Effects of cytochrome P450 2E1 modulators on the pharmacokinetics of chlorzoxazone and 6-hydroxychlorzoxazone in rats.
A previously observed correlation between the rate of 6-hydroxylation of chlorzoxazone (CZX), a potent skeletal muscle relaxant, and cytochrome P450 2E1 activity in vitro led to the postulation that this drug may be used as a non-invasive probe for P450 2E1 activity in vivo. In this study, comparative pharmacokinetics of CZX and 6-hydroxychlorzoxazone (OH-CZX) were conducted in rats pretreated with an inhibitor or inducer of P450 2E1. After administration of CZX (150 mumol/kg, i.v.) to rats, blood samples were taken at different time points and the plasma concentrations of CZX and OH-CZX were determined by HPLC. The concentrations for CZX and OH-CZX over time were simultaneously fitted to a model of first-order elimination of CZX and first-order formation and elimination of OH-CZX using the computer program PCNONLIN to give pharmacokinetic parameters. Diallyl sulfide, a P450 2E1 inhibitor, at an oral dose of 50 or 200 mg/kg 12 hr prior to the CZX dose markedly inhibited the hydroxylation of CZX. Pretreatment with ethanol (15% in the drinking water for six days), a condition known to induce P450 2E1, slightly enhanced the formation of OH-CZX. To observe possible involvement of enzymes other than P450 2E1 in CZX metabolism, dexamethasone and phenobarbital were also used. Pretreatment with dexamethasone (50 mg/kg, i.p. daily for four days) did not cause changes in CZX and OH-CZX pharmacokinetics. Pretreatment with phenobarbital (75 mg/kg, i.p. daily for three days) enhanced CZX metabolism slightly. Our results suggest that P450 2E1 plays a major role in CZX hydroxylation in rats, but other factors may also be involved in the metabolism in vivo.
Chen
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Laboratory for Cancer Research, College of Pharmacy, Rutgers University, Piscataway, NJ 08855-0789, USA.
Yang
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CS
D000498:Allyl Compounds; D000818:Animals; D002753:Chlorzoxazone / Q000031:analogs & derivatives* / Q000378:metabolism / Q000493:pharmacokinetics*; D019392:Cytochrome P-450 CYP2E1; D065607:Cytochrome P-450 Enzyme Inhibitors; D003577:Cytochrome P-450 Enzyme System / Q000096:biosynthesis*; D003907:Dexamethasone / Q000494:pharmacology; D004790:Enzyme Induction / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology; D000431:Ethanol / Q000494:pharmacology; D006900:Hydroxylation; D008297:Male; D009125:Muscle Relaxants, Central / Q000493:pharmacokinetics*; D010089:Oxidoreductases, N-Demethylating / Q000037:antagonists & inhibitors* / Q000096:biosynthesis*; D010634:Phenobarbital / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D013440:Sulfides / Q000494:pharmacology
D000498:Allyl Compounds; D065607:Cytochrome P-450 Enzyme Inhibitors; D004791:Enzyme Inhibitors; D009125:Muscle Relaxants, Central; D013440:Sulfides; C039289:6-hydroxychlorzoxazone; D000431:Ethanol; C038491:allyl sulfide; D003907:Dexamethasone; D003577:Cytochrome P-450 Enzyme System; D019392:Cytochrome P-450 CYP2E1; D010089:Oxidoreductases, N-Demethylating; D002753:Chlorzoxazone; D010634:Phenobarbital