Pharmacokinetics of primary metabolites 5-hydroxythalidomide and 5′-hydroxythalidomide formed after oral administration of thalidomide in the rabbit, a thalidomide-sensitive species

• Published in: Journal of toxicological sciences Vol. 46; no. 12; pp. 553 - 560
• Main Authors: Kuwagata, Makiko, Hasegawa, Takuro, Takashima, Hiromasa, Shimizu, Makiko, Kitajima, Satoshi, Yamazaki, Hiroshi
• Format: Journal Article
• Language: English
• Published: Japan The Japanese Society of Toxicology 2021; Japan Science and Technology Agency
• Subjects: 5-Hydroxythalidomide; Administration, Oral; Animals; Biocompatibility; Biotransformation; Blood; Blood plasma; Cytochrome; Cytochrome P450; Cytochromes P450; Drug dosages; Enzymes; Human; In vivo methods and tests; Liquid chromatography; Liver; Male; Males; Mass spectrometry; Mass spectroscopy; Metabolic activation; Metabolic rate; Metabolism; Metabolites; Mice; Oral administration; Oxidation; PBPK modeling; Pharmacokinetics; Pharmacology; Plasma; Rabbits; Rodents; Semen; Seminal plasma; Species; Teratogenicity; Thalidomide; Thalidomide - analogs & derivatives; Thalidomide - toxicity; Toxicity; Toxicity testing; Human; 5-Hydroxythalidomide; Seminal plasma; PBPK modeling
• ISSN: 0388-1350; 1880-3989
• DOI: 10.2131/jts.46.553

The teratogenicity of the chemotherapeutic drug thalidomide is species-specific and affects humans, non-human primates, and rabbits. The primary oxidation of thalidomide in previously investigated rodents predominantly resulted in the formation of deactivated 5′-hydroxythalidomide. In the current study, similar in vivo biotransformations to 5-hydroxythalidomide and 5′-hydroxythalidomide were confirmed by the analysis of blood plasma from male rabbits, a thalidomide-sensitive species, after oral administration of thalidomide (2.0 mg/kg). Similar levels of thalidomide in seminal plasma and in blood plasma were detected using liquid chromatography–tandem mass spectrometry at 4 hr and 7 hr after oral doses in male rabbits. Seminal plasma concentrations of 5-hydroxythalidomide and 5′-hydroxythalidomide were also seen in male rabbits in a roughly similar time-dependent manner to those in the blood plasma after oral doses of thalidomide (2.0 mg/kg). Furthermore, the values generated by a simplified physiologically based pharmacokinetic rabbit model were in agreement with the measured in vivo blood plasma data under metabolic ratios of 0.01 for the hepatic intrinsic clearance of thalidomide to both unconjugated 5-hydroxythalidomide and 5′-hydroxythalidomide. These results suggest that metabolic activation of thalidomide may be dependent on rabbit liver enzymes just it was for cytochrome P450 enzymes in humanized-liver mice; in contrast, rodent livers predominantly mediate biotransformation of thalidomide to 5′-hydroxythalidomide. A developmental toxicity test system with experimental animals that involves intravaginal exposures to the chemotherapeutic drug thalidomide via semen should be considered in the future.