Cytochrome P450 3A-dependent metabolism of a potent and selective γ-aminobutyric acidAα2/3 receptor agonist in vitro: Involvement of cytochrome P450 3A5 displaying biphasic kinetics

Drug Metabolism and Disposition

Volumn 35, Issue 8, 2007, Pages 1301-1307

  Ma, Bennett ^a   Polsky Fisher, Stacey L ^a   Vickers, Stanley ^a   Cui, Donghui ^a   Rodrigues, A David ^a,b  

^a MERCK RESEARCH LABORATORIES   (United States)

^b BRISTOL MYERS SQUIBB   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

3 BENZYLPHENOBARBITAL; 4 AMINOBUTYRIC ACID A ALPHA2 RECEPTOR AGONIST; 4 AMINOBUTYRIC ACID A ALPHA3 RECEPTOR AGONIST; 4 AMINOBUTYRIC ACID RECEPTOR STIMULATING AGENT; CYTOCHROME P450 3A; CYTOCHROME P450 3A4; CYTOCHROME P450 3A5; ENZYME; FURAFYLLINE; KETOCONAZOLE; MIFEPRISTONE; MONTELUKAST; N DEETHYLASE; PHENOBARBITAL DERIVATIVE; QUINIDINE; REDUCED NICOTINAMIDE ADENINE DINUCLEOTIDE PHOSPHATE; SULFAPHENAZOLE; TERT BUTYL HYDROXYLASE; TPA 023; TROLEANDOMYCIN; UNCLASSIFIED DRUG;

ARTICLE; BIOTRANSFORMATION; CATALYSIS; CHEMICAL REACTION; CONTROLLED STUDY; DRUG METABOLISM; DRUG POTENCY; ENZYME ACTIVITY; HUMAN; HUMAN TISSUE; HYDROXYLATION; IN VITRO STUDY; LIVER MICROSOME; MICHAELIS CONSTANT; N DEETHYLATION; PRIORITY JOURNAL; STATISTICAL SIGNIFICANCE;

ANIMALS; ANTIBODIES, MONOCLONAL; CYTOCHROME P-450 CYP3A; CYTOCHROME P-450 ENZYME SYSTEM; ENZYME INHIBITORS; HUMANS; HYDROXYLATION; KINETICS; MICROSOMES; MICROSOMES, LIVER; MIFEPRISTONE; PYRIDAZINES; RECEPTORS, GABA-A; RECOMBINANT PROTEINS; TRIAZOLES;

EID: 34547169021     PISSN: 00909556     EISSN: 1521009X     Source Type: Journal    
DOI: 10.1124/dmd.107.014753     Document Type: Article

References (32)

