Metabolic interactions between mibefradil and HMG-CoA reductase inhibitors: an in vitro investigation with human liver preparations.
OBJECTIVE
To determine the effects of mibefradil on the nletabolism in human liver microsomal preparations of the HMG-CoA reductase inhibitors simvastatin, lovastatin, atorvastatin, cerivastatin and fluvastatin.


METHODS
Metabolism of the above five statins (0.5, 5 or 10 microM), as well as of specific CYP3A4/5 and CYP2C8/9 marker substrates, was examined in human liver microsomal preparations in the presence and absence of mibefradil (0.1-50 microM).


RESULTS
Mibefradil inhibited, in a concentration-dependent fashion, the metabolism of the four statins (simvastatin, lovastatin, atorvastatin and cerivastatin) known to be substrates for CYP3A. The potency of inhibition was such that the IC50 values (<1 microM) for inhibition of all of the CYP3A substrates fell within the therapeutic plasma concentrations of mibefradil, and was comparable with that of ketoconazole. However, the inhibition by mibefradil, unlike that of ketoconazole, was at least in part mechanism-based. Based on the kinetics of its inhibition of hepatic testosterone 6beta-hydroxylase activity, mibefradil was judged to be a powerful mechanism-based inhibitor of CYP3A4/5, with values for Kinactivation, Ki and partition ratio (moles of mibefradil metabolized per moles of enzyme inactivated) of 0.4 min(-1), 2.3 microM and 1.7, respectively. In contrast to the results with substrates of CYP3A, metabolism of fluvastatin, a substrate of CYP2C8/9, and the hydroxylation of tolbutamide, a functional probe for CYP2C8/9, were not inhibited by mibefradil.


CONCLUSIONS
Mibefradil, at therapeutically relevant concentrations, strongly suppressed the metabolism in human liver microsomes of simvastatin, lovastatin, atorvastatin and cerivastatin through its inhibitory effects on CYP3A4/5, while the effects of mibefradil on fluvastatin, a substrate for CYP2C8/9, were minimal in this system. Since mibefradil is a potent mechanism-based inhibitor of CYP3A4/5, it is anticipated that clinically significant drug-drug interactions will likely ensue when mibefradil is coadministered with agents which are cleared primarily by CYP3A-mediated pathways.
Prueksaritanont
T
T
Department of Drug Metabolism, Merck Research Laboratories, West Point, Pennsylvania 19486, USA.
Ma
B
B
Tang
C
C
Meng
Y
Y
Assang
C
C
Lu
P
P
Reider
P J
PJ
Lin
J H
JH
Baillie
T A
TA
D001189:Aryl Hydrocarbon Hydroxylases; D000069059:Atorvastatin; D001562:Benzimidazoles / Q000378:metabolism / Q000494:pharmacology*; D051544:Cytochrome P-450 CYP3A; D065607:Cytochrome P-450 Enzyme Inhibitors; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D005229:Fatty Acids, Monounsaturated / Q000378:metabolism / Q000494:pharmacology; D000077340:Fluvastatin; D006538:Heptanoic Acids / Q000378:metabolism / Q000494:pharmacology; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000378:metabolism / Q000494:pharmacology*; D007211:Indoles / Q000378:metabolism / Q000494:pharmacology; D007654:Ketoconazole / Q000494:pharmacology; D007700:Kinetics; D008148:Lovastatin / Q000378:metabolism / Q000494:pharmacology; D020748:Mibefradil; D008862:Microsomes, Liver / Q000187:drug effects / Q000378:metabolism; D010089:Oxidoreductases, N-Demethylating / Q000037:antagonists & inhibitors / Q000378:metabolism; D011725:Pyridines / Q000378:metabolism / Q000494:pharmacology; D011758:Pyrroles / Q000378:metabolism / Q000494:pharmacology; D019821:Simvastatin / Q000378:metabolism / Q000494:pharmacology; D013764:Tetrahydronaphthalenes / Q000378:metabolism / Q000494:pharmacology*
D001562:Benzimidazoles; D065607:Cytochrome P-450 Enzyme Inhibitors; D005229:Fatty Acids, Monounsaturated; D006538:Heptanoic Acids; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D007211:Indoles; D011725:Pyridines; D011758:Pyrroles; D013764:Tetrahydronaphthalenes; D020748:Mibefradil; D000077340:Fluvastatin; D003577:Cytochrome P-450 Enzyme System; D008148:Lovastatin; D000069059:Atorvastatin; D019821:Simvastatin; C086276:cerivastatin; D001189:Aryl Hydrocarbon Hydroxylases; D051544:Cytochrome P-450 CYP3A; D010089:Oxidoreductases, N-Demethylating; D007654:Ketoconazole