Exposure of rats to inhalational anesthetics alters the hepatobiliary clearance of cholephilic xenobiotics.
Several recent studies indicate that anesthesia-induced alteration of UDP-glucuronic acid concentrations can affect the rate of xenobiotic glucuronidation by UDP-glucuronosyltransferases. Other data demonstrate that the biliary excretion of several cholephilic drugs is depressed in rats anesthetized with diethyl ether. The present study has examined the effect of 2% halothane, 1.5% isoflurane, 2% enflurane and 3% sevoflurane on the clearance and biliary excretion of acetaminophen, digoxin, phenol red and phenol-3,6-dibromphthalein disulfonate. All volatile anesthetics reduced hepatic UDP-glucuronic acid concentrations 50 to 75%. Biliary excretion of acetaminophen as well as the glucuronide and sulfate conjugates was depressed by all anesthetics for about 1 hr, whereas biliary excretion of the glutathione conjugate was increased during this time. Although total clearance, elimination half-life and steady-state volume of distribution were not altered, biliary clearance of acetaminophen was decreased by 39 to 50%. Formation of the glucuronide conjugate of phenol red and its biliary excretion were depressed by all volatile anesthetics; however, total clearance was increased by 15 to 25% during isoflurane or sevoflurane anesthesia. Total clearance and steady-state volume of distribution of digoxin were decreased only in rats exposed to halothane. There were no changes in biliary excretion. Urinary clearance of digoxin was increased by all volatile anesthetics, whereas biliary clearance was decreased by halothane and enflurane. Biliary excretion, clearance and volume of distribution of phenol-3,6-dibromphthalein disulfonate were not altered by the anesthetics. These data indicate that the hepatobiliary elimination of the glucuronidated metabolites is reduced in rats exposed to volatile anesthetics.
Watkins
J B
JB
Pharmacology Section, Indiana University School of Medicine, Bloomington.
D000082:Acetaminophen / Q000378:metabolism; D000280:Administration, Inhalation; D000777:Anesthetics / Q000494:pharmacology*; D000818:Animals; D001646:Bile / Q000378:metabolism*; D004077:Digoxin / Q000378:metabolism; D005965:Glucuronates / Q000378:metabolism*; D008099:Liver / Q000378:metabolism*; D008297:Male; D008657:Metabolic Clearance Rate / Q000187:drug effects; D011485:Protein Binding; D051381:Rats; D011919:Rats, Inbred Strains
D000777:Anesthetics; D005965:Glucuronates; D000082:Acetaminophen; D004077:Digoxin