Aprepitant inhibits cyclophosphamide bioactivation and thiotepa metabolism

Jonge, Milly E de; Huitema, Alwin D. R.; Holtkamp, M. J.; Dam, Selma M. van; Beijnen, Jos H.; Rodenhuis, S.

doi:10.1007/s00280-005-1005-4

Cited by 62 publications

(43 citation statements)

References 21 publications

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“…Phosphoramide mustard and acrolein are two active CP metabolites produced by liver microsomal enzymes (De Jonge et al, 2005). CP's antineoplastic effects are associated with phosphoramide mustard, while acrolein is linked with its toxic side effects (Kern & Kehrer, 2002).…”

Section: Discussionmentioning

confidence: 99%

Protective effects ofOriganum vulgareethanol extract against cyclophosphamide-induced liver toxicity in mice

Habibi

Shokrzadeh²,

Chabra³

et al. 2014

Pharmaceutical Biology

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Context: Despite its wide clinical use, cyclophosphamide (CP), an alkylating chemotherapeutic agent, possesses many adverse effects, including hepatotoxicity. Because Origanum vulgare L. (Lamiaceae) has antioxidative properties, it might protect against above-mentioned damage.Objective: This study evaluated the protective effects of O. vulgare extract on CP-induced liver toxicity. Materials and methods: Mice were pretreated with aerial parts of O. vulgare ethanolic extract (intraperitoneally) at doses of 50, 100, 200, and 400 mg/kg for 7 consecutive days before the administration of a single 200 mg/kg intraperitoneal dose of CP 1 h after the last injection of O. vulgare. After 24 h, animals were anesthetized, blood samples and hepatic tissues were collected and used for biochemical and histological examination. Results: Serum levels of hepatic markers were increased after CP treatment but restored in the O. vulgare-pretreated groups. The serum ALT, AST, and ALP of the CP group were 196.49 ± 3.82, 143.78 ± 4.79, and 203.18 ± 3.81 IU/l, respectively. However, pretreatment with 400 mg/kg O. vulgare significantly decreased the serum ALT, AST, and ALP to 52.49 ± 2.18, 44.78 ± 2.06, and 65.62 ± 1.73 IU/l, respectively (p50.001). Histological examinations also confirmed the protective effects of O. vulgare against CP-induced liver toxicity. Discussion and conclusion: Our results reveal that O. vulgare with high amount of flavonoids and phenolic compounds induces potent hepatoprotective mechanisms against CP. Therefore, O. vulgare might help defend the body against the side effects, particularly hepatic damages induced by chemotherapeutic agents.

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Section: Discussionmentioning

confidence: 99%

Protective effects ofOriganum vulgareethanol extract against cyclophosphamide-induced liver toxicity in mice

Habibi

Shokrzadeh²,

Chabra³

et al. 2014

Pharmaceutical Biology

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“…Competition with 4-hydroxylation is the major oxidative pathway that causes the dechloroethylation and the formation of the neurotoxic metabolites chloroacetaldehyde and 2-and3-dechloroethylifosfamide. The potential inhibition of CYP3A4 by aprepitant [18] may increase the levels of ifosfamide metabolites resulting in accumulation and further risk of encephalopathy and other side effects like hemorrhagic cystitis or neutropenia [14].…”

Section: Discussionmentioning

confidence: 99%

Ifosfamide Induced Neurotoxicity Secondary to Concomitant Aprepitant Use

Malhotra¹,

Poiesz²

2012

Adv Pharmacoepidem Drug Safety

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“…3 de Jonge et al 4 have shown that aprepitant inhibits cyclophosphamide metabolism, thus resulting in decreased formation of 4-HOCP.…”

