Cytochrome P450 isozymes 3A4 and 2B6 are involved in the in vitro human metabolism of thiotepa to TEPA

Jacobson, Pamala A.; Green, K; Birnbaum, Angela K.; Remmel, Rory P.

doi:10.1007/s00280-002-0453-3

Cited by 41 publications

(6 citation statements)

References 18 publications

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“…Thiotepa is primarily metabolized by the hepatic system, where it is rapidly biotransformed by CYP3A4 and CYP2B6 to its key metabolite, TEPA, which is also an alkylating agent [3, 17]. The plasma–concentration curves in pediatric patients with solid tumors or brain tumors, and malignant lymphoma showed a rapid decline in thiotepa concentration following IV administration, with a slower elimination phase for the TEPA metabolite, as expected.…”

Section: Discussionmentioning

confidence: 81%

“…Thiotepa ( N , N ′, N ″-triethylenethiophosphoramide) is an alkylating agent that has been used to treat solid tumors and hematological diseases since the 1950s [1, 2]. In vitro studies suggest that thiotepa is metabolized by cytochrome P450 3A4 (CYP3A4) and cytochrome P450 2B6 (CYP2B6) to triethylene phosphoramide (TEPA) [3], which shows a comparable alkylating activity to the parent drug [4]. Because of its broad-spectrum antitumor activity and relative lack of extramedullary toxicity, thiotepa has been incorporated in high-dose chemotherapy (HDT) with autologous hematopoietic stem cell transplantation (HSCT) for various solid tumors and hematological malignancies [5–9].…”

Section: Introductionmentioning

confidence: 99%

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Pharmacokinetics of thiotepa in high-dose regimens for autologous hematopoietic stem cell transplant in Japanese patients with pediatric tumors or adult lymphoma

Kondo

Ikeda

Goto

et al. 2019

Cancer Chemother Pharmacol

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PurposeThiotepa is used in high-dose chemotherapy (HDT) before autologous hematopoietic stem cell transplantation (HSCT) to treat solid tumors and hematological malignancies. This Phase 1 study was conducted to establish the pharmacokinetics (PK) of thiotepa in a Japanese population.MethodsHDT/HSCT was performed in pediatric patients (≥ 2 years) with solid tumors or brain tumors (thiotepa 200 mg/m2/day IV-infused over 24 h on HSCT Days − 12, − 11, − 5, and − 4 and melphalan 70 mg/m2/day IV-infused over 1 h on Days − 11, − 5, and − 4) and adult patients (≥ 16 years) with malignant lymphoma (thiotepa 200 mg/m2/day 2-h IV-infusion on HSCT Days − 4 and − 3 plus busulfan 0.8 mg/kg 2-h IV-infusion every 6 h from HSCT Days − 8 to − 5). Pharmacokinetics of thiotepa were assessed following initial dose. Safety and efficacy were also evaluated.ResultsNine pediatric and 10 adult patients were enrolled. Mean volume of distribution (Vz) of thiotepa normalized with body surface area (BSA) was lower for pediatric patients (16.4 L/m2) compared with adult patients (26.4 L/m2) as expected due to the higher specific surface area of children. Clearance and biological half-life were similar between pediatric and adult patients. Two serious adverse events (cardiac arrest and pulmonary edema) were observed. Survival rate (Day 100 post-HSCT) was 77.8% (95% CI 36.5–93.9%) for pediatric patients and 100% for adult patients.ConclusionThiotepa elimination was comparable in pediatric and adult patients with cancer. Lower Vz in pediatric compared with adult patients was expected. HDT with thiotepa prior to autologous HSCT was well tolerated.Study registrationJapic CTI-163433.Electronic supplementary materialThe online version of this article (10.1007/s00280-019-03914-2) contains supplementary material, which is available to authorized users.

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Section: Discussionmentioning

confidence: 81%

Section: Introductionmentioning

confidence: 99%

Pharmacokinetics of thiotepa in high-dose regimens for autologous hematopoietic stem cell transplant in Japanese patients with pediatric tumors or adult lymphoma

Kondo

Ikeda

Goto

et al. 2019

Cancer Chemother Pharmacol

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“…Drug-related iatrogenia is a major source of treatment failures, especially when multiple medications are used. CYP3A4 and CYP2B6 are the main cytochrome enzymes involved in the metabolism of thiotepa to tepa [ 12 , 13 ]. Thiotepa was described to be a highly potent, irreversible inhibitor of CYP2B6, which can lead to a risk of a self-induced overdose via a metabolic predisposition of each patient.…”

Section: Discussionmentioning

confidence: 99%

“…Its major metabolite tepa, has similar alkylating activity [ 10 , 11 ]. This hepatic biotransformation is mediated by CYP3A4 and CYP2B6, and conjugation is catalyzed by glutathione S-transferase (GST) [ 12 , 13 ]. Following intravenous administration, drug exposure in cerebrospinal fluid (CSF) is almost equivalent to that of the product in plasma [ 14 ].…”

