Equally potent inhibitors of cholesterol synthesis in human hepatocytes have distinguishable effects on different cytochrome P450 enzymes

Six 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors (t he present cholesterol-lowering drugs known as statins), lovastatin (L), si mvastatin (S), pravastatin (P), fluvastatin (F), atorvastatin (A) and ceriv astatin (C) are shown to be potent inhibitors of cholesterol synthesis in h uman hepatocytes, the target tissue for these drugs in man, All six inhibit ed in the nM range (IC50 values: 0.2-8.0 nM). As daily used cholesterol-low ering drugs they are likely coadministered with other drugs. While several cytochrome P450 (CYP) enzymes are involved in drug metabolism in the liver and thus play an important role in drug-drug interaction it was investigate d which of these enzymes are influenced by the active forms of the six stat ins. These enzyme activities were studied in human liver microsomal prepara tions, and in simian and human hepatocytes in primary culture. The followin g CYP reactions were used: nifedipine aromatization (CYP3A4), testosterone 6 beta -hydroxylation (CYP3A4), tolbutamide methylhydroxylation (CYP2C9), S -mephenytoin 4-hydroxylation (CYP2C19), bufuralol 1 ' -hydroxylation (CYP2D 6), aniline 4-hydroxylation (CYP2E1), coumarin 7-hydroxylation (CYP2A6) and 7-ethoxyresorufin O-dealkylation (CYP1A1/2). In the human liver microsomes the statins (concentrations up to 400 muM) did not influence the CYP1A1/2 activity and hardly the CYP2A6 and CYP2E1 activities. Except P, the other f ive statins were stronger inhibitors of the CYP2C19 activity with IC50 valu es around 200 muM and the same holds for the effect of A, C and F on the CY P2D6 activity. L and S were weaker inhibitors of the latter enzyme activity , whereas P did not influence both activities. About the same was observed for the statin effect on CYP2C9 activity, except that F was a strong inhibi tor of this activity (IC50 value: 4 muM). Using the assay of testosterone 6 beta -hydroxylation the CYP3A4 activity was decreased by L, S and F with I C50 values of about 200 muM and a little more by C and A (IC50 around 100 M ). P had hardly an effect on this activity, To a somewhat less extent the s ame trend was seen when CYP3A4 activity was measured using nifedipine as su bstrate. The inhibitory effects observed in microsomes were verified in sus pension culture of freshly isolated hepatocytes from Cynomolgus monkey (as a readily available model) and of human hepatocytes. In general the same tr ends were seen as in the human microsomes, except that in some cases the in hibition of the CYP activity was less, possibly by the induction of the par ticular CYP enzyme by incubation of the cells with a particular statin. F r emained a strong inhibitor of CYP2C9 activity in human and monkey hepatocyt es. A induced the CYP2C9 in monkey hepatocytes but was an inhibitor of the CYP2C9 in human hepatocytes. A, S, L and C were moderate inhibitors in both cellular systems of CYP3A4. P was not affecting any of the CYP activities in the three systems studied. It is concluded that different CYP enzymes in teract with different statins and therefore differences in between these dr ugs are to be expected when drug-drug interaction is considered. Copyright (C) 2000 John Wiley & Sons, Ltd.