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At least 19 recordsLinked to original sources
PubMed1985

Gas chromatographic analysis of triethylenethiophosphoramide and triethylenephosphoramide in biological specimens.

Comprehensive pharmacokinetic studies could realise a greater potential for the antitumour agent triethylenethiophosphoramide (ThioTEPA), and these would be aided by the development of a selective and sensitive assay. After extraction of ThioTEPA and its metabolite, triethylenephosphoramide (TEPA), from plasma using Sep-Pak C18 cartridges, the compounds were separated by capillary chromatography, detected using a nitrogen detector and quantified by reference to an internal standard, hexaethylphosphoramide. The limits of sensitivity were 1-5 ng/ml. Analytical recoveries were 74 and 95%, for TEPA and ThioTEPA, respectively, in the therapeutic range. At similar concentrations, extents of protein binding, determined by ultrafiltration, were not significant. Preliminary investigations of the elimination of ThioTEPA show that drug loss occurs more quickly in mice than in humans and in both species the metabolite is extensively recycled.

Animals↗
PubMed1988

High-performance liquid chromatography of the anti-tumour agent triethylenethiophosphoramide and its metabolite triethylenephosphoramide with sodium sulphide, taurine and o-phthalaldehyde as pre-column fluorescent derivatization reagents.

The method described is based on the reaction of triethylenethiophosphoramide (ThioTEPA) and triethylenephosphoramide (TEPA), through their ethyleneimine groups, with sodium sulphide, taurine and o-phthalaldehyde to give fluorescent products, and separation of the derivatives by reversed-phase high-performance liquid chromatography. The method was successfully applied to the determination of ThioTEPA and TEPA in rabbit plasma samples after clean-up with an Extrelut 3 column. The recoveries of ThioTEPA and TEPA from plasma were 66.1-80.3% and the limits of determination in plasma were ca. 10 and 20 ng/ml, respectively.

Animals↗
PubMed1991

Interaction of N,N',N''-triethylenethiophosphoramide and N,N',N''-triethylenephosphoramide with cellular DNA.

The antineoplastic agents N,N',N''-triethylenethiophosphoramide (thioTEPA) and N,N',N''-triethylenephosphoramide (TEPA) were studied for their interaction with the DNA of L1210 cells in the presence and absence of rat hepatic microsomes and NADPH. Alkaline elution was used to study 3 types of DNA lesions. When L1210 cells were incubated with thioTEPA alone, or with thioTEPA in the presence of microsomes and NADPH, no single-strand breaks were detected. However, incubation of L1210 cells for 2 h with thioTEPA, at concentrations greater than or equal to 100 microM, caused a dose-dependent increase in interstrand cross-linking that reached a maximum by 2 h after drug exposure. In the presence of rat hepatic microsomes and NADPH, this cross-linking was eliminated, but a different DNA lesion, alkali-labile sites, was produced. These alkali-labile sites were partially reparable with maximum repair achieved by 2 h after removal of drug. ThioTEPA was greater than 85% consumed by the microsomal incubation conditions employed, and TEPA was the only product of the microsomal metabolism of thioTEPA. Alkaline elution studies of L1210 cells that had been incubated with TEPA, alone or in the presence of microsomes and NADPH, demonstrated an elution pattern identical to that produced by thioTEPA in the presence of microsomes and NADPH. Lymphoblastoid cell lines derived from patients with Fanconi's anemia were far more sensitive to thioTEPA and mechlorethamine hydrochloride than were lymphoblasts derived from normal humans, but this hypersensitivity was not noted with TEPA or bleomycin. This is consistent with the known hypersensitivity of cells from patients with Fanconi's anemia to agents that produce interstrand cross-links and with the alkaline elution studies described above. In contrast, lymphoblastoid cell lines derived from patients with ataxia telangiectasia were no more sensitive to thioTEPA than were lymphoblasts derived from normal humans but were far more sensitive to bleomycin. One of these cell lines proved hypersensitive to TEPA, whereas the other was no more sensitive to TEPA than were lymphoblasts from normal humans. Our data imply that thioTEPA produces interstrand cross-links but that TEPA, the primary metabolite of thioTEPA, produces DNA lesions that are alkali labile.

