Nifedipine, cytochrome

In vitro studies show significant inhibition of the formation of oxidized irbesartan metabolites with the known cytochrome CYP2C9 substrates/inhibitors, tolbutamide, and nifedipine. However, clinical consequences were negligible. 

Ferenczy, G. G. and Morris, G. M. (1989) The active site of cytochrome P-450 nifedipine oxidase a model-building study. J. Mol. Graph. 7, 206-11. 

Cardiac depressant effects may occur when verapamil or diltiazem is combined with a (p-adrenoceptor antagonoist or a cardiac glycoside. Nifedipine and verapamil are metabolised by cytochrome P-450 3A4. Inhibitors of this enzyme, e.g. HIV-protease inhibitors, cimetidine, fluoxetine, ketoconazole, erythromycin, will increase plasma levels and the dose should be carefully monitored. Conversely, enzyme inducers, e.g. carbamazepine, rifampicin, phenytoin, will decrease their plasma concentrations. 

Koley AP, Robinson RC, Markowitz A, et al. Drug-drug interactions effect of quinidine on nifedipine binding to human cytochrome-P450 3A4. Biochem Pharmacol 1997 53 455 160. 

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. 

Bork RW, Muto T, Beaune PH, et al. Characterization of mRNA species related to human liver cytochrome P-450 nifedipine oxidase and the regulation of catalytic activity. J Biol Chem 1989 264 910-919. 

Cytochrome P450 3A4 is highly expressed in the human small intestinal mucosa, and is responsible for the metabolism of cyclosporine, midazolam, clozapine and saquinavir during passage across the intestinal mucosa. Indeed, inhibition of presystemic metabolic processes is likely to be a factor in a 34% to 103% increase in the bioavailability of nifedipine observed in individuals consuming grapefruit juice. 

Shimada T, Guengerich FP. 1989. Evidence for cytochrome P-450NF, the nifedipine oxidase, being the principal enzyme involved in the bioactivation of afla-toxins in human liver. Proc. Natl. Acad. Sci. USA 86 462-65... 

Patki, K.C., von Moltke, L.L. and Greenblatt, D.J. (2003) In vitro metabolism of midazolam, triazolam, nifedipine, and testosterone by human liver microsomes and recombinant cytochromes P-450 role of CYP3A4 and CYP3A5. Drug Metabolism and Disposition The Biological Fate of Chemicals, 31, 938-944. 

FP Guengerich. Low isotope effects in the hydrogenation of l,4-dihydro-2,6-dimethyl-4-(2-nitrophenyl)-3,5-pyridinedicarboxylic acid dimethyl ester (nifedipine) by cytochrome P450 enzymes are consistent with an electron/pro-ton/electron transfer mechanism. Chem Res Toxicol 3 21—26, 1990. 

F.P. Guengerich, and T. Shimada (1996). Roles of cytochrome b5 in the oxidation of testosterone and nifedipine by recombinant cytochrome P450 3A4 and by human liver microsomes. Arch. Biochem. Biophys. 325, 174-182. 

R.S. Lloyd, and F.P. Guengerich (1986). Isolation and sequence determination of a cDNA clone related to human cytochrome P-450 nifedipine oxidase. Proc. Natl. Acad. Sci. USA 83, 8064-8068. 

A sampling of commonly used drugs with cytochrome P450-mediated metabolism inhibited by ketoconazole or other azoles includes chlordiazepoxide, cisapride, cyclosporine, didanosine, fluoxetine, loratadine, lovastatin, methadone, nifedipine, phenytoin, quinidine. theophylline, verapamil, warfarin, and zolpidem. 

The effects of tangeretin on cytochrome P450 activity were first reported in 1995 by Obermeier et al., who showed 7-ethoxyresorufin-O-deethylase (classified as CYP lA) and nifedipine oxidase (CYP 3A4) in human liver microsomes to be inhibited by tangeretin in a noncompetitive manner [65]. 

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