IN VITRO METABOLIC FATE OF N-SUBSTITUTED DIBENZYLAMINES : INVESTIGATION OF BIOLOGICAL OXIDATION SITE ON NITROGEN COMPOUNDS WITH DIFFERENT pKa

Year 1998, Volume: 32 , 69 - 86, 09.09.2015

İ. Küçükgüzel M. Ülgen

Abstract

The in vitro rnicrosomal metabolism of four model tertiary amines ie. Nethyldibenzylamine (EDBA), tribenzylamine (TBA), N,N-dibenzylaniline
(DBAN) and N,N-dibenzylbenzarnide (BZDBA) was studied to establish whether
the corresponding N- and C-oxidation products such as the corresponding
arnides, dealkylation products, N-oxides and phenols formed. These compounds
were selected as substrates to establish the effect of the varying pK, and logP
characteristics on their iiz vitro metabolism. The substrates and their potential
metabolites were synthesized and then separated using HPLC. Incubations were
performed using rat microsomal preparations fortified with NADPH. The substrates and their potential metabolites were extracted into dichloromethane and examined by HPLC. Results from HPLC analysis indicated that all these substrates failed to produce the corresponding amides as metabolites. However, the dealkylation metabolites were observed with all the substrates used as major metabolites.
The substrates EDBA and TBA produced the corresponding N-oxide
metabolites: Three phenolic. metabolites of DBAN were also demonstrated.
These findings support the concept that nitrones are essential metabolic intermediates for the formation of arnides and this reaction reguees,a secondary mine as substrate. In addition, the metabolic N-oxidation of these substrates depends on the pKa of the constituent nitrogen of the molecule.

Key words :Tertiary amines, in vitro metabolism, the effect of pKa.

Keywords

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IN VITRO METABOLIC FATE OF N-SUBSTITUTED DIBENZYLAMINES : INVESTIGATION OF BIOLOGICAL OXIDATION SITE ON NITROGEN COMPOUNDS WITH DIFFERENT pKa

Abstract

The in vitro rnicrosomal metabolism of four model tertiary amines ie. Nethyldibenzylamine (EDBA), tribenzylamine (TBA), N,N-dibenzylaniline
(DBAN) and N,N-dibenzylbenzarnide (BZDBA) was studied to establish whether the corresponding N- and C-oxidation products such as the corresponding
arnides, dealkylation products, N-oxides and phenols formed. These compounds
were selected as substrates to establish the effect of the varying pK, and logP
characteristics on their iiz vitro metabolism. The substrates and their potential
metabolites were synthesized and then separated using HPLC. Incubations were
performed using rat microsomal preparations fortified with NADPH. The substrates and their potential metabolites were extracted into dichloromethane and
examined by HPLC. Results from HPLC analysis indicated that all these substrates failed to produce the corresponding amides as metabolites. However, the
dealkylation metabolites were observed with all the substrates used as major metabolites. The substrates EDBA and TBA produced the corresponding N-oxide
metabolites: Three phenolic. metabolites of DBAN were also demonstrated.
These findings support the concept that nitrones are essential metabolic intermediates for the formation of arnides and this reaction reguees,a secondary mine
as substrate. ~n.addition, the metabolic N-oxidation of these substrates depends
on the pKa of the constituent nitrogen of the molecule.

Keywords

Tertiary amine, in vitl-o metabolism, the effect of pK

References

• 1. Yeung, P.K.F., Hubbard, J.W., Korchinski, E.D., Midha, K.K., J.Plzarm.Sci., 76, 803-808 (1987).
• 2. Zhang, D., Evans, F.E., Freeman, J.P., Duhart, Jr. B., Cerniglia, C., Drug Metab.Dispos., 23, 1417-1425 (1995).
• 3. Wilson, K., Burnett, D., Oram, M., Reynolds, C.T., EurJ.Drug Metab. Pharmacokin., 6, 289-295 (198 1).
• 4. Gorrod, J.W., Gooderham, N.J., ibid., 6, 195-206 (1981).
• 5. Gorrod, J.W., Temple, D.J.,Xenobiotica, 6,265-274 (1976).
• 6. Oelschlger, H., Schmidt, W. , Arclz.Pharnz.(Weinheim) ,327, 163-167 (1994).
• 7. Ulgen, M., Gorrod, J.W., J.Pharnz.Phar?nacol., 48, 1320-1326 (1996).
• 8. Hall, L.R., Hanzlik, R.P., Xenobiotica, 21, 1 127-1 138 (1991).
• 9. Constantino, L., Rosa, E., Iley, J., Biochenz.Parmacol., 44,651-658 (1992).
• 10. Jacoby, W.B., Bend, J.R., Caldwell, J., Metabolic Basis of Detoxication, pp. 105-149, Academic Press, London (1982). I 1 I. agen M., Gorrod, J.W., Barlow, D.,Xenobiotica, 24,735-748 (1994).
• 12. Ulgen M., Ozer, U., Kiic;iikgiizet, I., Gorrod, J.W., Drug Metab.Drug blteract, 14, 83-98 (1996).
• 13. Kii$iikgiizel, I., Ulgen M., Gorrod, J.W., Eur.J.Drug Metab.Pharmacokin., 22, 351-358 (1997).
• 14. Kraft, F., Ber., 23,2780-2784 (1 890).
• 15. Holmes, E.L., Ingold, C.K., J.Chem.Soc, 127, 1800-182, (1925). i
• 16. Wang, J., Zhang, Y., Qi, W., Xu, Y., Wang, L., Youji Humce, 295-297 (1986) : Ref. C.A., 107,115328h (1987).
• 17. Bonnat, M., Hercouet, A., LeCorre, M., Synth.Cornmun., 21, 15-16 (1991) : Ref. C.A., 115, 231771m (1991).
• 18. Mason, A.T., J.Chenl.Soc., 63, 131 1-1314 (1893).
• 19. Wegler, R., Frank, W., Ber., 69 B, 207 1-2077 (1 936).
• 20. Davis, M.M., Hetzer, H.B., J.Am.Chenl.Soc., 76,4247-4260 (1954).
• 21. Mauudaira,C., Ber., 20, 1611-1617, (1887).
• 22. Seleznev, A., Groz~~enskii Nefryanik, 7,50-52 (1937) : Ref. C.A., 31, 44816, (1937).
• 23. Franzen, H., Ber., 42,2465-2468 (1909).
• 24. Blacher, C., ibid.,28,432-437 (1895).
• 25. Sekine, M., Satoh, M., Yamagata, H., Hata, T., J.Org.Chenl., 45, 4162-4167 (1980) : Ref. C.A., 93, 185341y, (1980).
• 26. Schenkman, J.B., Cinti, D.L., Metlzods in E~zqn~ol.,, 52 ,83-89 (1978).