Oxidative drug metabolism

The virtual compounds can be screened against structural models of the metabolizing enzymes, including the known SNP variants. These procedures are becoming widely adopted for the cytochrome P450 isozymes involved in oxidative drug metabolism. 

Oxidative drug metabolism is extremely complex and possibly the most poorly understood ADME property. Rapid metabolism is unacceptable for drug candidates, except for drugs whose metabolite is the active moiety, because it causes duration of action to be too short. Considerable work has focused on the liver enzyme CYP3A4, which is responsible for the metabolic clearance of approximately 50% of marketed drugs. Recent approaches used to model and understand drug metabolism include database matching, quantum mechanics, QSAR, and structure-based analyses. 

Wedlund, P.J., Aslanian, W.S., McAllister, C.B., Wilkinson, G.R. and Branch, R.A. (1984) Mephenytoin hydroxylation deficiency in Caucasians frequency of a new oxidative drug metabolism polymorphism. Clinical Pharmacology and Therapeutics, 36 (6), 773-780. 

Preskorn, S.H. (1997) Clinically relevant pharmacology of selective serotonin reuptake inhibitors. An overview with emphasis on pharmacokinetics and effects on oxidative drug metabolism. Clin Pharmacokinet 32 1-21. 

Three randomized clinical trials support the efficacy of bupropion in ADHD. The first used doses up to 6 mg/kg (98) the other two used doses of 100 to 300 mg per day in equally divided daily doses spaced at least 6 hours apart ( 99, 100). The concern with bupropion is its seizure risk, which requires that its daily dose stay below 450 mg per day in adults (i.e., approximately 6.5 mg/kg). Virtually no work has been done to determine the plasma concentrations of bupropion and its three active metabolites in children and adolescents. Hence, it is unknown whether a limit of 6.5 mg per kg is also appropriate for children. No data exist as to whether children are more or less sensitive to bupropion in terms of seizure risk at the same drug concentration. Also, little is known about pharmacokinetic drug-drug interactions that could reduce the clearance of bupropion. For these reasons, cautious dosing is advised when prescribing bupropion for children on other medications that can reduce oxidative drug metabolism (see Chapter 3 and Chapter 7 for more details). 

Wing LM, Miners JO. Cotrimoxazole as an inhibitor of oxidative drug metabolism effects of trimethoprim and sulphamethoxazole separately and combined on tolbutamide disposition. Br J Clin Pharmacol 1985 20(5) 482-5. 

Smith RL. Introduction human genetic variations in oxidative drug metabolism. Xenobiotica 1986 16 361-365. 

Wedlund PJ, Aslanian WS, McAllister CB. Mephenytoin hydroxylation deficiency in Caucasians frequency of a new oxidative drug metabolism polymorphism. Clin Pharmacol Ther 1984 36 773-780. 

Ortiz de Montellano, P.R. Correia, M.A. Suicidal destruction of cytochrome P-450 during oxidative drug metabolism. Ann Rev Pharmacol Toxicol, 1983 23 481-503... 

The major oxidative drug-metabolizing pathway is catalyzed by cytochrome P450 enzymes (Mulder, 2006). The abbreviation CYP is typically used in this context. More than 60 CYPs have been identified. These are identified by up to four characters (letters or numbers). For example, in the term CYP2A4 4 the letters and numbers indicate the following ... 

Guengerich FP, Martin MV, Beaune PH, et al. Characterization of rat and human liver microsomal cytochrome P-450 forms involved in nifedipine oxidation, a prototype for genetic polymorphism in oxidative drug metabolism. J Biol Chem 1986 261 5051-5060. 

Breimer DD, Schellens JHM. A cocktail strategy to assess in vivo oxidative drug metabolism in humans. Trends Pharmacol Sci 1990 11 223-225. 

Venkatakrishnan K, von Moltke LL, Greenblatt DJ. Effects of the antifungal agents on oxidative drug metabolism in humans clinical relevance. Clin Pharmacokinet 2000 38 111-180. 

Arinc, E., Schenkman, J. B., and Elodgson, E. (Eds.). Molecular and Applied Aspects of Oxidative Drug Metabolizing Enzymes, Kluwer Academic/Plenum Publishers, New York, 1999. Engel, P. C., Enzyme Kinetics, John Wiley Sons, New York, 1977. 

Engel G, Hofmann U, Heidemann H, Cosine J, Eichelbaum M. Antipyrine as a probe for human oxidative drug metabolism Identification of the cytochrome P450 enzymes catalyzing 4-hydroxyantipyrine, 3-hydroxymethylantipyrine, and norantipyrine formation. Clin Pharmacol Ther 1996 59 613-23. 

Danhof, M., Teunissen, M.W.E. Antipyrine as a model drug to assess oxidative drug metabolizing activity in man. Pharm. Int. 1984 5 11-15... 

Arvela P, Kraul H, Stenback E, and Pelkonen O (1991) The cerium-induced liver injury and oxidative drug metabolism in DBA/2 and C57BL/6 mice. Toxicology 69 1-9. 

Lasker JM, Huang M-T, Conney AH. 1984. In vitro and in vivo activation of oxidative drug metabolism by flavonoids. J. Pharmacol. Exp. Ther. 229 162-70... 

Anderson K, Conney AH, Kappas A. 1979. Nutrition and oxidative drug metabolism in man relative influence of dietary lipids, carbohydrate, and protein. Clin. Pharmacol. Ther. 26 493—501... 

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