Drug metabolizing capacity in vitro and in vivo--II. Correlations between hepatic microsomal monooxygenase markers in phenobarbital-induced rats.
Pretreatment with various doses of phenobarbital (PB) has been used to create a pool of rats with a wide range of hepatic microsomal monooxygenase activity to systematically examine relationships between and within in vivo and in vitro markers. The in vivo clearance of tolbutamide (TOL), theophylline (TH), antipyrine (AP) and its metabolites were determined in the same rats used for hepatic microsome preparation and assessment of P450 content and activities (via 7-ethoxycoumarin O-deethylase (ECOD), 7 ethoxyresorufin O-deethylase, 7-methoxycoumarin O-demethylase (MCOD) and aldrin epoxidase determinations). A graded dose-response relationship was found between PB treatment and most but not all parameters. The need for careful selection of in vivo and as well as in vitro markers is apparent from these studies. The most responsive parameters--TOL and AP clearances, MCOD and ECOD activities--were also those producing the strongest in vivo-in vitro correlations. Despite the diffuse nature of the PB induced response in P450 complement, good predictive relationships were apparent between ECOD and TOL clearance (r2 = 0.88).
Matthew
D E
DE
Department of Pharmacy, University of Manchester, U.K.
Houston
J B
JB
D015660:7-Alkoxycoumarin O-Dealkylase / Q000032:analysis; D000818:Animals; D000983:Antipyrine / Q000493:pharmacokinetics; D019363:Cytochrome P-450 CYP1A1; D003577:Cytochrome P-450 Enzyme System / Q000032:analysis; D004790:Enzyme Induction; D066298:In Vitro Techniques; D008297:Male; D008862:Microsomes, Liver / Q000201:enzymology*; D010088:Oxidoreductases / Q000032:analysis; D010634:Phenobarbital / Q000494:pharmacology*; D051381:Rats; D011919:Rats, Inbred Strains; D013806:Theophylline / Q000493:pharmacokinetics; D014044:Tolbutamide / Q000493:pharmacokinetics
D003577:Cytochrome P-450 Enzyme System; D014044:Tolbutamide; D013806:Theophylline; D010088:Oxidoreductases; D015660:7-Alkoxycoumarin O-Dealkylase; D019363:Cytochrome P-450 CYP1A1; D000983:Antipyrine; D010634:Phenobarbital