1. A receptors, is a nonsedating anxiolytic in rodents and primates. J Pharmacol Exp Ther 316:410-422.
2. A) α2/α3-subtype selective agonist that exhibits potent anxiolytic activity but is not sedating in animal models. J Med Chem 48:7089-7092.
3. 2,3 subtype-selective agonist, compared to lorazepam and placebo in healthy volunteers. J Psychopharmacol in press.
4. Galetin A, Brown C, Hallifax D, Ito K, and Houston JB (2004) Utility of recombinant enzyme kinetics in prediction of human clearance: impact of variability CYP3A5, and CYP2C19 on CYP3A4 probe substrates. Drug Metab Dispos 32:1411-1420.
5. Granfors MT, Wang J-S, Kajosaari LI, Laitila J, Neuvonen PJ, and Backman JT (2006) Differential inhibition of cytochrome P450 3A4, 3A5 and 3A7 by five human immunodeficiency virus (HIV) protease inhibitors in vitro. Basic Clin Pharmacol Toxicol 98:79-85.
6. He K, Woolf TF, and Hollenberg PF (1999) Mechanism-based inactivation of cytochrome P-450-3A4 by mifepristone (RU486). J Pharmacol Exp Ther 288:791-797.
7. Huang W, Lin YS, McConn DJ II, Calamia JC, Totah RA, Isoherranen N, Glodowski M, and Thummel KE (2004) Evidence of significant contribution from CYP3A5 to hepatic drug metabolism. Drug Metab Dispos 32:1434-1445.
8. Khan KK, He YQ, Correia MA, and Halpert JR (2002) Differential oxidation of mifepristone by cytochromes P450 3A4 and 3A5: selective inactivation of P450 3A4. Drug Metab Dispos 30:982-990.
9. Klees TM, Sheffels P, Dale O, and Kharasch ED (2005) Metabolism of alfentanil by cytochrome P4503A (CYP3A) enzymes. Drug Metab Dispos 33:303-311.
10. Korzekwa KR, Krishnamachary N, Shou M, Ogai A, Parise RA, Rettie AE, Gonzalez FJ, and Tracy TS (1998) Evaluation of atypical cytochrome P450 kinetics with two-substrate-models: evidence that multiple substrates can simultaneously bind to cytochrome P450 active sites. Biochemistry 37:4137-4147.
11. Kronbach T, Mathys D, Umeno M, Gonzalez FJ, and Meyer UA (1989) Oxidation of midazolam and triazolam by human liver cytochrome P450IIIA4. Mol Pharmacol 36:89-96.
12. 5 in modulating peroxide-supported CYP3A4 activity: evidence for a conformational transition and cytochrome P450 heterogeneity. Drug Metab Dispos 33:1131-1136.
13. A receptor antagonist in human liver microsomes. Drug Metab Dispos 32:473-478.
14. McConn DJ II, Lin YS, Allen K, Kunze KL, and Thummel KE (2004) Differences in the inhibition of cytochromes P450 3A4 and 3A5 by metabolite-inhibitor complex-forming drugs. Drug Metab Dispos 32:1083-1091.
15. McCune JS, Risler LJ, Philips BR, Thummel KE, Blough D, and Shen DD (2005) Contribution of CYP3A5 to hepatic and renal ifosfamide N-dechloroethylation. Drug Metab Dispos 33:1074-1081.
16. Mei Q, Tang C, Assang C, Lin Y, Slaughter D, Rodrigues AD, Baillie TA, Rushmore TH, and Shou M (1999) Role of a potent inhibitory monoclonal antibody to cytochrome P-450 3A4 in assessment of human drug metabolism. J Pharmacol Exp Ther 291:749-759.
17. Mei Q, Tang C, Lin Y, Rushmore TH, and Shou M (2002) Inhibition kinetics of monoclonal antibodies against cytochrome P450. Drug Metab Dispos 30:701-708.
18. Newton DJ, Wang RW, and Lu AYH (1995) Evaluation of specificities in the in vitro metabolism of therapeutic agents by human liver microsomes. Drug Metab Dispos 23:154-158.
19. Patki KC, von Moltke LL, and Greenblatt (2003) In vitro metabolism of midazolam, trazolam, nifedipine, and testosterone by human liver microsomes and recombinant cytochromes P450: role of CYP3A4 and CYP3A5. Drug Metab Dispos 31:938-944.
20. α2/3 receptor agonist in healthy male volunteers. Drug Metab Dispos 34:1004-1011.
21. Prueksaritanont T, Gorham LM, Ma B, Liu L, Yu X, Zhao JJ, Slaughter DE, Arison BH, and Vyas KP (1997) In vitro metabolism of simvastatin in humans [sbt] Identification of metabolizing enzymes and effect of the drug on hepatic P450s. Drug Metab Dispos 25:1191-1199.
22. 5. Pharmacol Ther 97:139-152.
23. Segel IH (1975) Enzyme Kinetics: Behavior and Analysis of Rapid Equilibrium and Steady-State Enzyme Systems. John Wiley and Sons, Inc., New York.
24. Shen L, Fitzloff JF, and Cook CS (2004) Differential enantioselectivity and product-dependent activation and inhibition in metabolism of verapamil by human CYP3As. Drug Metab Dispos 32:186-196.
25. Shou M, Mei Q, Ettore MW, Dai R, Baillie TA, and Rushmore TH (1999) Sigmoidal kinetic model for two co-operative substrate-binding sites in a cytochrome P450 3A4 active site: an example of the metabolism of diazepam and its derivatives. Biochem J 340:845-853.
26. A receptor subtypes. Curr Top Med Chem 2:795-816.
27. Suzuki H, Kneller MB, Haining RL, Trager WF, and Rettie AE (2002) (+)-N-3-benzyl-nirvanol and (-)-N-3-benzyl-phenobarbital: new potent and selective in vitro inhibitors of CYP2C19. Drug Metab Dispos 30:235-239.
28. Walsky RL, Obach RS, Gaman EA, Gleeson J-PR, and Proctor WR (2005) Selective inhibition of human cytochrome P4502C8 by montelukast. Drug Metab Dispos 33:413-418.
29. Wang Y-H, Jones DR, and Hall SD (2005) Differential mechanism-based inhibition of CYP3A4 and CYP3A5 by verapamil. Drug Metab Dispos 33:664-671.
30. Williams JA, Ring BJ, Cantrell VE, Jones DR, Eckstein J, Ruterbories K, Hamman MA, Hall SD, and Wrighton SA (2002) Comparative metabolic capabilities of CYP3A4, CYP3A5, and CYP3A7. Drug Metab Dispos 30:883-891.
31. Wrighton SA and Stevens JC (1992) The human hepatic cytochromes P450 involved in drug metabolism. CRC Crit Rev Toxicol 22:1-21.
32. Zhuo X, Zheng N, Felix CA, and Blair IA (2004) Kinetics and regulation of cytochrome P450-mediated etoposide metabolism. Drug Metab Dispos 32:993-1000.