Thalidomide Pharmacokinetics and Metabolite Formation in Mice, Rabbits, and Multiple Myeloma Patients
Purpose: 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. Experimental Design: Mice and rabbits were administered...
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Published in | Clinical cancer research Vol. 10; no. 17; pp. 5949 - 5956 |
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Main Authors | , , , , , , , |
Format | Journal Article |
Language | English |
Published |
Philadelphia, PA
American Association for Cancer Research
01.09.2004
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Subjects | |
Online Access | Get full text |
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Summary: | Purpose: 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.
Experimental Design: 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 μmol/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. |
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Bibliography: | ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 |
ISSN: | 1078-0432 1557-3265 |
DOI: | 10.1158/1078-0432.CCR-04-0421 |