title: Contrasting effect of isoflurane on drug metabolism: decreased type I and increased type II substrate metabolism in guinea pig liver microsomes.
abstract: Inhalation anaesthetics might affect perioperative drug elimination by altering drug distribution, hepatic blood flow or drug metabolism. The in vitro effects of isoflurane on aniline hydroxylation and aminopyrine N-demethylation were investigated with guinea pig liver microsomes to assess the role of isoflurane on oxidative drug metabolism through the hepatic mixed-function oxidase system. p-Aminophenol and formaldehyde were measured spectrophotometrically as metabolic products of aniline hydroxylation and aminopyrine N-demethylation, respectively, where the reaction mixture consisted of a microsomal suspension, NADPH, aminopyrine or aniline, with or without isoflurane. The rate of cytochrome P-450 reduction by NADPH affected in the presence of isoflurane was investigated by spectrometric measurement of the CO-cytochrome P-450 complex formation at various times. Due to the addition of isoflurane, the Vmax values for aniline hydroxylation evidently increased except in high isoflurane concentration (3.33 mM) and for aminopyrine N-demethylation the value was significantly low only in the presence of a high isoflurane concentration, whereas the K(m) values significantly decreased in aniline hydroxylation and increased in aminopyrine N-demethylation, and isoflurane also accelerated the rate of cytochrome P-450 reduction by NADPH. These results reflect the inhibition of aminopyrine N-demethylation and activation of aniline hydroxylation in the presence of isoflurane as a consequence of isoflurane-accelerated cytochrome P-450 reduction by NADPH and/or drug-enzyme binding properties, and may have implications on the metabolism of perioperatively administered drugs during isoflurane anaesthesia.
authors.affiliation: Department of Anesthesiology and Critical Care Medicine, Hiroshima University School of Medicine, Japan.
authors.forename: M M
authors.initials: MM
authors.lastname: Rahman
authors.forename: K
authors.initials: K
authors.lastname: Fujii
authors.forename: M
authors.initials: M
authors.lastname: Kawamoto
authors.forename: O
authors.initials: O
authors.lastname: Yuge
mesh_terms: D000633:Aminopyrine N-Demethylase / Q000378:metabolism; D018685:Anesthetics, Inhalation / Q000494:pharmacology; D000815:Aniline Hydroxylase / Q000378:metabolism; D000818:Animals; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D006168:Guinea Pigs; D007530:Isoflurane / Q000494:pharmacology*; D008297:Male; D008862:Microsomes, Liver / Q000187:drug effects* / Q000378:metabolism; D013997:Time Factors
chemical_list: D018685:Anesthetics, Inhalation; D003577:Cytochrome P-450 Enzyme System; D007530:Isoflurane; D000815:Aniline Hydroxylase; D000633:Aminopyrine N-Demethylase