Teratogen metabolism: Thalidomide activation is mediated by cytochrome P-450

Braun, Andrew G.; Harding, Fiona; Weinreb, Steven L.

doi:10.1016/0041-008x(86)90449-7

Cited by 63 publications

(38 citation statements)

References 3 publications

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“…2,[10][11][12] Although the main transformation of thalidomide is spontaneous non-enzymatic hydrolysis, these breakdown products are not responsible for its activity. 13 Yaccoby et al demonstrated that the presence of human liver tissue markedly increases thalidomide's antimyeloma efficacy using the myelomatous severe combined immunodeficiency-human (SCID-hu) model.…”

Section: © F E R R a T A S T O R T I F O U N D A T I O Nmentioning

confidence: 99%

Polymorphisms of CYP2C19 gene are associated with the efficacy of thalidomide-based regimens in multiple myeloma

Hou²,

Jiang

et al. 2007

Haematologica

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In this study, CYP2C19 genotypes were tested by the polymerase chain reactionrestriction fragment length polymorphism (PCR-RFLP) method in 92 patients with multiple myeloma (MM). Sixty-two patients were treated with thalidomide plus dexamethasone (Thal+Dex) and 30 with thalidomide combined with chemotherapy (Thal+CC). The overall response rate of extensive metabolizers (EMs) was statistically higher than that of poor metabolizers (PMs) (62.6% vs. 33.3%, p<0.05). Similar results were also observed in the Thal+Dex cohort. For the first time, our primary data suggested that the polymorphisms of CYP2C19 gene are associated with the efficacy of thalidomide based regimens in MM.

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Section: © F E R R a T A S T O R T I F O U N D A T I O Nmentioning

confidence: 99%

Polymorphisms of CYP2C19 gene are associated with the efficacy of thalidomide-based regimens in multiple myeloma

Hou²,

Jiang

et al. 2007

Haematologica

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“…Marked differences reportedly exist between various animal species with regard to their susceptibility to thalidomide which may be associated with species-specific differences in the biotransformation of this compound by cytochrome P450 [32,33]. Recently, in a series of experiments we have found that oral administration of thalidomide (3 mg/kg/day) to female Wistar rats resulted in a modification of both, the activity of hepatic P450 isozymes and their inducibility by the concurrently administered HCB, a well-known porphyrinogenic agent [18].…”

Section: Discussionmentioning

confidence: 99%

Treatment of Porphyria cutanea tarda with Oral Thalidomide

Monastirli

Georgiou²,

Bolsen³

et al. 1999

Skin Pharmacol Physiol

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Eight male patients with overt clinical and biochemical features of porphyria cutanea tarda (PCT) were orally treated with 300 mg/day thalidomide for 1 week and with 200 mg/day for 3 more weeks. Already after the first week of treatment no new vesicles and/or bullae could be observed. Spontaneous blisters completely disappeared, increased skin fragility subsided and skin hyperpigmentation receded about 2 months after completion of therapy, whereas hypertrichosis persisted. There was a rapid decrease in the urinary total porphyrin excretion which reached normal levels in all patients by the end of the fourth week of therapy, whereas the posttreament chromatographic pattern of urinary porphyrins revealed a slight reduction of higher carboxylated porphyrin metabolites and an increase in the amount of the excreted coproporphyrin, as compared to the pretreatment period. Somnolence, intermittent constipation and dry mouth occurred in all patients, 2 patients additionally experienced dizziness. No evidence of peripheral neuropathy could be detected and laboratory investigations revealed no abnormalities, as compared to the pretreatment period. During the 16- to 28-month follow-up of the patients, no clinical or biochemical relapse was observed. In view of the encouraging results of the present investigation, further studies are now warranted in order to definitely answer the question whether oral thalidomide may be regarded as an effective alternative approach to the treatment of PCT.

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“…Hepatic isoforms of these enzymes are especially involved in the metabolism of a number of drugs. Braun et al [10] provided the first pieces of evidence that thalidomide is activated by CYP enzymes. The CYP-catalysed hydroxylation seems to activate thalidomide to its therapeutic active form, although the enzymatic activity is rather low [11].…”

Section: Introductionmentioning

confidence: 99%