Contrasting effect of isoflurane on drug metabolism: decreased type I and increased type II substrate metabolism in guinea pig liver microsomes.
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.
Rahman
M M
MM
Department of Anesthesiology and Critical Care Medicine, Hiroshima University School of Medicine, Japan.
Fujii
K
K
Kawamoto
M
M
Yuge
O
O
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
D018685:Anesthetics, Inhalation; D003577:Cytochrome P-450 Enzyme System; D007530:Isoflurane; D000815:Aniline Hydroxylase; D000633:Aminopyrine N-Demethylase