Animals↗
PubMed1990

Biotransformation of N,N',N''-triethylenethiophosphoramide: oxidative desulfuration to yield N,N',N''-triethylenephosphoramide associated with suicide inactivation of a phenobarbital-inducible hepatic P-450 monooxygenase.

Oxidative metabolism of the polyfunctional alkylating agent N,N',N''-triethylenethiophosphoramide (thio-TEPA) was studied in isolated rat liver microsomes and purified, reconstituted cytochrome P-450 (P-450) enzyme systems in order to elucidate the pathways of drug oxidation and to identify the possible contributions of individual P-450 enzymes to the bioactivation of this chemotherapeutic agent. Rat liver microsomes were found to catalyze conversion of thio-TEPA to its oxo metabolite, N,N',N''-triethylenephosphoramide (TEPA), in a P-450-dependent reaction that was markedly stimulated by prior in vivo treatment with drug inducers of hepatic P-450 subfamily IIB (phenobarbital), but not by pretreatment with inducers of P-450 subfamilies IA (beta-naphthoflavone) or IIE (isoniazid). Thio-TEPA depletion and TEPA formation catalyzed by phenobarbital-induced liver microsomes were both inhibited by greater than 90% by antibodies selectively reactive with P-450 PB-4 (gene product IIB1), the major phenobarbital-inducible rat liver microsomal P-450 form, but not by antibodies inhibitory toward 7 other rat hepatic P-450s. Oxidation of thio-TEPA to TEPA was also catalyzed by purified P-450 PB-4 (Km (app) 19 microM; Vmax (app) = 11 mol thio-TEPA metabolized/min/mol P-450 PB-4) following reconstitution of the cytochrome with NADPH P-450 reductase in a lipid environment. Metabolism of thio-TEPA by P-450 PB-4 was associated with a suicide inactivation of the cytochrome characterized by kinactivation = 0.096 min-1, KI = 24 microM, and a partition ratio of 136 +/- 28 (SD) mol thio-TEPA metabolized/mol P-450 inactivated. The thio-TEPA metabolite TEPA, however, did not inactivate the cytochrome, nor was it subject to further detectable metabolism. In microsomal incubations, metabolism of thio-TEPA led to the inactivation of P-450 PB-4 (steroid 16 beta-hydroxylase) as well as P-450 IIIA-related enzymes (steroid 6 beta-hydroxylase) and the P-450-independent enzyme steroid 17 beta-hydroxysteroid:NADP+ 17-oxidoreductase, as demonstrated by use of the P-450 form-selective steroidal substrate androst-4-ene-3,17-dione. In contrast, little or no inactivation of microsomal P-450 IIA-related enzymes (steroid 7 alpha-hydroxylase) or microsomal NADPH P-450 reductase was observed.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗
PubMed1991

N,N',N''-triethylenethiophosphoramide (thio-TEPA) oxygenation by constitutive hepatic P450 enzymes and modulation of drug metabolism and clearance in vivo by P450-inducing agents.

