Synthesis of a New Lipophilic Bilirubin. Conformation, Transhepatic Transport and Glucuronidation

Analogs of symmetrical bilirubin isomers with vinyl groups replaced by n-butyls (1 and 2) were synthesized and found to be much more soluble in nonpolar solvents than either bilirubin itself or its analogs with ethyls in place of vinyls (3 and 4). The increased lipophilicity of 1 and 2 allowed, for the first time, vapor pressure osmometric molecular wt. determinations of a bilirubin acid, showing in CHCl3 solvent: MWobs=632±10 for 1, and 637±10 for 2 (both formula weight 644)—data that clearly indicate monomers and no dimers. The induced circular dichroism (ICD) spectra of 1 and 2, with negative exciton chirality Cotton effects, are quite like those of 3 and 4 in chloroform containing quinine, but the ICDs in aqueous buffer containing human serum albumin differ considerably. Rubins 1, 3 and 4 exhibit dissimilar but positive exciton chirality Cotton effects, while 2 shows a negative exciton chirality Cotton effect. The metabolism of the n-butyl rubins in the rat is highly dependent on the specific endo or exo location of the n-butyl groups. Rubin 2, with two endo n-butyl groups was metabolized rather like the corresponding mesobilirubin (4) or natural bilirubin itself, being converted to a mono and diglucuronide that were excreted promptly in bile. The presence of the bulky endo-n-butyl groups and the high lipophilicity of the compound seemed to interfere with glucuronidation in the liver only slightly. In contrast, the similar, yet even more lipophilic n-butyl rubin 1, which has two exo n-butyl groups, was glucuronidated and excreted in bile in the rat rather poorly.