Thalidomide pharmacokinetics and metabolite formation in mice, rabbits, and multiple myeloma patients.
OBJECTIVE
Thalidomide has a variety of biological effects that vary considerably according to the species tested. We sought to establish whether differences in pharmacokinetics could form a basis for the species-specific effects of thalidomide.


METHODS
Mice and rabbits were administered thalidomide (2 mg/kg) p.o. or i.v., and plasma concentrations of thalidomide were measured after drug administration using high performance liquid chromotography. Plasma samples from five multiple myeloma patients over 24 hours after their first dose of thalidomide (200 mg) were similarly analyzed and all data were fitted to a one-compartment model. Metabolites of thalidomide in plasma were identified simultaneously using liquid chromatography-mass spectrometry.


RESULTS
Plasma concentration-time profiles for the individual patients were very similar to each other, but widely different pharmacokinetic properties were found between patients compared with those in mice or rabbits. Area under the concentration curve values for mice, rabbits, and multiple myeloma patients were 4, 8, and 81 micromol/L. hour, respectively, and corresponding elimination half-lives were 0.5, 2.2, and 7.3 hours, respectively. Large differences were also observed between the metabolite profiles from the three species. Hydrolysis products were detected for all species, and the proportion of hydroxylated metabolites was higher in mice than in rabbits and undetectable in patients.


CONCLUSIONS
Our results show major interspecies differences in the pharmacokinetics of thalidomide that are related to the altered degree of metabolism. We suggest that the interspecies differences in biological effects of thalidomide may be attributable, at least in part, to the differences in its metabolism and hence pharmacokinetics.
Chung
Francisco
F
Auckland Cancer Society Research Centre, Faculty of Medical and Health Sciences, University of Auckland, Auckland, New Zealand.
Lu
Jun
J
Palmer
Brian D
BD
Kestell
Philip
P
Browett
Peter
P
Baguley
Bruce C
BC
Tingle
Malcolm
M
Ching
Lai-Ming
LM
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D020533:Angiogenesis Inhibitors / Q000008:administration & dosage / Q000378:metabolism* / Q000493:pharmacokinetics*; D000818:Animals; D019540:Area Under Curve; D002851:Chromatography, High Pressure Liquid; D002853:Chromatography, Liquid; D005260:Female; D006801:Humans; D008297:Male; D013058:Mass Spectrometry; D051379:Mice; D008810:Mice, Inbred C57BL; D008875:Middle Aged; D009101:Multiple Myeloma / Q000097:blood*; D011817:Rabbits; D013045:Species Specificity; D013792:Thalidomide / Q000008:administration & dosage / Q000378:metabolism* / Q000493:pharmacokinetics*
D020533:Angiogenesis Inhibitors; D013792:Thalidomide