The cancer chemotherapeutic drug N,N',N''-triethylenephosphoramide (thio-TEPA) is oxidatively desulfurated to yield the active metabolite N,N',N''-triethylenephosphoramide (TEPA) in a reaction catalyzed by the phenobarbital-inducible rat liver P450 enzyme IIB1. In the current study, the role of constitutively expressed P450 enzymes in thio-TEPA metabolism was studied using purified P450s, isolated liver microsomes, and intact rats. Metabolism of thio-TEPA (100 microM) to TEPA by uninduced adult female and male rat liver microsomes proceeded at initial rates of 0.10 and 0.28 nmol TEPA formed/min/mg microsomal protein, respectively. Although these rates are low compared to those catalyzed by phenobarbital-induced liver microsomes (3.5 nmol TEPA/min/mg), they are sufficient to contribute to the systemic metabolism of this drug. Thio-TEPA metabolism catalyzed by uninduced female liver microsomes was approximately 70% inhibitable by antibodies selectively reactive with P450 IIC6. For the uninduced male liver microsomes, which exhibit a severalfold higher rate of thio-TEPA metabolism, enzyme activity was only 15-20% inhibitable by these antibodies but was 80-85% inhibited by an anti-P450 IIC6 monoclonal antibody cross-reactive with P450 IIC11, which is expressed only in the males. Consistent with these observations, purified P450s IIC11 and IIC6 both oxidized thio-TEPA in reconstituted systems (turnover, 1.1 and 0.3 min-1 P450-1, respectively, at 100 microM substrate), while several other constitutive hepatic P450s exhibited significantly lower or undetectable activities (turnover, less than or equal to 0.15 min-1 P450-1). Metabolism of thio-TEPA by purified P450 IIC11 was associated with a time-dependent inactivation of the cytochrome analogous to that previously shown to accompany thio-TEPA metabolism catalyzed by P450 IIB1. Depletion of hepatic P450 IIC11 by cisplatin treatment of adult male rats led to a 70% reduction of TEPA formation catalyzed by the isolated liver microsomes, suggesting that cisplatin may influence thio-TEPA pharmacokinetics when these two drugs are given in combination. The extent to which hepatic P450s contribute to thio-TEPA metabolism and clearance in vivo was assessed by monitoring thio-TEPA and TEPA pharmacokinetics in rats that exhibit widely differing rates of microsomal thio-TEPA metabolism, i.e., uninduced female and male rats, and male rats treated with the P450 IIB1 inducers clofibrate and phenobarbital. In accord with the microsomal activities, conversion of thio-TEPA to TEPA was less extensive and thio-TEPA elimination slower in female than in male rats.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗
PubMed1987

Influence of the tissue distribution of ThioTEPA and its metabolite, TEPA, on the response of murine colon tumours.

Disposition studies in the same animals as those used for assessment of antitumor and toxic effects could increase understanding of the variation in response to cytotoxic drugs. Tissue and plasma levels of ThioTEPA and triethylenephosphoramide (TEPA) were measured to see if any correlation existed between them and the effects of the drug on a series of mouse colon tumours (MAC). The tumour panel included an ascitic form (MAC 15A), an anaplastic (MAC 13) and a well-differentiated (MAC 26) solid tumour, all grown subcutaneously. The maximum tolerated dose of ThioTEPA was 20 mg kg-1 in females bearing MAC 13 and 15 mg kg-1 in males having MAC 15A or 26. The diverse growth characteristics of the tumour cell lines necessitated the use of different methods for assessment of response. After administration of the maximum tolerated dose, the greatest response was observed in MAC 26, in which a growth delay of 15 days-twice the doubling time of the tumour volume-occurred. ThioTEPA produced 58% inhibition of MAC 13 tumour weight, but MAC 15A was unresponsive. One hour after intraperitoneal administration of Thio-TEPA (20 mg kg-1), ratios of tissue to plasma concentration were 1.13, 0.87 and 1.17 in tumours and 0.80, 0.75 and 0.73 in spleens of mice bearing MAC 13, 15A and 26 respectively. These data show greater accumulation of drug in neoplastic than in normal tissues. The pattern of distribution of the metabolite was similar, but there was a lesser degree of tissue accumulation than by the drug. Concentrations of drug and metabolite in neoplastic tissues related to their protein content were 116.0, 126.3 and 183.3 micrograms ThioTEPA/g and 57.5, 83.1 and 78.6 micrograms TEPA/g in MAC 13, 15A and 26 respectively. Combination of these chemosensitivity and pharmacokinetic data indicates that differences in response of these tumours to ThioTEPA cannot be explained by the availability of the drug and metabolite. The therapeutic effects of ThioTEPA cannot be predicted purely from a knowledge of drug and metabolite disposition.

Adenocarcinoma↗
PubMed1991

Metabolism and alkylating activity of thio-TEPA in rat liver slice incubation.

