Drug interactions with calcium channel blockers: possible involvement of metabolite-intermediate complexation with CYP3A.
Article Details
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Ma B, Prueksaritanont T, Lin JH
Drug interactions with calcium channel blockers: possible involvement of metabolite-intermediate complexation with CYP3A.
Drug Metab Dispos. 2000 Feb;28(2):125-30.
- PubMed ID
- 10640508 [ View in PubMed]
- Abstract
The inhibitory effects of six commonly used calcium channel blockers on three major cytochrome P-450 activities were examined and characterized in human liver microsomes. All six compounds reversibly inhibited CYP2D6 (bufuralol 1'-hydroxylation) and CYP2C9 (tolbutamide methyl hydroxylation) activities. The IC(50) values for the inhibition of CYP2D6 and CYP2C9 for nicardipine were 3 to 9 microM, whereas those for all others ranged from 14 to >150 microM. Except for nifedipine, all calcium channel blockers showed increased inhibitory potency toward CYP3A activities (testosterone 6beta-hydroxylation and midazolam 1'-hydroxylation) after 30-min preincubation with NADPH. IC(50) values for the inhibition of testosterone 6beta-hydroxylase obtained in the NADPH-preincubation experiment for nicardipine (1 microM), verapamil (2 microM), and diltiazem (5 microM) were within 10-fold, whereas those for amlodipine (5 microM) and felodipine (13 microM) were >200-fold of their respective plasma concentrations reported after therapeutic doses. Similar results also were obtained based on midazolam 1'-hydroxylase activity. Unlike the observations with mibefradil, a potent irreversible inhibitor of CYP3A, the NADPH-dependent inhibition of CYP3A activity by nicardipine and verapamil was completely reversible on dialysis, whereas that by diltiazem was partially restored (80%). Additional experiments revealed that nicardipine, verapamil, and diltiazem formed cytochrome P-450-iron (II)-metabolite complex in both human liver microsomes and recombinant CYP3A4. Nicardipine yielded a higher extent of complex formation ( approximately 30% at 100 microM), and was a much faster-acting inhibitor (maximal inhibition rate constant approximately 2 min(-1)) as compared with verapamil and diltiazem. These present findings that the CYP3A inhibition caused by nicardipine, verapamil, and diltiazem is, at least in part, quasi-irreversible provide a rational basis for pharmacokinetically significant interactions reported when they were coadministered with agents that are cleared primarily by CYP3A-mediated pathways.
DrugBank Data that Cites this Article
- Drug Enzymes
Drug Enzyme Kind Organism Pharmacological Action Actions Amlodipine Cytochrome P450 2D6 Protein Humans UnknownInhibitorDetails Felodipine Cytochrome P450 2C9 Protein Humans UnknownInhibitorDetails Felodipine Cytochrome P450 2D6 Protein Humans UnknownInhibitorDetails Nifedipine Cytochrome P450 2C9 Protein Humans UnknownInhibitorInducerDetails Nifedipine Cytochrome P450 2D6 Protein Humans UnknownInhibitorDetails - Drug Interactions
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