Chemistry, pharmacology and pharmacokinetics of N,N′,N′′ -triethylenethiophosphoramide (ThioTEPA)

Maanen, Maria J. van; Smeets, C.J.M.; Beijnen, Jos H.

doi:10.1053/ctrv.2000.0170

Cited by 110 publications

(56 citation statements)

References 62 publications

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“…Thiotepa and tepa have comparable alkylating activity. 28 As a result, only summed AUCs were used in the statistical analyses. The summed AUC of thiotepa and tepa is mainly determined by the AUC of tepa, which is 1.5-2 fold greater than the AUC of the parent compound.…”

Section: Compound Median Total Auc (Lower-upper) Permanent Alopecia Imentioning

confidence: 99%

Relationship between irreversible alopecia and exposure to cyclophosphamide, thiotepa and carboplatin (CTC) in high-dose chemotherapy

Jonge

Mathôt

Dalesio

et al. 2002

Bone Marrow Transplant

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Summary:Reversible alopecia is a commonly observed, important and distressing complication of chemotherapy. Permanent alopecia, however, is rare after standard-dose therapy, but has occasionally been observed after high-dose chemotherapy with cyclophosphamide, thiotepa and carboplatin (CTC). We evaluated the relationships between total exposure to these three compounds and their different metabolites in the high-dose CTC regimen, and the subsequent development of irreversible alopecia. Twenty-four patients received two or three courses of high-dose CTC, each followed by peripheral blood progenitor cell transplantation. Plasma levels of cyclophosphamide, its active metabolite 4-hydroxycyclophosphamide, thiotepa, its active metabolite tepa, and carboplatin were determined, and the area-under-theplasma concentration-versus-time curves (AUC) of the compounds were calculated. Eight of the 24 patients included in the study developed permanent alopecia, while seven had normal hair regrowth and nine patients developed incomplete and/or thin hair regrowth. The carboplatin AUC and the summed AUC of thiotepa and tepa were both significantly associated with increasing irreversibility of hair loss. These results suggest that high exposure to carboplatin and the sum of the thiotepa and tepa exposure may lead to the development of permanent alopecia. This knowledge could guide therapeutic drug monitoring in order to prevent the occurrence of permanent alopecia and thereby improve the patients' quality of life.

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Section: Compound Median Total Auc (Lower-upper) Permanent Alopecia Imentioning

confidence: 99%

Relationship between irreversible alopecia and exposure to cyclophosphamide, thiotepa and carboplatin (CTC) in high-dose chemotherapy

Jonge

Mathôt

Dalesio

et al. 2002

Bone Marrow Transplant

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“…N,NЈ,NЉ-Triethylenethiophosphoramide (tTEPA) is a nonspecific antineoplastic agent that is used in the treatment of ovarian, breast, and bladder cancers (van Maanen et al, 2000). This drug was developed in the 1950s and has experienced a renewed interest due to its efficiency in treating cancer in high-dose regimens.…”

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confidence: 99%

Metabolism ofN,N′,N″-Triethylenethiophosphoramide by CYP2B1 and CYP2B6 Results in the Inactivation of Both Isoforms by Two Distinct Mechanisms