Precision-cut rat-liver slices were used to study the metabolism of the alkylating agent N,N',N''-triethylenethiophosphoramide (thio-TEPA). Exposure to high concentrations (1-10 mM) of thio-TEPA for 6 h did not prove to be toxic to the liver slices as indicated by insignificant leakage of potassium from the cells. The time course of the disappearance of thio-TEPA (initial concentration, 5.2 microM) from the buffer during incubation followed first-order kinetics. Formation of N,N'N''-triethylenephosphoramide (TEPA) apparently accounted for the elimination of thio-TEPA. Pretreatment of the rats with phenobarbital significantly increased the reaction rate. Conversely, pretreatment with the cytochrome P-450 inhibitor allylisopropylacetamide significantly reduced the metabolic rate. The elimination of thio-TEPA and formation of TEPA occurred independently of thio-TEPA concentration, which ranged from 5.2 to 104 microM. Thio-TEPA's oxo-analogue TEPA, which was not further metabolized, was the only metabolite identified. However, a significantly time-related increase in 4-(nitrobenzyl)-pyridine (NBP) alkylating activity was observed following incubation of liver slices with thio-TEPA but not after their incubation with TEPA. This may possibly indicate the formation of unknown active metabolites.

Alkylation↗
PubMed1991

Phase I/pharmacokinetic reevaluation of thioTEPA.

Because the initial evaluation of N,N',N''-triethylenethiophosphoramide (thioTEPA) preceded the standardized approach to the Phase I trials, uncertainty surrounds the recommended dose. Since it has recently been demonstrated that an almost 100-fold increase in dose can be administered in bone marrow transplant regimens, we conducted a Phase I reevaluation of thioTEPA. ThioTEPA was administered i.v. in 50 ml 5% dextrose in water over 10 min. Twenty-seven patients were entered at doses ranging from 30 to 75 mg/m2. The major toxic effect was myelosuppression; thrombocytopenia greater than or equal to grade 3 occurred in four of seven patients, and leukopenia greater than or equal to grade 3 in two of seven patients at 75 mg/m2. Among eight patients at 65 mg/m2 only two had greater than or equal to grade 3 myelosuppression making this the recommended new phase II dose for the majority of patients. Moderate (grade 2) easily controlled nausea and vomiting was the only other major side effect. There was no alopecia or mucosal or neurological toxicity. Three partial remissions were observed among nine previously treated ovarian cancer patients. Plasma concentrations of thioTEPA and its major active metabolite triethylenephosphoramide (TEPA) were measured by gas chromatography. The half-life of thioTEPA ranged from 51.6 to 211.8 min, and its pharmacokinetics was dose dependent; total body thioTEPA clearance decreased with increasing dose. The half-life of TEPA was considerably longer than that of the parent compound (3.0 to 21.1 h); as a result, the area under the plasma concentration-time curve (AUC) of TEPA was severalfold greater than that of the parent compound. The ratio of TEPA AUC to thioTEPA AUC decreased with increasing dose, suggesting that formation of TEPA is a saturable step in elimination. The AUC and total body clearance of thioTEPA, but not of TEPA, were closely correlated with neutrophil but not platelet toxicity.

Dose-Response Relationship, Drug↗
PubMed1990

Preclinical studies relating to the use of thiotepa in the high-dose setting alone and in combination.

