The metabolic fate of thalidomide

Faigle, J. W.; Keberle, H; Rieß, W.; Schmid, Karl

doi:10.1007/bf02151479

Cited by 102 publications

(26 citation statements)

References 58 publications

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“…Nonenzymatic hydrolysis of Thal was observed in this study, confirming previous results from other groups in a number of species, including rats, humans, and rabbits (Faigle, 1962;Keberle et al, 1965;Schumacher et al, 1965;Williams et al, 1965). In addition, we have found evidence of significant enzymatic hydrolysis of Thal to phthaloylisoglutamine in rabbit hepatic microsomes.…”

Section: Discussionsupporting

confidence: 92%

Metabolism of Thalidomide in Liver Microsomes of Mice, Rabbits, and Humans

Lu¹,

Helsby²,

Palmer³

et al. 2004

J Pharmacol Exp Ther

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Thalidomide is increasingly important in clinical treatment, not only of various inflammatory conditions but also in multiple myeloma and other malignancies. Moreover, the metabolism of thalidomide varies considerably among different species, indicating a need to understand its mechanistic basis. Our previous in vivo studies showed the plasma half-life of thalidomide to be much shorter in mice than in humans, with rabbits showing intermediate values. We were unable to detect hydroxylated thalidomide metabolites in humans and suggested that interspecies differences in thalidomide hydroxylation might account for the differences in plasma half-life. We sought here to establish whether these species differences in the formation of hydroxylated thalidomide metabolites could be discerned from in vitro studies. Liver microsomes of mice, rabbit, and human donors were incubated with thalidomide and analyzed using liquid chromatography-mass spectrometry. Hydrolysis products were detected for all three species, and the rates of formation were similar to those for spontaneous hydrolysis, except in rabbits where phthaloylisoglutamine formation increased linearly with microsomal enzyme concentration. Multiple hydroxylation products were detected, including three dihydroxylated metabolites not observed in vivo. Thalidomide-5-O-glucuronide, detected in vivo, was absent in vitro. The amount of 5-hydroxythalidomide formed was high in mice, lower in rabbits, and barely detectable in humans. We conclude that major interspecies differences in hepatic metabolism of thalidomide relate closely to the rate of in vivo metabolite formation. The very low rate of in vitro and in vivo hydroxylation in humans strongly suggests that thalidomide hydroxylation is not a requirement for clinical anticancer activity.Thalidomide (␣-phthalimidoglutarimide, Thal), despite its teratogenicity (McBride, 1961;Lenz, 1962), is attracting increasing clinical interest, initially as an anti-inflammatory agent (Sheskin, 1965;Zwingenberger and Wnendt, 1996;Calabrese and Fleischer, 2000) and more recently for the treatment of malignancies, particularly of multiple myeloma (Singhal et al., 1999;Eisen, 2000). Differences in metabolism among different species represent an important feature of its pharmacology. It has been suggested that Thal exerts its teratogenicity through an active metabolite, which is produced by human and rabbit liver microsome preparations but not by mouse liver microsomes (Gordon et al., 1981). After in vivo administration, Thal is both hydrolyzed chemically to a series of acid derivatives and hydroxylated by liver enzymes. In a previous study , we showed that the plasma half-life of Thal in mice was much shorter than that in patients with multiple myeloma, with New Zealand White rabbits showing an intermediate half-life. We also showed that hydroxylated metabolites were not detected in multiple myeloma patients but were found in C57/Bl/6 mice and rabbits, suggesting that relative rates of Thal hydroxylation in different species could...

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Section: Discussionsupporting

confidence: 92%

Metabolism of Thalidomide in Liver Microsomes of Mice, Rabbits, and Humans

Lu¹,

Helsby²,

Palmer³

et al. 2004

J Pharmacol Exp Ther

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“…More recently, thalidomide was shown to have numerous therapeutic effects and was reintroduced for medicinal use in treating diseases such as erythema nodosum leprosum, human immunodeficiency virus-related wasting syndrome and esophageal ulcers, graft versus host disease, arthritis, and tuberculosis (Nightingale, 1998;Calabrese and Fleischer, 2000). Many hypotheses have been proposed to explain thalidomide teratogenesis, including DNA intercalation, acetylation of macromolecules, interference in glutamate metabolism, folic acid antagonism, and others (Faigle et al, 1962;Kemper, 1962;Jonsson, 1972;Stephens, 1988). Two recently presented hypotheses have suggested a thalidomide-induced disruption in angiogenesis and the decreased expression of adhesion receptors as possible teratogenic mechanisms (D'Amato et al, 1994;Neubert et al, 1996).…”

mentioning

confidence: 99%

Thalidomide Modulates Nuclear Redox Status and Preferentially Depletes Glutathione in Rabbit Limb versus Rat Limb

Hansen¹,

Harris²,

Philbert³

et al. 2002

J Pharmacol Exp Ther

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Thalidomide produces numerous birth defects, the most notable being phocomelia. Mechanisms behind thalidomide-induced malformations have not been fully elucidated, although recent evidence suggests a role for reactive oxygen species. A thalidomide-resistant (rat) and -sensitive (rabbit) species were used to compare potential inherent differences related to oxidative stress that may provide a more definitive understanding of mechanisms of thalidomide embryopathy. Limb bud cells (LBCs) were removed from the rat and rabbit embryo, dissociated, and plated in culture for 24 h. A fluorescence (6-carboxy-2Ј,7Ј-dichlorofluorescin diacetate; DCF) assay for oxidative stress was used with varying concentrations of thalidomide (5-100 M). Thalidomide (100 M) showed a 6-fold greater production of oxidative stress in rabbit cultures than in rat. Lower concentrations (50 and 25 M) also showed a significant increase in reactive oxygen species. Confocal microscopy revealed DCF fluorescence preferentially in rabbit LBC nuclei compared with the uniform distribution of DCF fluorescence in rat LBC. Localization of glutathione (GSH) was determined using 5-chloromethylfluorescein diacetate fluorescent confocal microscopy. In rat cultures, significant thalidomide-induced GSH depletion was detected in the cytosol but the nuclei maintained its GSH content, but rabbit LBC showed significant GSH depletion in both compartments. GSH depletion was confirmed by high-performance liquid chromatography analysis. These observations provide evidence that thalidomide preferentially produces oxidative stress in the thalidomide-sensitive species but not the thalidomide-resistant species. Nuclear GSH content in the rabbit LBC is selectively modified and indicates a shift in the nuclear redox environment. Redox shifts in the nucleus may result in the misregulation of transcription factor/ DNA interactions and cause defective growth and development.

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“…However, great variation in the susceptibility has been presented in different species and strains. Basil et al (1) and Faigle et al (2) have shown that the metabolite of thalidomide responsible for the teratogenicity is probably its hydrolytic product of the peptide bonds present in the molecule and that the metabolite interferes with incorporation of glutamine or glutamic acid into the cell constituents. There are some other possible mechanisms of thalidomide for the teratogenicity (3).…”

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confidence: 99%