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confidence: 99%

“…3 The alkylating agent cyclophosphamide is an inactive prodrug that requires activation to form its active metabolite 4-hydroxycyclophosphamide (4-HOCP), with major participation by CYP2A6, CYP2B6 and CYP3A4. 3 de Jonge et al 4 have shown that aprepitant inhibits cyclophosphamide metabolism, thus resulting in decreased formation of 4-HOCP.…”

mentioning

confidence: 99%

“…Warr et al 2 have suggested that aprepitant could be a useful antiemetic for prevention of CINV associated with moderately emetogenic chemotherapy, such as the adriamycin/cyclophosphamide (AC) regimen used for breast cancer treatment.Aprepitant is metabolized primarily via cytochrome P-450 (CYP) 3A4-mediated oxidation, with minor metabolism by other cytochromes.3 The alkylating agent cyclophosphamide is an inactive prodrug that requires activation to form its active metabolite 4-hydroxycyclophosphamide (4-HOCP), with major participation by CYP2A6, CYP2B6 and CYP3A4.3 de Jonge et al 4 have shown that aprepitant inhibits cyclophosphamide metabolism, thus resulting in decreased formation of 4-HOCP.It was with great interest that we read the recent paper by Yeo et al 5 concerning aprepitant-based CINV prophylaxis in moderately emetogenic chemotherapy. They studied a homogeneous group of Chinese breast cancer patients who underwent adjuvant AC chemotherapy (i.e.…”

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confidence: 99%

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Does neurokinin-1-receptor antagonist aprepitant diminish the efficacy of cyclophosphamide-based chemotherapy?

Paiva

Michelin

2009

Sao Paulo Med. J.

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Neurokinin-1-receptor antagonist aprepitant has been approved for clinical use based on two prospective phase III trials conducted with cisplatin-based highly emetogenic chemotherapy.1 It was developed for use in combination with a 5-HT3-receptor antagonist and corticosteroid in order to prevent both acute and delayed chemotherapy-induced nausea and vomiting (CINV). Warr et al. 2 have suggested that aprepitant could be a useful antiemetic for prevention of CINV associated with moderately emetogenic chemotherapy, such as the adriamycin/cyclophosphamide (AC) regimen used for breast cancer treatment.Aprepitant is metabolized primarily via cytochrome P-450 (CYP) 3A4-mediated oxidation, with minor metabolism by other cytochromes.3 The alkylating agent cyclophosphamide is an inactive prodrug that requires activation to form its active metabolite 4-hydroxycyclophosphamide (4-HOCP), with major participation by CYP2A6, CYP2B6 and CYP3A4.3 de Jonge et al. 4 have shown that aprepitant inhibits cyclophosphamide metabolism, thus resulting in decreased formation of 4-HOCP.It was with great interest that we read the recent paper by Yeo et al. 5 concerning aprepitant-based CINV prophylaxis in moderately emetogenic chemotherapy. They studied a homogeneous group of Chinese breast cancer patients who underwent adjuvant AC chemotherapy (i.e. doxorubicin 60 mg/m 2 and cyclophosphamide 600 mg/m 2 ). They unexpectedly found lower incidences of neutropenia of grade ≥ 3, and delay in the subsequent chemotherapy cycle. These important results led us to consider the possibility that aprepitant and cyclophosphamide drug interactions could decrease 4-HOCP formation and affect treatment efficacy.By considering cytochrome P450 genetic polymorphisms among different breast cancer populations, we think that the clinical relevance of the aforementioned drug interaction should be urgently addressed in new studies and in different ethnic groups.

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Aprepitant inhibits cyclophosphamide bioactivation and thiotepa metabolism

Cited by 62 publications

References 21 publications

Protective effects ofOriganum vulgareethanol extract against cyclophosphamide-induced liver toxicity in mice

Protective effects ofOriganum vulgareethanol extract against cyclophosphamide-induced liver toxicity in mice

Ifosfamide Induced Neurotoxicity Secondary to Concomitant Aprepitant Use

Does neurokinin-1-receptor antagonist aprepitant diminish the efficacy of cyclophosphamide-based chemotherapy?

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