In vitro and in vivo studies with N,N',N''-triethylene-thiophosphoramide (thiotepa) alone and in combination with cyclophosphamide (CTX) were carried out using the MCF-7 human breast carcinoma cell line and the EMT6 mouse mammary carcinoma cell line. In vitro, survival curves were essentially linear. The cytotoxicity of thiotepa toward MCF-7 cells was markedly dependent on the presence of oxygen during the period of drug exposure, with a 3-log greater cell kill at 500 mumol with cells that were normally oxygenated compared with hypoxic cells. Incubation of thiotepa with an Aroclor 1254-induced rat liver S-9 homogenate in the presence of a reduced nicotinamide adenine dinucleotide phosphate-regenerating system resulted in an eightfold increase in cytotoxicity toward the MCF-7 cells over a wide range of drug concentrations. The thiotepa metabolite N,N',N''-triethylenephosphoramide (TEPA) was significantly less cytotoxic toward the MCF-7 cells than was thiotepa. Simultaneous and immediately sequential treatments with thiotepa and CTX produced supra-additive cell killing of both cell lines, although the magnitude of the supra-additivity was greater in the MCF-7 cell line than in the EMT6 cell line. These drugs Vppeared to be equally effective as thiol-depleting agents. By DNA alkaline elution, there was a pattern of increasing DNA cross-linking similar to the increasing levels of cytotoxicity of this drug combination as the concentrations of thiotepa increased. In the EMT6 tumor in vivo, the maximally tolerated combination therapy (5 mg/kg x 6, thiotepa, and 100 mg/kg x 3, CTX) produced about 25 days of tumor growth delay, which was not significantly different than expected for additivity of the individual drugs. The survival of EMT6 tumor cells after treatment of the animals with the various single doses of thiotepa and CTX was assayed. Tumor cell killing by thiotepa produced a very steep, linear survival curve through 5 logs with increasing dose. The tumor cell survival cure for CTX to 500 mg/kg had linear tumor cell kill through almost 4 logs. In vivo modeling of quasicontinuous exposure (3 intraperitoneal over 9 hours) versus pulse (single-dose) administration of thiotepa and CTX compared EMT6 tumor cell survival with survival of bone marrow as a representative sensitive normal tissue. With CTX, there was a considerable increase in the therapeutic index (killing of tumor cells/killing of colony forming units-granulocyte macrophage) when the same total dose of drug was administered in multiple injections versus a single injection. For thiotepa, smaller increases in therapeutic index were also observed with the multiple-injection schedule.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗
PubMed1986

Pharmacokinetics of intraventricular and intravenous N,N',N''-triethylenethiophosphoramide (thiotepa) in rhesus monkeys and humans.

The cerebrospinal fluid (CSF) and plasma pharmacokinetics of N,N',N"-triethylenethiophosphoramide (thiotepa), an alkylating agent used for treatment of carcinomatous meningitis, were determined in rhesus monkeys in order to assess the relative advantage of intraventricular versus systemic administration of the drug. Following an i.v. thiotepa dose of 0.9 mg/kg (11 mg/sq m), peak plasma levels of parent drug reached approximately 1 microgram/ml. Thiotepa was rapidly equilibrated with lumbar and ventricular CSF. Systemic, lumbar, and ventricular exposure to the drug, measured as area under the curve (AUC), were similar in all cases. After a 1-mg intraventricular dose of thiotepa, peak ventricular levels were greater than 100 micrograms/ml. However, peak levels in the lumbar CSF at 1 h after intraventricular administration were less than 10 micrograms/ml. The AUC for ventricular CSF was nearly 100-fold greater for the intraventricular route than for the i.v. route; however, the AUC for lumbar CSF following intraventricular delivery was only 5% of the AUC for ventricular CSF. N,N',N''-Triethylenephosphoramide, an active metabolite of thiotepa observed in all fluids, appeared to have a much slower total body clearance than thiotepa. Comparison of the data obtained from monkey experiments with data from a patient with meningeal disease supports the use of the monkey as a model for intraventricular pharmacokinetics. The data presented indicate that there is no relative advantage to intraventricular administration of thiotepa at the doses currently used in clinical trials.

Animals↗
PubMed1995

Modulation of thiotepa antitumor activity in vivo by alteration of liver cytochrome P450-catalyzed drug metabolism.