Harleton

Webster

Bumpus

et al. 2004

J Pharmacol Exp Ther

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The anticancer drug N,N,ЉNЉ-triethylenethiophosphoramide (tTEPA) inactivated CYP2B6 and CYP2B1 in the reconstituted system in a time-, concentration-, and NADPH-dependent manner indicative of mechanism-based inactivation. The K I value for the inactivation of CYP2B1 was 38 M, the k inact was 0.3 min Ϫ1 , and the t 1/2 value was 2.5 min. Spectral carbon monoxide (CO) binding and high-performance liquid chromatography heme studies of the tTEPA-inactivated CYP2B1 suggest that the loss in the enzymatic activity was primarily due to the binding of a reactive tTEPA intermediate to the 2B1 apoprotein. Inactivation by tTEPA in the presence of 7-ethoxycoumarin, an alternate substrate, reduced the rate of inactivation of CYP2B1. Incubations with tTEPA and NADPH resulted in greater than 90% loss in the 7-ethoxy-4-(trifluoromethyl)coumarin O-deethylation and testosterone hydroxylation activity of CYP2B1. In contrast, benzphetamine metabolism was significantly less inhibited (47%). CYP2B6 was inactivated by tTEPA with a K I value of 50 M, a k inact value of 0.1 min Ϫ1 , and a t 1/2 value of 14 min. However, unlike CYP2B1, the tTEPA-inactivated human isoform showed losses in the cytochrome P450 (P450) CO spectrum, the pyridine hemochrome spectrum, and in the amount of native heme that were comparable with the loss in the 7-EFC and benzphetamine activity, suggesting that activity loss was brought about by a tTEPA-reactive intermediate damaging the CYP2B6 heme. CYP2B6 could only be protected from the tTEPA-dependent inactivation by the 2B6-specific substrate bupropion but not by other substrates of CYP2B such as benzphetamine, testosterone, or 7-ethoxycoumarin. The data indicate that tTEPA metabolism by these two 2B isoforms results in inactivation of the P450s by two distinct mechanisms.Cytochromes P450 (P450s) catalyze the metabolism of both endogenous substrates such as steroids, fatty acids, and fatsoluble vitamins, as well as exogenous compounds such as drugs and pesticides. CYP2B1, the major phenobarbital-inducible isoform found in rat (Gonzalez, 1988) and CYP2B6, the human isoform of CYP2B1, share greater than 70% sequence homology.Inhibition of P450 enzymes by certain drugs such as raloxifene, mifepristone, and ketoconazole, or compounds found in food such as bergamottin and sylibin can pose a problem in the clinic when these enzymes are required for the metabolism of coadministered drugs (Guengerich, 1995;Schmiedlin-

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“…Toxicities associated with thiotepa treatment are mainly mucositis and central nervous system toxicity. The most frequently aVected organs being the liver and gastrointestinal tract, resulting in nausea, vomiting and diarrhoea [4]. Moreover, a relation between ASAT toxicity and thiotepa AUC has been demonstrated [2].…”

Section: Discussionmentioning

confidence: 99%

“…Less than 2% of the administered dose of thiotepa is eliminated unchanged in the urine. Renal elimination of tepa accounts for approximately 11% of the administered dose [4,5]. Carboplatin is a platinum compound, with renal elimination accounting for almost all drug elimination.…”

Section: Introductionmentioning

confidence: 99%

Altered cyclophosphamide and thiotepa pharmacokinetics in a patient with moderate renal insufficiency

Ekhart

Kerst

Rodenhuis

et al. 2008

Cancer Chemother Pharmacol

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Purpose We report a patient with renal insuYciency (creatinine clearance, CL cr = 38 mL/min) who received high-dose chemotherapy with cyclophosphamide (1,500 mg/m 2 day ¡1 ), thiotepa (120 mg/m 2 day ¡1 ) and carboplatin (AUC = 5 mg min/mL day ¡1 ) for four consecutive days. Methods Blood samples were collected on day 1 and 3 and plasma levels of cyclophosphamide, its active metabolite 4-hydroxycyclophosphamide, thiotepa, its main metabolite tepa and carboplatin were determined. Results Pharmacokinetic analyses indicated that the elimination of cyclophosphamide, thiotepa, carboplatin, but especially tepa was strongly reduced in this patient, resulting in increased exposures to these compounds of 67, 43, 30 and 157%, respectively, compared to a reference population (n = 24) receiving similar doses. Exposure to 4-hydroxycyclophosphamide increased 11%. Conclusion These results suggest that it may not be necessary to alter the dose of cyclophosphamide in patients with moderate renal impairment. However, because high exposures to thiotepa and tepa have been correlated with increased toxicity, caution should be applied when administering thiotepa to patients with renal insuYciency.

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Chemistry, pharmacology and pharmacokinetics of N,N′,N′′ -triethylenethiophosphoramide (ThioTEPA)

Cited by 110 publications

References 62 publications

Relationship between irreversible alopecia and exposure to cyclophosphamide, thiotepa and carboplatin (CTC) in high-dose chemotherapy

Relationship between irreversible alopecia and exposure to cyclophosphamide, thiotepa and carboplatin (CTC) in high-dose chemotherapy

Metabolism ofN,N′,N″-Triethylenethiophosphoramide by CYP2B1 and CYP2B6 Results in the Inactivation of Both Isoforms by Two Distinct Mechanisms

Altered cyclophosphamide and thiotepa pharmacokinetics in a patient with moderate renal insufficiency

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