Depletion of hepatic uridine diphosphoglucuronic acid decreases the biliary excretion of drugs.
Hepatic levels of uridine diphosphoglucuronic acid (UDPGA) in rats decreased substantially (greater than 80%) 40 min after galactosamine (GAL) (600 mg/kg i.p.) or after 1 hr of diethyl ether (DE) narcosis. Biliary excretion of several cholephils requiring glucuronidation before excretion was reduced by GAL 76, 62, 92, 90 and 97% for bilirubin, diethylstilbestrol, iopanoic acid, phenolphthalein and valproic acid, respectively. GAL treatment caused delayed plasma clearances of the parent compounds and reductions in plasma concentrations and biliary excretions of glucuronide conjugates. The degree of this reduction was related to the maximal excretion rate of the individual compounds. For phenolphthalein glucuronide and phenol-3,6-dibromphthalein disulfonate, which do not undergo conjugation, GAL had no effect on their biliary excretion. DE-induced UDPGA depletion had no effect on phenolphthalein glucuronide excretion but reduced that of phenol-3,6-dibromphthalein disulfonate 25%. DE did not affect the plasma elimination or biliary secretion of phenolphthalein. Of the other cholephils requiring conjugation, DE reduced the excretion of bilirubin, diethylstilbestrol, iopanoic acid and valproic acid by 41, 29, 76 and 28%, respectively. DE decreased the plasma elimination of the parent compounds and the appearance of the conjugates in both plasma and bile. Reduction of glucuronide excretion into bile was less pronounced at higher doses of the cholephilic anions. Neither treatment reduced in vitro hepatic UDP-glucuronosyltransferase activity toward these substrates or substantially altered extrahepatic UDPGA concentrations. Thus, both GAL and DE decreased UDPGA to similar concentrations, but the biliary excretion of compounds requiring glucuronidation before secretion was depressed to a greater extent by GAL.
D000818:Animals; D001646:Bile / Q000502:physiology; D004986:Ether / Q000008:administration & dosage*; D005019:Ethyl Ethers / Q000008:administration & dosage*; D005260:Female; D005688:Galactosamine / Q000008:administration & dosage*; D014453:Glucuronosyltransferase / Q000378:metabolism; D008099:Liver / Q000378:metabolism*; D010635:Phenolphthaleins / Q000378:metabolism; D051381:Rats; D011919:Rats, Inbred Strains; D013448:Sulfobromophthalein / Q000031:analogs & derivatives / Q000378:metabolism; D014535:Uridine Diphosphate Glucuronic Acid / Q000378:metabolism*; D014539:Uridine Diphosphate Sugars / Q000378:metabolism*; D014635:Valproic Acid / Q000378:metabolism
D005019:Ethyl Ethers; D010635:Phenolphthaleins; D014539:Uridine Diphosphate Sugars; D013448:Sulfobromophthalein; D004986:Ether; C016651:phenolphthalein glucuronide; C012479:dibromosulphthalein; D014535:Uridine Diphosphate Glucuronic Acid; D014635:Valproic Acid; D005688:Galactosamine; D014453:Glucuronosyltransferase