Influence of Mitotane on the Hypoprothrombinemic Effect of Warfarin

Pg, Cuddy; Ls, Loftus

doi:10.1097/00007611-198603000-00037

Cited by 13 publications

(8 citation statements)

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“…A case report previously described the 0 C o n t r o l 0 . 1 hypoprothrombinemic effects of warfarin, a substrate of CYP2C9, during mitotane treatment (Cuddy & Loftus 1986). In this study, we showed that mitotane induces CYP2B6 and UGT1A1 as well as CYP3A4 in human liverderived cells.…”

Section: Discussionmentioning

confidence: 54%

Mitotane induces CYP3A4 expression via activation of the steroid and xenobiotic receptor

Takeshita¹,

Igarashi-Migitaka²,

Koibuchi³

et al. 2012

Journal of Endocrinology

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Adrenocortical carcinoma (ACC) is a rare disease with an extremely poor prognosis. Mitotane alone or in combination with other cytotoxic drugs is a common therapeutic option for ACC. In addition to its adrenolytic function, mitotane has been known for decades to increase the metabolic clearance of glucocorticoids. It was recently shown that the tyrosine kinase inhibitor sunitinib is also rapidly metabolized in patients treated with mitotane, indicating that mitotane engages in clinically relevant drug interactions. Although the precise mechanism of these interactions is not well understood, cytochrome P450 mono-oxygenase 3A4 (CYP3A4) is a key enzyme to inactivate both glucocorticoids and sunitinib. The nuclear receptor steroid and xenobiotic receptor (SXR (NR1I2)) is one of the key transcriptional regulators of CYP3A4 gene expression in the liver and intestine. A variety of xenobiotics bind to SXR and stimulate transcription of xenobiotic-response elements (XREs) located in the CYP3A4 gene promoter. In this study, we evaluated the effects of mitotane on SXR-mediated transcription in vitro by luciferase reporter analysis, SXR-steroid receptor coactivator 1 (SRC1) interactions, quantitative real-time PCR analysis of CYP3A4 expression, SXR knockdown, and CYP3A4 enzyme activity assays using human hepatocyte-derived cells. We found that mitotane activated SXR-mediated transcription of the XREs. Mitotane recruited SRC1 to the ligand-binding domain of SXR. Mitotane increased CYP3A4 mRNA levels, which was attenuated by SXR knockdown. Finally, we showed that mitotane increased CYP3A4 enzyme activity. We conclude that mitotane can induce CYP3A4 gene expression and suggest that mitotane is used cautiously due to its drug-drug interactions.

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Section: Discussionmentioning

confidence: 54%

Mitotane induces CYP3A4 expression via activation of the steroid and xenobiotic receptor

Takeshita¹,

Igarashi-Migitaka²,

Koibuchi³

et al. 2012

Journal of Endocrinology

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“…1 , 2 S i milar effects have been observed with other cytotoxic agents, such as merc a p t o p u r i n e 3 (which is chemically related to azathioprine and its active metabolite), cyclophosphamide, 4 and mitotane. 5 The mechanism of impairment of anticoagulation by these agents is not known. Martini and Jahnchen 6 suggested that mercaptopurine has a role in the activation or enhanced synthesis of prothrombin.…”

Section: Effect Of Azathioprine On the Anticoagulant Activity Of Warfmentioning

confidence: 99%

“…5 The patient had been treated with pipotiazine and trihexyphenidyl for 12 years and had no history of thrombocytopenia or symptoms of bleeding. Pipotiazine and trihexyphenidyl were withdrawn and not reintroduced, but the interval between drug ingestion and the initial occurrence of thrombocytopenia has been reported to be usually less than one day to three years 4 ; therefore, the imputability of these two drugs is unlikely.…”

