Cytochrome P450s metabolism

Maurel, P. (1996) The CYP3A family, in Cytochrome P450 Metabolic and Toxicological Aspects, (ed. Ioannides C.) CRC Press, Boca Raton, FL, pp. 241-270. 

The lability of benzylic positions to cytochrome P450 metabolism has been exploited to decrease the unacceptably low clearance and resultant long half-life of various compounds. For example celecoxib, a selective cyclooxygenase inhibitor, has a half-life of 3.5 h in the rat. Early structural leads, represented by compoimds in... 

Nevirapine has been shown to be an inducer of hepatic cytochrome P450 metabolic enzymes 3A4 and 2B6. The pharmacokinetics of autoinduction are characterized by an approximately 1.5- to 2-fold increase in the apparent oral clearance of nevirapine as treatment continues from a single dose to 2 to 4 weeks of dosing with 200 to 400 mg/day. Auto-induction also results in a corresponding decrease in the terminal phase half-life of nevirapine in plasma from approximately 45 hours (single dose) to approximately 25 to 30 hours following multiple dosing with 200 to 400 mg/day. 

Yamashita, F., Hara, H., Ito, T., Hashida, M. Novel hierarchical classification and visualization method for multiobjective optimization of drug properties application to structure-activity relationship analysis of cytochrome P450 metabolism. J. Chem. Inf. Model. 2008, 48, 364-9. 

Oral contraceptives Probable induction of cytochrome P450 metabolic pathway Reduced blood levels with risk of breakthrough bleeding Possible failure to prevent conception Weigh benefits of continuing use of SJW and possibiy reduced contraceptive effect... 

Rodgers, J.F. A.N. Nafziger and J.S. Bertino. Pharmacogenetics affects dosing, efficacy, and toxicity of cytochrome P450-metabolized drugs, American Journal of Medicine 113 (2002) 746-750. 

Fenofibrate appears to be complementary with certain statins in the treatment of familial combined hyperlipoproteinemia and other conditions involving elevations of both LDL and VLDL. The combination of fenofibrate with rosuvastatin is particularly effective. Some other statins may interact unfavorably owing to effects on cytochrome P450 metabolism. 

Drugs that may inhibit cytochrome P450 metabolism of other drugs include amiodarone, androgens, atazanavir, chloramphenicol, cimetidine, ciprofloxacin, clarithromycin, cyclosporine, delavirdine, diltiazem, diphenhydramine, disulfiram, enoxacin, erythromycin, fluconazole, fluoxetine, fluvoxamine, furanocoumarins (substances in grapefruit juice), indinavir, isoniazid, itraconazole, ketoconazole, metronidazole, mexile-tine, miconazole, nefazodone, omeprazole, paroxetine, propoxyphene, quinidine, ritonavir, sulfamethizole, verapamil, voriconazole, zafirlukast, and zileuton. 

This has been found to be the case with valproic acid (2-propylpentanoic acid) (12), which is hepatotoxic, and 2-fluorovalproic add (22), which is much less hepatotoxic, discussed in Sedion 4.3.1. The hepatoxidty of 12 involves cytochrome P450 abstraction of its C-2 hydrogen atom. The C-2 fluorine atom of 22 cannot be removed by cytochrome P450 metabolism. It would be interesting to observe if the same isosteric replacement would reduce the hepatoxidty of other carboxylic acids, such as the widely used 2-ethylhexanoic add. 

Alosetron is a highly potent and specific antagonist of the 5-HT3 receptor. It is rapidly absorbed from the gastrointestinal tract with a bioavailability of 50-60% and has a plasma half-life of 1.5 hours but a much longer duration of effect. It undergoes extensive hepatic cytochrome P450 metabolism with renal excretion of most metabolites. 

Ronis MJJ, Lindros KO, Ingelman-Sundberg M. The CYP2E1 subfamily. In Ioannides C, ed. Cytochromes P450 Metabolic and Toxicological Aspects. Boca Raton, FL CRC Press, 1996 211-239. 

Ewing, T.J.A., Kocher, J-P, Tieu, H. and Korzekwa, K.R., Predicting susceptibility of reactive sites on molecules to metabolism and accessibility correction factors for electronic models of cytochrome P450 metabolism, U.S. Patent Application Publication, 2002. 

The symptoms may have been due to a direct effect of clarithromycin or else inhibition of hepatic cytochrome P450 metabolism, leading to fluoxetine toxicity. Clarithromycin occasionally causes hallucinations. 

Vermeulen NPE (1996) Role of metabolism in chemical toxicity. In Ioannides C (ed) Cytochromes P450 metabolic and toxicological aspects. CRC Press, New York, p 29... 

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