RT Journal Article SR Electronic T1 Slipping Past UGT1A1 and Multidrug Resistance-Associated Protein 2 in the Liver: Effects of Steric Compression and Hydrogen Bonding on the Hepatobiliary Elimination of Synthetic Bilirubins JF Drug Metabolism and Disposition JO Drug Metab Dispos FD American Society for Pharmacology and Experimental Therapeutics SP 930 OP 936 DO 10.1124/dmd.107.019778 VO 36 IS 5 A1 Antony F. McDonagh A1 Stefan E. Boiadjiev A1 David A. Lightner YR 2008 UL http://dmd.aspetjournals.org/content/36/5/930.abstract AB The hepatobiliary metabolism and excretion of three isomeric bilirubin analogs with propanoic replaced by benzoic acid side-chains were studied in the rat. Despite their isomeric relationship and similar constitutions, the three analogs were metabolized quite differently from each other and from bilirubin. In the di-o-benzoic compound, steric hindrance involving the phenyl groups reinforces intramolecular hydrogen bonding of the two carboxyl groups. This compound is considerably less polar than bilirubin on reverse-phase high-performance liquid chromatography and, like bilirubin, was not excreted in bile in UGT1-deficient (Gunn) rats. But, quite unlike bilirubin, it was not glucuronidated or excreted in bile in normal rats. In contrast to both bilirubin and the di-o-benzoic isomer, the more polar m- and p-isomers, in which intramolecular hydrogen bonding of carboxyl groups is sterically difficult, were excreted rapidly in bile in unchanged form in both normal and Gunn rats. However, only one of them, the di-m-isomer, was excreted rapidly and unchanged in bile in rats (TR- rats) congenitally deficient in the canalicular ATP-binding cassette transporter Mrp2. The marked differences in hepatobiliary metabolism of the three isomers studied can be rationalized on the basis of their computed three-dimensional structures and minimum-energy conformations and the remote effects of steric compression on intramolecular hydrogen bonding. The American Society for Pharmacology and Experimental Therapeutics