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confidence: 99%

Effect of Azathioprine on the Anticoagulant Activity of Warfarin

Rotenberg

Levy²,

Shoenfeld³

et al. 2000

Ann Pharmacother

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Glimepiride-induced thrombocytopenic purpuraTO THE EDITOR: Oral sulfonylurea antidiabetic drugs such as glyburide 1 and chlorpropamide 2 , 3 are known to induce thrombocytopenia. George et a l . 4 recently reviewed published reports of drug-induced thrombocytopenia and proposed criteria to evaluate the level of evidence for a causal relationship of each drug to thrombocytopenia. We report a patient who developed thrombocytopenia after glimepiride treatment. According to the criteria developed by George et al., our observations support the existence of a causal relationship between glimepiride and thrombocytopenia.Case Report. A 68-year-old white man was referred to our hospital on April 21, 1998, with a petechial rash associated with hematoma on his trunk, legs, and face. Clinical examination showed hemorrhagic bullae in the mouth and gingival bleeding. No lymphadenopathy or hepatosplenomegaly was observed. His previous medical history included chronic psychosis, which had been treated for 12 years by pipotiazine 12.5 mg every six weeks (last injection April 3, 1998) and trihexyphenidyl 4 mg/d. In February 1998, his physician prescribed glimepiride 1 mg/d, an oral sulfonylurea antidiabetic drug, for hyperglycemia. Platelet counts at the outset of treatment and during the following weeks were not available, but the patient reported no symptoms of bleeding and stopped glimepiride after several weeks of treatment. On April 19, the patient restarted glimepiride treatment and, on April 21, was referred for hemorrhagic syndrome. His platelet count confirmed thrombocytopenia (1 × 1 0 9 /L). A bone marrow aspirate was diluted with peripheral blood, but showed no malignant cells, and there was no serologic evidence of recent viral infection (HIV-1, -2; hepatitis B, C, A; cytomegalovirus; Epstein-Barr virus). The platelet count was too low to assess platelet-associated immunoglobulins, but platelet receptor antibodies were found. All medication was withdrawn; prednisone 1 mg/kg/d and human immunoglobulins 0.4 g/kg/d for 2 d were prescribed. The hemorrhagic syndrome decreased on day 7, but the platelet count was 2 × 1 0 9 /L. After two weeks, the platelet count increased to 23 × 1 0 9 /L and was completely normalized after four weeks of prednisone therapy (281 × 10 9 /L). Prednisone was progressively reduced, and platelet count was normal (346 × 1 0 9 /L) six months after glimepiride was discontinued.

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“…However, organochlorine insecticides, to which mitotane is chemically closely related, induce microsomal liver enzymes (8). In accordance, a case report described an interaction between mitotane and the anticoagulant warfarin which resulted in increased warfarin requirements, suggesting induction of metabolizing enzymes by mitotane (9). Additionally, a substantial increase in steroid requirement was described in two patients, but observed generally in clinical practice, on mitotane therapy which was explained by hepatic microsomal enzyme induction (10).…”

Section: Introductionmentioning

confidence: 80%

Mitotane has a strong and a durable inducing effect on CYP3A4 activity

Erp

Guchelaar

Ploeger³

et al. 2011

European Journal of Endocrinology

103

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Objective: The effects of mitotane on the pharmacokinetics (PK) of co-administered drugs are mostly unknown. The aim of the present study was to describe the effects of mitotane on the PK of the phenotypic probe midazolam and of the tyrosine kinase inhibitor sunitinib. Design: A serendipitous observation was made in two of nine patients who volunteered in a sunitinib pharmacokinetic study. Both patients were diagnosed with adrenocortical carcinoma (ACC) and were exposed to mitotane. The sunitinib PK study was designed to determine the relationship between CYP3A4 activity and sunitinib exposure using 7.5 mg midazolam orally as a phenotypic probe. Patient and methods: Serial blood samples for PK analysis of midazolam, 1-hydroxy-midazolam, and sunitinib were collected at steady-state sunitinib PK (between days 14 and 20). To confirm this observation in the mitotane-exposed patients, midazolam PK was evaluated in two additional patients with ACC and mitotane treatment. Results: The four mitotane-treated patients showed highly induced CYP3A4 activity, even after interrupting mitotane therapy months before study entry, reflected by decreased midazolam exposure compared with the other seven patients (mean AUC 0-12 h (95% CI): 7.6 (5.5-9.7) vs 139.0 (95.1-182.9) mg!h/l respectively PZ0.001) and increased 1-hydroxy-midazolam exposure (mean AUC 0-12 h (95% CI): 409.6 (290.5-528.7) vs 35.0 (26.4-43.6) mg!h/l, PZ0.008). Sunitinib exposure was decreased in the two patients who were co-treated with mitotane (267 and 268 mg!h/l versus 1344 (1079-1609) (mean (95% CI)) mg!h/l). Conclusion: Mitotane has a strong and long-lasting inducing effect on CYP3A4 activity, which will result in clinically relevant interactions with multiple drugs since many drugs are metabolized by this enzyme.

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Influence of Mitotane on the Hypoprothrombinemic Effect of Warfarin

Cited by 13 publications

References 0 publications

Mitotane induces CYP3A4 expression via activation of the steroid and xenobiotic receptor

Mitotane induces CYP3A4 expression via activation of the steroid and xenobiotic receptor

Effect of Azathioprine on the Anticoagulant Activity of Warfarin

Mitotane has a strong and a durable inducing effect on CYP3A4 activity

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