Gemfibrozil inhibits CYP2C8-mediated cerivastatin metabolism in human liver microsomes.
نویسندگان
چکیده
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) (IC(50)) value of 69 (95) micro M, whereas inhibition of M-1 formation was weaker with a K(i) (IC(50)) value of 273 (>250) micro M. 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 (IC(50) = 68 micro M) and M-1 (IC(50) = 78 micro M) in recombinant CYP2C8 but not in recombinant CYP3A4. Additionally, gemfibrozil inhibited paclitaxel 6 alpha-hydroxylation [K(i) (IC(50)) = 75 micro M (91 micro M)], a CYP2C8 marker reaction, but did not inhibit testosterone 6 beta-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.
منابع مشابه
Glucuronidation converts gemfibrozil to a potent, metabolism-dependent inhibitor of CYP2C8: implications for drug-drug interactions.
Gemfibrozil more potently inhibits CYP2C9 than CYP2C8 in vitro, and yet the opposite inhibitory potency is observed in the clinic. To investigate this apparent paradox, we evaluated both gemfibrozil and its major metabolite, an acyl-glucuronide (gemfibrozil 1-O-beta-glucuronide) as direct-acting and metabolism-dependent inhibitors of the major drug-metabolizing cytochrome P450 enzymes (CYP1A2, ...
متن کاملAccelerated Communication GLUCURONIDATION CONVERTS GEMFIBROZIL TO A POTENT, METABOLISM- DEPENDENT INHIBITOR OF CYP2C8: IMPLICATIONS FOR DRUG-DRUG INTERACTIONS
Gemfibrozil more potently inhibits CYP2C9 than CYP2C8 in vitro, and yet the opposite inhibitory potency is observed in the clinic. To investigate this apparent paradox, we evaluated both gemfibrozil and its major metabolite, an acyl-glucuronide (gemfibrozil 1-Oglucuronide) as direct-acting and metabolism-dependent inhibitors of the major drug-metabolizing cytochrome P450 enzymes (CYP1A2, 2B6, 2...
متن کاملShort Communication CYTOCHROME P450 2C8 (CYP2C8)-MEDIATED HYDROXYLATION OF AN ENDOTHELIN ETA RECEPTOR ANTAGONIST IN HUMAN LIVER MICROSOMES
In vitro studies were performed to identify the human cytochrome P450 enzyme(s) involved in the hydroxylation (isopropyl moiety) of a previously reported endothelin ETA receptor antagonist, compound A [( )-(5S,6R,7R)-2-isopropylamino-7-{4-methoxy-2-[(2R)3-methoxy-2-methylpropyl]}-5-(3,4-methylenedioxyphenyl)cyclopenteno(1,2-b) pyridine 6-carboxylic acid]. Several lines of evidence indicated tha...
متن کاملShort Communication CYTOCHROME P450 2C8 (CYP2C8)-MEDIATED HYDROXYLATION OF AN ENDOTHELIN ETA RECEPTOR ANTAGONIST IN HUMAN LIVER MICROSOMES
In vitro studies were performed to identify the human cytochrome P450 enzyme(s) involved in the hydroxylation (isopropyl moiety) of a previously reported endothelin ETA receptor antagonist, compound A [( )-(5S,6R,7R)-2-isopropylamino-7-{4-methoxy-2-[(2R)3-methoxy-2-methylpropyl]}-5-(3,4-methylenedioxyphenyl)cyclopenteno(1,2-b) pyridine 6-carboxylic acid]. Several lines of evidence indicated tha...
متن کاملذخیره در منابع من
با ذخیره ی این منبع در منابع من، دسترسی به آن را برای استفاده های بعدی آسان تر کنید
برای دانلود متن کامل این مقاله و بیش از 32 میلیون مقاله دیگر ابتدا ثبت نام کنید
ثبت ناماگر عضو سایت هستید لطفا وارد حساب کاربری خود شوید
ورودعنوان ژورنال:
- Drug metabolism and disposition: the biological fate of chemicals
دوره 30 12 شماره
صفحات -
تاریخ انتشار 2002