Thalidomide does not alter estrogen-progesterone hormone single-dose pharmacokinetics

Scheffler, Michael R.; Colburn, Wayne A.; Kook, Karin A.; Thomas, Steve

doi:10.1016/s0009-9236(99)70067-6

Cited by 23 publications

(15 citation statements)

References 18 publications

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“…Hydroxylated metabolites can be detected in vitro but only at concentrations of Thal (200 -600 M) that are well above the highest plasma concentrations of Thal (50 M) that have reported in human studies (Figg et al, 1999). These results suggest that Thal is unlikely to interact with other drugs extensively metabolized by human P450 system (Trapnell et al, 1998;Scheffler et al, 1999;Teo et al, 2000), which makes it a good candidate for combined chemotherapy. The data also strongly suggest that hydroxylated metabolites are unlikely to be involved in the mechanism of action of Thal in humans and that the parent compound and/or its hydrolysis product(s) are involved in its action.…”

Section: Discussionmentioning

confidence: 79%

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: Discussionmentioning

confidence: 79%

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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“…Although induction of total P450 contents by thalidomide in rat livers have been reported, 15 apparently no interaction of thalidomide has been shown with ethinyl estradiol (P450 3A4 substrate and inhibitor) in humans. 16 In vivo cooperativity of human P450 3A enzymes was also reported as another aspect, with a higher area under the curve for 1′- hydroxymidazolam following co treatment with thalidomide in the humanized mice. 14 It is important to evaluate any drug interactions through human P450 enzymes by concomitant thalidomide therapy using the basic research technique.…”

Section: Introductionmentioning

confidence: 96%

Thalidomide Increases Human Hepatic Cytochrome P450 3A Enzymes by Direct Activation of the Pregnane X Receptor

Murayama

Beuningen

Suemizu

et al. 2014

Chem. Res. Toxicol.

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Heterotropic cooperativity of human cytochrome P450 (P450) 3A4/3A5 by the teratogen thalidomide was recently demonstrated by H. Yamazaki et al. (2013) using the model substrate midazolam in various in vitro and in vivo models. Chimeric mice with humanized liver also displayed enhanced midazolam clearance upon pre treatment with orally administered thalidomide, presumably because of human P450 3A induction. In the current study, we further investigated the regulation of human hepatic drug metabolizing enzymes. Thalidomide enhanced levels of P450 3A4 and 2B6 mRNA, protein expression, and/or oxidation activity in human hepatocytes, indirectly suggesting activation of upstream transcription factors involved in detoxication, e.g. the nuclear receptors pregnane X receptor (PXR) and constitutive androstane receptor (CAR). A key event after ligand binding is an alteration of nuclear receptor conformation and recruitment of co regulator proteins that alter chromatin accessibility of target genes. To investigate direct engagement and functional alteration of PXR and CAR by thalidomide, we utilized a peptide microarray with 154 co regulator derived nuclear receptor interaction motifs and co regulator and nuclear receptor boxes, which serves as a sensor for nuclear receptor conformation and activity status as a function of ligand. Thalidomide and its human proximate metabolite 5 hydroxythalidomide displayed significant modulation of co regulator interaction with PXR and CAR ligand binding domains, similar to established agonists for these receptors. These results collectively suggest that thalidomide acts as a ligand for PXR and CAR and causes enzyme induction leading to increased P450 enzyme activity. The possibilities of drug interactions during thalidomide therapy in humans require further evaluation.

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“…No saturation was seen at the much lower human therapeutic dose of 1–3 mg/kg (200 mg/day) (Teo et al, 2001c). There were no sex differences in pharmacokinetic exposure in mice (Teo, unpublished findings), rats (Teo, unpublished findings), rabbits, dogs (Teo, unpublished findings), and humans (Teo et al, 1999b; Scheffler et al, 2000). The apparent difference in C max in rabbits is possibly due to animal and assay variability and is unlikely to be a true sex effect (Table 9).…”

Section: Discussionmentioning

confidence: 99%

Effects of thalidomide on reproductive function and early embryonic development in male and female New Zealand white rabbits

Teo¹,

Denny

Stirling³

et al. 2004

Birth Defects Research Pt B

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Thalidomide had no adverse effects on mating and fertility in male and female rabbits dosed up to 500 and 100 mg/kg/day, respectively, for 14 days prior to mating. After 56 day of dosing, histopathologic changes with no associated sperm abnormalities were observed in the testicles. Embryonic development NOAEL for treated females mated to untreated males was <10 mg/kg. Corresponding fertility NOAEL for treated males mated to untreated females was 500 mg/kg.

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Thalidomide does not alter estrogen-progesterone hormone single-dose pharmacokinetics

Cited by 23 publications

References 18 publications

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

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

Thalidomide Increases Human Hepatic Cytochrome P450 3A Enzymes by Direct Activation of the Pregnane X Receptor

Effects of thalidomide on reproductive function and early embryonic development in male and female New Zealand white rabbits

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