TY - JOUR
T1 - Metabolic interactions between mibefradil and HMG-CoA reductase inhibitors
T2 - an in vitro investigation with human liver preperations
AU - Prueksaritanont, Thomayant
AU - Ma, Bennett
AU - Tang, Cuyue
AU - Meng, Yuan
AU - Assang, Carol
AU - Lu, Ping
AU - Reider, Paul J.
AU - Lin, Jiunn H.
AU - Baillie, Thomas A.
PY - 1999
Y1 - 1999
N2 - Aims. To determine the effects of mibefradil on the metabolism in human liver microsomal preparations of the HMG-CoA reductase inhibitors simvastatin, lovastatin, atorvastatin, cerivastatin and fluvastatin. Methods. Metabolism of the above five strains (0.5, 5 or 10 μM), as well as of specific CYP3A4/5 and CYP2C8/9 marker substrates, was examined in human liver microsomal preparations in the presence and abscence of mibefradil (0.1-50 μM). 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 μM) 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 6β-hydroxylase activity, mibefradil was judged to be a powerful mechanism-based inhibitor of CYP3A4/5, with values for K(inactivation), K(i) and partition ratio (moles of mibefradil metabolized per moles of enzyme inactivated) of 0.4 min-1, 2.3 μM 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.
AB - Aims. To determine the effects of mibefradil on the metabolism in human liver microsomal preparations of the HMG-CoA reductase inhibitors simvastatin, lovastatin, atorvastatin, cerivastatin and fluvastatin. Methods. Metabolism of the above five strains (0.5, 5 or 10 μM), as well as of specific CYP3A4/5 and CYP2C8/9 marker substrates, was examined in human liver microsomal preparations in the presence and abscence of mibefradil (0.1-50 μM). 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 μM) 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 6β-hydroxylase activity, mibefradil was judged to be a powerful mechanism-based inhibitor of CYP3A4/5, with values for K(inactivation), K(i) and partition ratio (moles of mibefradil metabolized per moles of enzyme inactivated) of 0.4 min-1, 2.3 μM 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.
KW - CYP3A
KW - Drug interactions
KW - HMG-CoA reductase inhibitor
KW - In vitro metabolism
KW - Mibefradil
KW - Statins
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U2 - 10.1046/j.1365-2125.1999.00903.x
DO - 10.1046/j.1365-2125.1999.00903.x
M3 - Article
C2 - 10215754
AN - SCOPUS:0033026601
SN - 0306-5251
VL - 47
SP - 291
EP - 298
JO - British Journal of Clinical Pharmacology
JF - British Journal of Clinical Pharmacology
IS - 3
ER -