Thalidomide metabolites in mice and patients with multiple myeloma.
OBJECTIVE
This research examines the profile of metabolites of thalidomide that are formed in refractory multiple myeloma patients undergoing thalidomide therapy in comparison with those that are detected in healthy mice.


METHODS
Urine or plasma samples from patients during thalidomide therapy (100-400 mg daily), or from mice treated i.p. (100 mg/kg) or p.o. with thalidomide (50 mg/kg) were analyzed using liquid chromatography-mass spectrometry. Metabolites in each of the peaks observed in the UV- and mass spectrometry-detected high-performance liquid chromatography traces were identified by comparison of retention times and spectra with those of authentic standards.


RESULTS
Plasma and urine samples from mice 4 h after treatment with thalidomide contained eight major metabolites formed by hydroxylation and/or hydrolysis of thalidomide. In contrast, urine samples from seven multiple myeloma patients at steady state levels of thalidomide therapy showed the presence of only three hydrolysis breakdown products and no hydroxylated metabolites.


CONCLUSIONS
Our results show that thalidomide metabolite profiles in multiple myeloma patients differ considerably from those in mice. The lack of measurable hydroxylated metabolites in urine and in 1 case plasma of these patients suggests that such metabolites are not responsible for the therapeutic effects of thalidomide in multiple myeloma. We suggest that thalidomide may act directly, down-regulating growth factors essential for multiple myeloma growth.
Lu
Jun
J
Auckland Cancer Society Research Centre, Faculty of Medical and Health Sciences, The University of Auckland, New Zealand.
Palmer
Brian D
BD
Kestell
Phillip
P
Browett
Peter
P
Baguley
Bruce C
BC
Muller
George
G
Ching
Lai-Ming
LM
D020533:Angiogenesis Inhibitors / Q000493:pharmacokinetics*; D000818:Animals; D001711:Biotransformation; D016022:Case-Control Studies; D002853:Chromatography, Liquid; D006801:Humans; D006868:Hydrolysis; D006900:Hydroxylation; D008297:Male; D013058:Mass Spectrometry; D051379:Mice; D008810:Mice, Inbred C57BL; D009101:Multiple Myeloma / Q000097:blood* / Q000652:urine*; D013792:Thalidomide / Q000493:pharmacokinetics*
D020533:Angiogenesis Inhibitors; D013792:Thalidomide