Hydroxylated Metabolites of Thalidomide: Formation In-vitro and In-vivo in Man

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Abstract
There is renewed interest in the clinical use of thalidomide, because of its unique immunomodulating action. Because data on the metabolism of thalidomide in man are very sparse, the aim of this study was to develop HPLC assays for the 5-hydroxy, 5,6-dihydroxy, 4,5-dihydroxy and 5′-hydroxy metabolites of thalidomide and to investigate their possible formation in man—in-vitro in liver homogenates and in-vivo in healthy volunteers. Reversed-phase HPLC assays with UV detection were developed for quantification of the metabolites in the low ng mL−1 range in plasma and incubate samples. The stability of the metabolites was investigated and degradation was avoided by rapid chilling and acidification of the samples. After incubation of thalidomide with fraction S9 from human liver, formation of the 5-hydroxy and 5′-hydroxy metabolites could be demonstrated. The 5′-hydroxy metabolite was found, in low concentrations, in plasma samples from eight healthy male volunteers who had received thalidomide orally. The other three metabolites could not be found by HPLC with detection limits of 1–2 ng mL−1. Thus the formation of two hydroxylated metabolites of thalidomide in the liver in man was demonstrated, but only one of these could be detected in the circulation.