Pharmacokinetics of thalidomide in an elderly prostate cancer population

Figg, William D.; Raje, Sangeeta; Bauer, Kenneth S.; Tompkins, Anne; Venzon, David; Bergan, Raymond C.; Chen, Alice; Hamilton, Michael; Pluda, James M.; Reed, Eddie

doi:10.1021/js980172i

Cited by 109 publications

(54 citation statements)

References 22 publications

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“…The data support in vivo data showing that hydroxylated metabolites are not detectable in patients with multiple myeloma (Lu et al, 2003; or with Hansen's disease (Teo et al, 2000). 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.…”

Section: Discussionsupporting

confidence: 84%

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: 84%

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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Section: Pharmacologymentioning

confidence: 99%

“…The time to peak concentration varies from 3 to 6 hours indicating a slow absorption [5]. No significant binding by plasma proteins have been described and it seems to have a large apparent volume of distribution [5,6]. Most of the thalidomide appears to undergo spontaneous non-enzymatic hydrolytic cleavage in the circulation into several metabolites, many of which are active.…”

Section: Pharmacologymentioning

confidence: 99%

Thalidomide as an anti‐cancer agent

Kumar

Witzig

Rajkumar

2002

J Cellular Molecular Medi

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Thalidomide is a glutamic acid derivative initially introduced as a sedative hypnotic nearly forty years ago. It was withdrawn following numerous reports linking it to a characteristic pattern of congenital abnormalities in babies born to mothers who used the drug for morning sickness. It has gradually been re-introduced into clinical practice over the past two decades, albeit under strict regulation, since it was found to be useful in the management of erythema nodosum leprosum and HIV wasting syndrome. Recognition of its anti-angiogenic effect led to its evaluation in the treatment of various malignancies, where angiogenesis has been shown to play an important role. Numerous clinical trials done over the past four years have confirmed the significant anti-myeloma activity of this drug. It has also shown promise in preliminary trials in the treatment of a variety of different malignant diseases. The mechanisms of its antineoplastic effects continue to be the focus of ongoing research. It has become clear that even though its anti angiogenic effects play a significant role in the anti-tumor activity, there are other properties of this drug which are responsible as well. It also possesses anti-TNF alpha activity, which has led to its evaluation in several inflammatory states. In this concise review, we briefly describe the historical background and pharmacological aspects of this drug. We have concisely reviewed the current knowledge regarding mechanisms of its anti-neoplastic activity and the results of various clinical trials in oncology. Keywords:

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“…4, 5). Specifically, thalidomide metabolites were placed upon cells in culture for 8 h, a time approximating the elimination half-life of the parental drug in blood [53][54][55] and the cell proliferation ELISA run as described below.…”

Section: Synthesis Of Thalidomide Metabolitesmentioning

confidence: 99%

Effects of Putative Hydroxylated Thalidomide Metabolites on Blood Vessel Density in the Chorioallantoic Membrane (CAM) Assay and on Tumor and Endothelial Cell Proliferation.

Marks

Shi

Fry

et al. 2002

Biological & Pharmaceutical Bulletin

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Angiogenesis, the process of blood vessel formation from pre-formed vessels, has recently become a primary target of anticancer therapy. This is due in part to the finding that removing the blood supply to a tumor can not only prevent further growth but can also starve the existing cells to death.2) In the past several years there have been many potential anti-angiogenic agents developed acting by many mechanisms including interruption of growth factor receptor phosphorylation, [3][4][5] growth factor-receptor binding, 6,7) cell adhesion molecule expression and signaling 8,9) and alterations in endothelial cell apoptosis. 10,11) In addition, several agents such as thalidomide have been shown to inhibit angiogenesis by an as yet not fully understood mechanism.12-18) Furthermore, thalidomide has been shown to reduce tumor growth both in model systems [19][20][21] and in patients. [22][23][24][25][26][27][28] Clinically, however, thalidomide has a fairly weak effect as a monotherapy in patients with solid tumors [22][23][24] but is showing tremendous promise against multiple myeloma.25-28) It has been shown that activation of thalidomide by human or rabbit liver enzymes, but not by rat liver enzymes, significantly enhances the anti-angiogenic effect of the drug in rat aortic sections or isolated endothelial cells.29) This is very interesting because thalidomide is virtually non-toxic to rats when given orally (PO). Intraperitoneal (IP), administration however, commonly associated with "first-pass" hepatic metabolism, 30) recapitulates the teratogenic effect of thalidomide in rats. 31)Kenyon et al. 19) also showed that thalidomide given IP was effective as an anti-angiogenic agent in the mouse corneal model, whereas thalidomide given PO was inactive. In addition, thalidomide teratogenesis was only found to occur after activation of the drug by liver enzymes. 13,[32][33][34][35] Furthermore, in a Xenopus oocyte assay of teratogenesis, activation of thalidomide by a single cytochrome P450 enzyme, CYP2E1, lead to a teratogenic compound whereas unactivated thalidomide was non-teratogenic.35) Thus metabolism of thalidomide is critical to its anti-angiogenic and teratogenic activity. However, the identity of the active anti-angiogenic and teratogenic moiety or moieties of thalidomide are still unknown.The goal of this work was to explore the effect of putative hydroxylated thalidomide metabolites on blood vessel density and target cell proliferation. Since the anti-angiogenic activity of thalidomide was first reported, 36) only a limited number of thalidomide metabolites have been tested for antiangiogenic activity. Figure 1 shows known and hypothesized metabolites of thalidomide (structures M1-M8) based on extensive literature review. [37][38][39][40][41][42][43][44][45] Thalidomide can be metabolized through hydrolysis at the glutarimide and/or phthalimide ring to yield metabolites such as M6-M8. Its hydroxylation can occur on glutarimide or phthalimide ring to yield metabolites M1-M5. Interestingly, only metabolites M5...

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Pharmacokinetics of thalidomide in an elderly prostate cancer population

Cited by 109 publications

References 22 publications

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

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

Thalidomide as an anti‐cancer agent

Effects of Putative Hydroxylated Thalidomide Metabolites on Blood Vessel Density in the Chorioallantoic Membrane (CAM) Assay and on Tumor and Endothelial Cell Proliferation.

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