Determination of Pharmacokinetic and Toxicological Parameters of Some Commonly Used Statin Group Drugs

Öz

Statins work as inhibitors of the HMG-CoA reductase enzyme and are the most commonly prescribed cholesterol-lowering drug group for people with cardiovascular disease or risk. This study aimed to determine the pharmacokinetic parameters and toxicities of conventional and new-generation cholesterol drugs such as atorvastatin, fluvastatin, lovastatin, pravastatin, simvastatin, rosuvastatin and pitavastatin. Absorption, distribution, metabolism, and excretion (ADME) parameters and toxicity predictions of drugs were made using in silico modeling, which gives faster results than animal experiments and does not involve any laboratory costs. In calculations made using structural similarity, compounds' pharmacokinetic properties and toxicity predictions are obtained based on previously known structure-activity data. The study results showed that the toxicity classifications of the drugs were 5 (LD: 5000 mg/kg) for atorvastatin and 6 (LD: 8939 mg/kg) for pravastatin, respectively. The toxicity classes were found to be 4 for all the other statin group drugs. The results showed that pravastatin had the lowest toxicity among investigated cholesterol drugs, while pitavastatin and fluvastatin had the highest toxic effects. Accordingly, it is recommended that the consequences of using pravastatin and atorvastatin, cholesterol drugs with lower toxicity classes, should be investigated more seriously in terms of minimum toxic substance intake for patient groups requiring high doses of medication.

Anahtar Kelimeler

• Statin group drugs
• Molecular modeling
• In silico investigations

Kaynakça

1. Civek S. ve Akman M. Dünyada ve Türkiye’de kardiyovasküler hastalıkların sıklığı ve riskin değerlendirilmesi. Jour Turk Fam Phy 2022; 13 (1): 21-28. Doi: 10.15511/tjtfp.22.00121.
2. Alenghat FJ, Davis AM (February 2019). "Management of Blood Cholesterol". JAMA. 321 (8): 800–801. doi:10.1001/jama.2019.0015. PMC 6679800.
3. National Clinical Guideline Centre (UK) (July 2014). Lipid Modification: Cardiovascular Risk Assessment and the Modification of Blood Lipids for the Primary and Secondary Prevention of Cardiovascular Disease. National Institute for Health and Clinical Excellence: Guidance. London: National Institute for Health and Care Excellence (UK). PMID 25340243. NICE Clinical Guidelines, No. 181 – via NIH National Library of Medicine.
4. Endo, A. A gift from nature: the birth of the statins. Nat Med 14, 1050–1052 (2008). https://doi.org/10.1038/nm1008-1050
5. Sweetman SC, ed. (2009). "Cardiovascular drugs". Martindale: the complete drug reference (36th ed.). London: Pharmaceutical Press. pp. 1155–1434.
6. MarvinSketch
7. PreADMET, https://preadmet.qsarhub.com/, (2022).
8. ProTox-II- Prediction of Toxicity of Chemicals, (2022).

9. Yong-Jin Wu, Heterocycles and Medicine, Progress in Heterocyclic Chemistry, 2012
10. https://www.stereoelectronics.org/webDD/DD_05.html
11. Furuya, Y., Sekine, Y., Kato, H., Miyazawa, Y., Koike, H., & Suzuki, K. (2016). Low-density lipoprotein receptors play an important role in the inhibition of prostate cancer cell proliferation by statins. Prostate international, 4(2), 56-60.
12. Alan Talevi, Pablo A. M. Quiroga, (2018). ADME Processes in Pharmaceutical Sciences.
13. Olson, R. E., & Christ, D. D. (1996). Plasma protein binding of drugs. In Annual reports in medicinal chemistry (Vol. 31, pp. 327-336). Academic Press.
14. Libralato, G., Annamaria, V. G., & Francesco, A. (2010). How toxic is toxic? A proposal for wastewater toxicity hazard assessment. Ecotoxicology and Environmental Safety, 73(7), 1602-1611.
15. DePass, L. R. (1989). Alternative approaches in median lethality (LD50) and acute toxicity testing. Toxicology letters, 49(2-3), 159-170./