Drug metabolizing capacity in vitro and in vivo--I. Correlations between hepatic microsomal monooxygenase markers in beta-naphthoflavone-induced rats.
Relationships between and within in vivo and in vitro markers of drug oxidative metabolism have been investigated in rats displaying a wide range of hepatic microsomal monooxygenase activity due to prior treatment with various doses of the inducing agent beta-naphthoflavone (BNF). BNF induction produced large dose-related changes in the in vivo clearance (CL) of theophylline (TH), antipyrine (AP) and the individual AP metabolite formation clearances, 4-hydroxyantipyrine (4H) and norantipyrine, and the in vitro parameters, 7-ethoxycoumarin O-deethylase, 7-ethoxyresorufin and P450. No trends were observed with the formation clearance of 3-hydroxymethylantipyrine and 7-methoxycoumarin O-demethylase whilst a negative response was observed with aldrin epoxidase. The selectivity of the markers towards BNF induction was coincident with the degree of covariance observed between these parameters. Strong correlations were observed in particular between CL(TH) and CL(4H) and ECOD and EROD indicating the high predictive value of these parameters. These studies demonstrate that under the well controlled conditions which may be imposed in animal environments predictively useful relationships (r2 greater than 0.8) can be established between in vitro and in vivo markers of hepatic microsomal monooxygenase activity.
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; D001571:Benzoflavones / Q000494:pharmacology*; D019363:Cytochrome P-450 CYP1A1; D003577:Cytochrome P-450 Enzyme System / Q000032:analysis; D004790:Enzyme Induction; D005419:Flavonoids / Q000494:pharmacology*; D066298:In Vitro Techniques; D008297:Male; D008862:Microsomes, Liver / Q000201:enzymology*; D010088:Oxidoreductases / Q000032:analysis; D051381:Rats; D011919:Rats, Inbred Strains; D013806:Theophylline / Q000493:pharmacokinetics; D019324:beta-Naphthoflavone
D001571:Benzoflavones; D005419:Flavonoids; D019324:beta-Naphthoflavone; D003577:Cytochrome P-450 Enzyme System; D013806:Theophylline; D010088:Oxidoreductases; D015660:7-Alkoxycoumarin O-Dealkylase; D019363:Cytochrome P-450 CYP1A1; D000983:Antipyrine