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The approved drug thalidomide is teratogenic in humans, nonhuman primates, and rabbits but not in rodents. The extensive biotransformation of 5'-hydroxythalidomide after oral administration of thalidomide (250 mg/kg) in rats was investigated in detail using liquid chromatography-tandem mass spectrometry. Probable metabolites 5'-hydroxythalidomide sulfate and glucuronide were extensively formed, with approximately tenfold and onefold peak areas, respectively, to the primary 5'-hydroxythalidomide measured using authentic standards. As a minor metabolite, 5-hydroxythalidomide was also detected. The output of simplified physiologically based pharmacokinetic rat models was consistent with the observed in vivo data under a metabolic ratio of 0.05 for the hepatic intrinsic clearance of thalidomide to unconjugated 5'-hydroxythalidomide. The aggregate of unconjugated and sulfate/glucuronide conjugated 5'-hydroxythalidomide forms appear to be the predominant metabolites in rats. Two hours after oral administration of thalidomide (100 mg/kg) to chimeric mice humanized with four different batches of genotyped human hepatocytes, the plasma concentration ratios of 5-hydroxythalidomide to 5'-hydroxythalidomide were correlated with replacement indexes of human liver cells previously transplanted in immunodeficient mice. These results indicate that rodent livers mediate thalidomide primary oxidation, leading to extensive deactivation in vivo to unconjugated/conjugated 5'-hydroxythalidomide and suggest that thalidomide activation might be dependent on the humanized livers in mice transplanted with human hepatocytes.

Pharmacokinetics of primary oxidative metabolites of thalidomide in rats and in chimeric mice humanized with different human hepatocytes