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Vol. 30, Issue 12, 1352-1356, December 2002
Department of Clinical Pharmacology, University of Helsinki and
Helsinki University Central Hospital, Helsinki, Finland
To explore the mechanism of the interaction between gemfibrozil and
cerivastatin, the enzyme mapping of the oxidative metabolism of
cerivastatin and the effect of gemfibrozil on cerivastatin metabolism
were studied using human liver microsomes and expressed cytochrome P450
(P450) CYP2C8 and 3A4 isoforms. Based on studies with
isoform-selective chemical inhibitors and expressed enzymes, CYP2C8 and
CYP3A4 were equally important in the formation of desmethylcerivastatin (M-1), whereas the formation of the quantitatively most important hydroxy metabolite (M-23) was predominantly mediated via CYP2C8; other
P450 isoforms played a negligible role. In human liver microsomes, gemfibrozil markedly inhibited M-23 formation, with a
Ki (IC50) value of 69 (95) µM,
whereas inhibition of M-1 formation was weaker with a
Ki (IC50) value of 273 (>250)
µM. The inhibitory effect of gemfibrozil was attributable to
inhibition of CYP2C8 rather than CYP3A4, as evidenced by potent
inhibition of the formation of M-23 (IC50 = 68 µM)
and M-1 (IC50 = 78 µM) in recombinant CYP2C8 but not
in recombinant CYP3A4. Additionally, gemfibrozil inhibited paclitaxel
6
-hydroxylation [Ki
(IC50) = 75 µM (91 µM)], a CYP2C8 marker
reaction, but did not inhibit testosterone 6
-hydroxylation (CYP3A4).
The present in vitro findings suggest that inhibition of CYP2C8
activity by gemfibrozil at least partially explains the interaction
between gemfibrozil and cerivastatin. The formation of M-23 acid from
cerivastatin is mediated mainly by CYP2C8 and thus may be a suitable
CYP2C8 probe reaction. Inhibition of CYP2C8-mediated metabolism by
gemfibrozil warrants further in vivo exploration.
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