Human N-demethylation of (S)-mephenytoin by cytochrome P450S 2C9 and 2B6

Drug Metabolism and Disposition

Volumn 26, Issue 8, 1998, Pages 775-778

  Ko, Jae Wook ^b   Desta, Zeruesenay ^b   Flockhart, David A ^a  

^a GEORGETOWN UNIVERSITY MEDICAL CENTER   (United States)

^b NONE

Author keywords

[No Author keywords available]

Indexed keywords

CYTOCHROME P450 ISOENZYME; MEPHENYTOIN; NORMEPHENYTOIN; RECOMBINANT PROTEIN; SULFAPHENAZOLE;

ARTICLE; CONTROLLED STUDY; DEMETHYLATION; DRUG METABOLISM; ENZYME KINETICS; HUMAN; HUMAN TISSUE; LIVER MICROSOME; PRIORITY JOURNAL;

ANTICONVULSANTS; ARYL HYDROCARBON HYDROXYLASES; CYTOCHROME P-450 ENZYME SYSTEM; HUMANS; ISOENZYMES; KINETICS; MEPHENYTOIN; METHYLATION; MICROSOMES, LIVER; OXIDOREDUCTASES, N-DEMETHYLATING; PHENOTYPE; STEREOISOMERISM; STEROID 16-ALPHA-HYDROXYLASE; STEROID HYDROXYLASES; SUBSTRATE SPECIFICITY;

EID: 0031845066     PISSN: 00909556     EISSN: None     Source Type: Journal    
DOI: None     Document Type: Article

References (21)

1. Baldwin SJ, Bloomer JC, Smith GJ, Aynon AD, Clarke SE and Chenery RJ (1995) Ketoconazole and sulfaphenazole as the respective selective inhibitors of P450 3A and 2C9. Xenobiotica 25:261-270.
2. Black DJ, Kunze KL, Wienkers LC, Gidal BE, Seaton TL, McDonnell ND, Evans JS, Bauwens JE and Trager WF (1996) A metabolically based drug interaction between fluconazole and warfarin: in vivo studies. Drug Metab Dispos 24:422-428.
3. Code EL, Cresoi CL, Penman BW, Gonzalez FJ, Chang TKH and Waxman DJ (1997) Human cytochrome P450 2B6: interindividual hepatic expression, substrate specificity, and role in procarcinogen activation. Drug Metab Dispos 25:985-992.
4. Ekins S, VandenBranden M, Ring BJ and Wrighton SA (1997) Examination of purported probes of human CYP2B6. Pharmacogenetics 7:165-171.
5. Goldstein JA, Faletto MB, Romkes-Sparks M, Sullivan TJ, Kitareewan S, Raucy JL, Lasker JM and Ghanayem BI (1994) Evidence that CYP2C19 is the major (S)-mephenytoin 4-hydroxylase in humans. Biochemistry 33:1743-1752.
6. Guo Z, Raeissi S, White RB and Stevens JC (1997) Orphenadrine and methimazole inhibit multiple cytochrome P450 enzymes in human liver microsomes. Drug Metab Dispos 25:390-393.
7. Hall SD, Guengerich FP, Branch RA and Wilkinson GR (1987) Characterization and inhibition of mephenytoin 4-hydroxylase activity in human liver microsomes. J Pharmacol Exp Ther 240:216-222.
8. Harris JW, Rahman A, Kim B-R, Guengerich FP and Collins JM (1994) Metabolism of taxol by human hepatic microsomes and liver slices: participation of cytochrome P450 3A4 and an unknown P450 enzyme. Cancer Res 54:4026-4035.
9. Heyn H, White RB and Stevens JC (1996) Catalytic role of cytochrome P450 2B6 in the N-demethylation of S-mephenytoin. Drug Metab Dispos 24:948-954.
10. Jurima M, Inaba T and Kalow W (1985) Mephenytoin metabolism in vitro by human liver. Drug Metab Dispos 13:151-155.
11. Ko J-W, Sukhova N, Thacker D, Chen P and Flockhart DA (1997) Evaluation of omeprazole and lansoprazole as inhibitors of cytochrome P450 isoforms. Drug Metab Dispos 25:853-862.
12. Küpfer A, Desmond P, Patwardhan R, Schenker S and Branch RA (1984) Mephenytoin hydroxylation deficiency: kinetics after repeated doses. Clin Pharmacol Ther 35:33-39.
13. Küpfer A, Roberts RK, Schenker S and Branch RA (1981) Stereoselective metabolism of mephenytoin in man. J Pharmacol Exp Ther 218:193-199.
14. Meier UT, Kronbach T and Meyer UA (1985) Assay of mephenytoin metabolism in human liver microsomes by high-performance liquid chromatography. Anal Biochem 151:286-291.
15. Mitra A., Thummel KE, Kalhom TF, Kharasch ED, Unadkat JD and Slattery JT (1996) Inhibition of sulfamethoxazole hydroxylamine formation by fluconazole in human liver microsomes and healthy volunteers. Clin Pharmacol Ther 59:332-340.
16. Pollard HB, Menard R, Brandt HA, Pazolzs CJ, Creutz CE and Ramu A (1978) Application of Bradford's protein assay to adrenal gland subcellular fractions. Anal Biochem 86:761-763.
17. Relling MV, Aoyama T, Gonzalez FJ and Meyer UA (1990) Tolbutamide and mephenytoin hydroxylation by human cytochrome P450s in the CYP2C subfamily. J Pharmacol Exp Ther 252:442-447.
18. Troupin AS, Friel P, Lovely MP and Wilensky AJ (1979) Clinical pharmacology of mephenytoin and ethotoin. Ann Neurol 6:410-414.
19. Troupin AS, Ojemann LM and Dodrill CB (1976) Mephenytoin: a reappraisal. Epilepsia 17:403-414.
20. Wedlund PJ, Aslanian WS, McAllister CB, Wilkinson GR and Branch RA (1984) Mephenytoin hydroxylation deficiency in Caucasians: frequency of a new oxidative drug metabolism polymorphism. Clin Pharmacol Ther 36:773-780.
21. Wrighton SA, Stevens JC, Becker GW and VandenBranden M (1993) Isolation and characterization of human liver cytochrome P450 2C19: correlation between 2C19 and S-mephenytoin 4′-hydroxylation. Arch Biochem Biophys 306:240-245.