2013
DOI: 10.2133/dmpk.dmpk-12-rv-089
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Abstract: The teratogenic effects of thalidomide have been studied for more than 50 years. However, there have been few studies of the pharmacokinetic changes occurring during thalidomide therapy. Thalidomide was originally developed as a sedative. However, thalidomide induces multiple birth defects when used in pregnant women. Thalidomide is now used in the treatment of multiple myeloma (MM) and erythema nodosum leprosum (ENL) in Japan. Rational use of thalidomide is problematic due to a lack of basic research regardin… Show more

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Cited by 10 publications
(7 citation statements)
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References 54 publications
(73 reference statements)
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“…Genetic factors including single nucleotide polymorphisms (SNPs) that change cytochrome P450 (CYP) activity and epigenetic regülation that modifies CYP expression levels may contribute to the change in pharmocokinetics and adverse drug reactions (ADRs) (Nakamura et al, 2013). In this study, we investigated relationship between TNFα, NOS3, MDR1 genes polymorphisms and clinical parameters, prognosis and survival for the VAD (Vincristine-Adriamycine-Dexamethasone), MP (Mephalane-Prednisolone), autologous stem cell transplantation (ASCT), BODEC (Bortezomib-Dexamethasone-Cyclophosphamide) and TD (Thalidomide-Dexamethasone) treatment of multiple myeloma.…”
Section: Introductionmentioning
confidence: 99%
“…Genetic factors including single nucleotide polymorphisms (SNPs) that change cytochrome P450 (CYP) activity and epigenetic regülation that modifies CYP expression levels may contribute to the change in pharmocokinetics and adverse drug reactions (ADRs) (Nakamura et al, 2013). In this study, we investigated relationship between TNFα, NOS3, MDR1 genes polymorphisms and clinical parameters, prognosis and survival for the VAD (Vincristine-Adriamycine-Dexamethasone), MP (Mephalane-Prednisolone), autologous stem cell transplantation (ASCT), BODEC (Bortezomib-Dexamethasone-Cyclophosphamide) and TD (Thalidomide-Dexamethasone) treatment of multiple myeloma.…”
Section: Introductionmentioning
confidence: 99%
“…2,3 Because of the recent emergence of thalidomide as a drug with clinical potential, there is renewed interest in both its toxicity and pharmacological mechanisms. Various hypotheses (for both) have been proposed, including generation of reactive oxygen species, 4 generation of reactive acylating 5 and arene oxide intermediates, 6 inhibition of angiogenesis, 7 and inhibition of the protein cereblon.…”
Section: Introductionmentioning
confidence: 99%
“…The metabolism of thalidomide is important for both teratogenicity and anticancer efficacy. Thalidomide is metabolized via P450-mediated oxidation . Various P450s oxidize thalidomide to 5-hydroxy-, 5′-hydroxy-, and dihydroxythalidomide products (Figure A), with a major one being P450 2C19. , Recently, we reported that human P450 3A4 and 3A5 also oxidize thalidomide to the 5-hydroxy and dihydroxy metabolites. The second oxidation step in the P450 3A4 pathway generates a reactive intermediate, possibly an arene oxide (as initially suggested by Gordon et al) that can be trapped by GSH to give GSH adducts, as confirmed in humanized mouse models using LC-MS/MS methods. , The secondary oxidation of 5-hydoxythalidomide was faster than the primary thalidomide 5-hydoxylation mediated by recombinant human P450 3A4/5 .…”
Section: Metabolic Activation Of Thalidomide In Humanized Liver Micementioning
confidence: 81%
“…Thalidomide is metabolized via P450-mediated oxidation. 34 Various P450s oxidize thalidomide to 5-hydroxy-, 5′-hydroxy-, and dihydroxythalidomide products (Figure 1A), with a major one being P450 2C19. 35,36 Recently, we reported that human P450 3A4 and 3A5 also oxidize thalidomide to the 5-hydroxy and dihydroxy metabolites.…”
Section: Metabolic Activation Of Thalidomide In Humanized Liver Micementioning
confidence: 99%