Gemfibrozil inhibits CYP2C8-mediated cerivastatin metabolism in human liver microsomes

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 K-i (IC50) value of 69 (95) muM, whereas inhibition of M-1 formation was weaker with a K-i (IC50) value of 273 (>250) muM. 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 muM) and M-1 ( IC50 = 78 muM) in recombinant CYP2C8 but not in recombinant CYP3A4. Additionally, gemfibrozil inhibited paclitaxel 6alpha-hydroxylation [K-i (IC50) = 75 muM (91 muM)], a CYP2C8 marker reaction, but did not inhibit testosterone 6beta-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. value of 273 (>250) muM. 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 muM) and M-1 (IC50 = 78 muM) in recombinant CYP2C8 but not in recombinant CYP3A4. Additionally, gemfibrozil inhibited paclitaxel 6alpha-hydroxylation [K-i (IC50) = 75 muM (91 muM)], a CYP2C8 marker reaction, but did not inhibit testosterone 6beta-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.