS methods for metabolism profiles and pharmacokinetics of major compounds in Xuanmai Ganjie Granules. Biomedical Chroma-tography, 33(3), e4449. doi:https://doi.org/10.1002/bmc.4449 google scholar
Xing, J., Zang, M., Zhang, H., & Zhu, M. (2015). The application of high-resolution mass spectrometry-based data-mining tools in tandem to metabolite profiling of a triple drug combination in humans. Analytica Chimica Acta, 897, 34-44. doi:10.1016/j. aca.2015.09.034 google scholar
Yoshimura, H., Oguri, K., & Tsukamoto, H. (1968). Metabolism of drugs. LX. The synthesis of codeine and morphine glucuronides. Chemical and Pharmaceutical Bulletin, (Tokyo), 16(11), 2114-2119. doi:10.1248/cpb.16.2114 google scholar
Youssif, S. (2001). Recent trends in the chemistry of pyridine N-oxides. J Arkivoc, 1, 242-268. google scholar
Zhang, D., Freeman, J. R., Sutherland, J. B., Walker, A. E., Yang, Y., & Cerniglia, C. E. (1996). Biotransformation of chlorpromazine and methdilazine by Cunninghamella elegans. Applied and Environ-mental Microbiology, 62(3), 798-803. doi:10.1128/AEM.62.3.798-803.1996 google scholar
Schroer, K., Kittelmann, M., & Lutz, S. (2010). Recombinant human cytochrome R450 monooxygenases for drug metabolite synthe-sis. Biotechnology & Bioengineering, 106(5), 699-706. google scholar

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Primary Language	English
Subjects	Pharmacology and Pharmaceutical Sciences
Journal Section	Review
Authors	Zafer Şahin 0000-0002-5976-676X Pınar Sinem Omurtag Özgen This is me 0000-0003-2493-9664 Sevim Rollas This is me 0000-0002-4144-6952
Publication Date	August 30, 2023
Submission Date	January 18, 2022
Published in Issue	Year 2023 Volume: 53 Issue: 2

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APA	Şahin, Z., Omurtag Özgen, P. S., & Rollas, S. (2023). Importance and review of drug metabolite synthesis. İstanbul Journal of Pharmacy, 53(2), 251-269. https://doi.org/10.26650/IstanbulJPharm.2023.1033045
AMA	Şahin Z, Omurtag Özgen PS, Rollas S. Importance and review of drug metabolite synthesis. iujp. August 2023;53(2):251-269. doi:10.26650/IstanbulJPharm.2023.1033045
Chicago	Şahin, Zafer, Pınar Sinem Omurtag Özgen, and Sevim Rollas. “Importance and Review of Drug Metabolite Synthesis”. İstanbul Journal of Pharmacy 53, no. 2 (August 2023): 251-69. https://doi.org/10.26650/IstanbulJPharm.2023.1033045.
EndNote	Şahin Z, Omurtag Özgen PS, Rollas S (August 1, 2023) Importance and review of drug metabolite synthesis. İstanbul Journal of Pharmacy 53 2 251–269.
IEEE	Z. Şahin, P. S. Omurtag Özgen, and S. Rollas, “Importance and review of drug metabolite synthesis”, iujp, vol. 53, no. 2, pp. 251–269, 2023, doi: 10.26650/IstanbulJPharm.2023.1033045.
ISNAD	Şahin, Zafer et al. “Importance and Review of Drug Metabolite Synthesis”. İstanbul Journal of Pharmacy 53/2 (August 2023), 251-269. https://doi.org/10.26650/IstanbulJPharm.2023.1033045.
JAMA	Şahin Z, Omurtag Özgen PS, Rollas S. Importance and review of drug metabolite synthesis. iujp. 2023;53:251–269.
MLA	Şahin, Zafer et al. “Importance and Review of Drug Metabolite Synthesis”. İstanbul Journal of Pharmacy, vol. 53, no. 2, 2023, pp. 251-69, doi:10.26650/IstanbulJPharm.2023.1033045.
Vancouver	Şahin Z, Omurtag Özgen PS, Rollas S. Importance and review of drug metabolite synthesis. iujp. 2023;53(2):251-69.

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