The mibefradil derivative NNC55-0396, a specific T-type calcium channel antagonist, exhibits less CYP3A4 inhibition than mibefradil.
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Bui PH, Quesada A, Handforth A, Hankinson O
The mibefradil derivative NNC55-0396, a specific T-type calcium channel antagonist, exhibits less CYP3A4 inhibition than mibefradil.
Drug Metab Dispos. 2008 Jul;36(7):1291-9. doi: 10.1124/dmd.107.020115. Epub 2008 Apr 14.
- PubMed ID
- 18411403 [ View in PubMed]
- Abstract
A novel mibefradil derivative, NNC55-0396, designed to be hydrolysis-resistant, was shown to be a selective T-type Ca(2+) channel inhibitor without L-type Ca(2+) channel efficacy. However, its effects on cytochromes P450 (P450s) have not previously been examined. We investigated the inhibitory effects of NNC55-0396 toward seven major recombinant human P450s--CYP3A4, CYP2D6, CYP1A2, CYP2C9, CYP2C8, CYPC19, and CYP2E1--and compared its effects with those of mibefradil and its hydrolyzed metabolite, Ro40-5966. Our results show that CYP3A4 and CYP2D6 are the two P450s most affected by mibefradil, Ro40-5966, and NNC55-0396. Mibefradil (IC(50) = 33 +/- 3 nM, K(i) = 23 +/- 0.5 nM) and Ro40-5966 (IC(50) = 30 +/- 7.8 nM, K(i) = 21 +/- 2.8 nM) have a 9- to 10-fold greater inhibitory activity toward recombinant CYP3A4 benzyloxy-4-trifluoromethylcoumarin-O-debenzylation activity than NNC55-0396 (IC(50) = 300 +/- 30 nM, K(i) = 210 +/- 6 nM). More dramatically, mibefradil (IC(50) = 566 +/- 71 nM, K(i) = 202 +/- 39 nM) shows 19-fold higher inhibition of CYP3A-associated testosterone 6beta-hydroxylase activity in human liver microsomes compared with NNC55-0396 (IC(50) = 11 +/- 1.1 microM, K(i) = 3.9 +/- 0.4 microM). Loss of testosterone 6beta-hydroxylase activity by recombinant CYP3A4 was shown to be time- and concentration-dependent with both compounds. However, NNC55-0396 (K(I) = 3.87 microM, K(inact) = 0.061/min) is a much less potent mechanism-based inhibitor than mibefradil (K(I) = 83 nM, K(inact) = 0.048/min). In contrast, NNC55-0396 (IC(50) = 29 +/- 1.2 nM, K(i) = 2.8 +/- 0.3 nM) and Ro40-5966 (IC(50) = 46 +/- 11 nM, K(i) = 4.5 +/- 0.02 nM) have a 3- to 4-fold greater inhibitory activity toward recombinant CYP2D6 than mibefradil (IC(50) = 129 +/- 21 nM, K(i) = 12.7 +/- 0.9 nM). Our results suggest that NNC55-0396 could be a more favorable T-type Ca(2+) antagonist than its parent compound, mibefradil, which was withdrawn from the market because of strong inhibition of CYP3A4.
DrugBank Data that Cites this Article
- Drug Enzymes
Drug Enzyme Kind Organism Pharmacological Action Actions Mibefradil Cytochrome P450 2D6 Protein Humans UnknownInhibitorDetails Mibefradil Cytochrome P450 3A4 Protein Humans UnknownSubstrateInhibitorDetails Mibefradil Cytochrome P450 3A5 Protein Humans UnknownInhibitorDetails Mibefradil Cytochrome P450 3A7 Protein Humans UnknownInhibitorDetails - Drug Transporters
Drug Transporter Kind Organism Pharmacological Action Actions Mibefradil P-glycoprotein 1 Protein Humans UnknownSubstrateInhibitorDetails