Section: Introductionmentioning

confidence: 99%

High-dose thiotepa-related neurotoxicity and the role of tramadol in children

Maritaz¹,

Lemare²,

Laplanche³

et al. 2018

BMC Cancer

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BackgroundSerious neurological adverse events (NAE) have occurred during treatment with high-dose thiotepa regimens of children with high-risk solid tumours. The objective was to assess the incidence of NAE related to high-dose thiotepa and to identify potential contributing factors that could exacerbate the occurrence of this neurotoxicity.MethodsFrom May 1987 to March 2011, children with solid tumours treated with high-dose thiotepa were retrospectively identified. Each NAE detected led to an independent case analysis. Potential contributing factors were pre-specified and univariate/multivariable analyses were performed.ResultsThree hundred seven courses of thiotepa (251 patients) were identified. The total dose per treatment ranged from 600 to 900 mg/m2. 81 NAE (26%) were identified. 46 NAE were related to high-dose thiotepa during the first course (18.3%) and 11 during the second course (19.6%). The symptoms appeared in a median time of 2 days after the introduction of thiotepa. Central and peripheral symptoms were headaches, tremors, confusion, seizures, cerebellar syndrome, and coma. High-dose thiotepa was reintroduced in 18 cases and symptoms reappeared in 5 children. For 3 patients who had seizures during the first course, premedication with clonazepam for the second course has prevented recurrence of NAE. As contributing factors, brain tumour and tramadol treatment increased the risk of thiotepa-related neurotoxicity by 2 to 6 times respectively.ConclusionsThe incidence of neurotoxicity was 18.3%. Brain tumours and tramadol treatment are risk factors to consider when using high-dose thiotepa. The outcome of patients was favourable without sequelae in all cases and rechallenge with thiotepa was possible.

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“…ThioTEPA-mercapturate was generated from thioTEPA through the intermediate metabolites monoglutathionylthioTEPA and thioTEPA-cysteinate [8–9]. Previous studies have suggested that cytochrome P450s CYP3A4, 2B1, 2B6, and 2C11 were the primary metabolic enzymes involved in the conversion of thioTEPA to TEPA [10–12]. In addition, monochloroTEPA can be produced non-enzymatically from TEPA in vivo and in vitro , which is highly dependent on pH [13].…”

Section: Introductionmentioning

confidence: 99%

A comprehensive understanding of thioTEPA metabolism in the mouse using UPLC–ESI-QTOFMS-based metabolomics

Patterson

Höfer³

et al. 2011

Biochemical Pharmacology

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ThioTEPA, an alkylating agent with anti-tumor activity, has been used as an effective anticancer drug since the 1950s. However, a complete understanding of how its alkylating activity relates to clinical efficacy has not been achieved, the total urinary excretion of thioTEPA and its metabolites is not resolved, and the mechanism of formation of the potentially toxic metabolites S-carboxymethylcysteine (SCMC) and thiodiglycolic acid (TDGA) remains unclear. In this study, the metabolism of thioTEPA in a mouse model was comprehensively investigated using ultra-performance liquid chromatography coupled with electrospray ionization quadrupole time-of-flight mass spectrometry (UPLC-ESI-QTOFMS) based-metabolomics. The nine metabolites identified in mouse urine suggest that thioTEPA underwent ring-opening, N-dechloroethylation, and conjugation reactions in vivo. SCMC and TDGA, two downstream thioTEPA metabolites, were produced from thioTEPA from two novel metabolites 1,2,3-trichloroTEPA (VII) and dechloroethyltrichloroTEPA (VIII). SCMC and TDGA excretion were increased about 4-fold and 2-fold, respectively, in urine following the thioTEPA treatment. The main mouse metabolites of thioTEPA in vivo were TEPA (II), monochloroTEPA (III) and thioTEPA-mercapturate (IV). In addition, five thioTEPA metabolites were detected in serum and all shared similar disposition. Although thioTEPA has a unique chemical structure which is not maintained in the majority of its metabolites, metabolomic analysis of its biotransformation greatly contributed to the investigation of thioTEPA metabolism in vivo, and provides useful information to understand comprehensively the pharmacological activity and potential toxicity of thioTEPA in the clinic.

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Cytochrome P450 isozymes 3A4 and 2B6 are involved in the in vitro human metabolism of thiotepa to TEPA

Abstract: Thiotepa is metabolized in human liver microsomes by CYP3A4 (major) and CYP2B6 (minor). There is a potential for CYP-mediated drug interactions with thiotepa. Pharmacokinetic variability of thiotepa may be related to expression of hepatic CYP isozymes.

Cited by 41 publications

References 18 publications

Pharmacokinetics of thiotepa in high-dose regimens for autologous hematopoietic stem cell transplant in Japanese patients with pediatric tumors or adult lymphoma

Pharmacokinetics of thiotepa in high-dose regimens for autologous hematopoietic stem cell transplant in Japanese patients with pediatric tumors or adult lymphoma

High-dose thiotepa-related neurotoxicity and the role of tramadol in children

A comprehensive understanding of thioTEPA metabolism in the mouse using UPLC–ESI-QTOFMS-based metabolomics

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