HEPATIC-UPTAKE, TRANSPORT AND METABOLISM OF ALKYLATED BILIRUBINS IN GUNN-RATS AND SPRAGUE-DAWLEY RATS

We studied the metabolism and biliary excretion of four novel analogs of bilirubin in homozygous Gunn rats and Sprague-Dawley rats. All four compounds closely resemble bilirubin in constitutional structure but two of them contain strategically-placed geminal dimethyl substituents . These substituents destabilize, by steric buttressing, preferred rid ge-tile conformational isomers and weaken intramolecular hydrogen bond ing. The two analogs which lack geminal dimethyl substitutents behaved like bilirubin itself-after intravenous administration they were meta bolized to monoglucuronides and diglucuronides in Sprague-Dawley rats and not excreted significantly in bile in Gunn rats. The corresponding gem-dimethyl compounds-which, counterintuitively, are much more polar than bilirubin-were, nevertheless, not excreted efficiently in bile G unn rats. But, surprisingly, in Sprague-Dawley rats they were each met abolized predominantly to a single glucuronide metabolite, apparently a monoglucuronide. Thus, apparently minor constitutional changes, prov oking subtle alterations of three-dimensional structure and hydrogen b onding, can have marked effects on the metabolism and hepatic processi ng of bilirubins in vivo.