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 ridge-tile conformational isomers and weaken intramolecular hydrogen bonding. The two analogs which lack geminal dimethyl substituents behaved like bilirubin itself--after intravenous administration they were metabolized to monoglucuronides and diglucuronides in Sprague-Dawley rats and not excreted significantly in bile in Gunn rats. The corresponding gem-dimethyl compounds--which, counter-intuitively, are much more polar than bilirubin--were, nevertheless, not excreted efficiently in bile Gunn rats. But, surprisingly, in Sprague-Dawley rats they were each metabolized predominantly to a single glucuronide metabolite, apparently a monoglucuronide. Thus, apparently minor constitutional changes, provoking subtle alterations of three-dimensional structure and hydrogen bonding, can have marked effects on the metabolism and hepatic processing of bilirubins in vivo.