The anticancer drug and alkylating agent thiotepa is metabolized by oxidative desulfuration to yield the alkylating metabolite N,N',N"-triethylenephosphoramide (TEPA) in a reaction that is catalyzed by specific liver cytochrome P450 (CYP) enzymes, including CYP2B1, the major phenobarbital-inducible P450 of rat liver, and CYP2C11, a constitutively expressed, male-specific form. The present study investigates the potential for modulating the cytotoxicity and antitumor activity of thiotepa by prior treatment of tumor-bearing rats with the CYP2B1 inducer phenobarbital or the CYP2C11 inhibitor 2-diethylaminoethyl-2,2-diphenylvalerate hydrochloride (SKF-525A) and examines the role of TEPA in the cytotoxicity of thiotepa in vivo. Administration of thiotepa to adult male rats bearing 9L gliosarcoma, grown s.c., resulted in dose-dependent cytotoxicity (ED90 approximately 12 mg/kg i.v., single dose), as determined by a tumor excision/in vitro colony formation assay carried out 24 hr after drug treatment. Tumor growth delay experiments revealed that thiotepa (5 mg/kg) inhibited 9L tumor growth over a 5- to 7-day period after alkylating agent treatment and this effect was accompanied by moderate body weight loss. Pretreatment with phenobarbital, under conditions in which liver CYP2B1 levels and liver microsomal thiotepa desulfuration to yield TEPA are both markedly increased, did not alter thiotepa's short-term (24-hr) cytotoxicity, as judged by a tumor excision assay, nor did it affect the extent of bone marrow toxicity associated with drug treatment. However, phenobarbital did block the tumor growth delay effect of thiotepa and it also attenuated the body weight loss that occurred during the first 5 days after drug treatment.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1994

In the search for new anticancer drugs. 26. A comparison of anticancer activities of several TEPA, thio-TEPA, Seleno-TEPA, and azetidine analogs, including congeners containing an aminoxyl moiety.

A series of TEPA, Thio-TEPA, Seleno-TEPA, and azetidine analogs, including congeners containing an aminoxyl moiety, were synthesized and evaluated in vivo for anticancer activity against the murine lymphocytic leukemia P388. All aziridine derivatives were found to be active with an increase in life span ranging from 42% to 272%, and all azetidine analogs were rated as inactive with one marginal exception. An attempt was made to rationalize the results on the basis of the lipophilic properties of the compounds. The most active compound (8) possessed the most balanced lipophilic properties, corresponding to a log P value near zero.

Animals↗
PubMed1984

Thiono compounds. 4. In vitro mutagenic and antineoplastic activity of TEPA and thio-TEPA.

Tris (1-aziridinyl) phosphine oxide (TEPA) and tris (1-aziridinyl) phosphine sulfide (thio-TEPA) induced base pair mutations in the Ames mutagenic assay. Thio-TEPA required metabolic activation while TEPA was active without metabolic activation. Growth of a human vaginal carcinoma (A431), a human breast carcinoma (MDA-MB-231), and a human cervical carcinoma (HeLa) were inhibited in soft agar in vitro at concentrations which induced mutagenesis in the Ames Assay. A fourth line, JEG choriocarcinoma, was sensitive to the antigrowth properties of both drugs at concentrations below that which induced mutagenesis. These data suggest that as more antineoplastic agents become available, and as mean survival times increase, knowledge of the relative in vitro sensitivity of a patient's neoplasm to a specific antineoplastic drug (i.e., dose required for growth inhibition) as a function of its mutagenic index might be useful for prediction of clinical remission, as well as the risk of secondary neoplasm induction.

Antineoplastic Agents↗
PubMed1979

Effects of alkylating agents on lymphocytes from controls and from patients with Fanconi's anemia. Studies of sister chromatid exchanges, chromosome aberrations, and kinetics of cell division.

The frequency of sister chromatid exchanges (SCE) and chromosome aberrations and the dynamics of cell division in peripheral blood lymphocytes of four patients with Fanconi's anemia were studied after in vitro exposure to alkylating agents TEPA and mitomycin. SCE frequency was significantly increased even after very low doses of mutagens, while chromosome aberrations were significantly increased only after high doses (0.160 micrograms/ml mitomycin and 10(-5) M TEPA). The responses of Fanconi's anemia cells and control cells did not differ significantly. The increased frequency of both SCE and chromosome aberrations was accompanied by gradual delay of cell division, which was most conspicuous in cells from patients with Fanconi's anemia.

Anemia, Aplastic↗
PubMed1990

Long-term pharmacokinetics of thio-TEPA, TEPA and total alkylating activity following i.v. bolus administration of thio-TEPA in ovarian cancer patients.

The serum pharmacokinetics of unchanged thio-TEPA and the active metabolite TEPA and the urinary excretion of thio-TEPA, TEPA and total alkylating activity were studied after a single i.v. bolus injection of thio-TEPA in six ovarian cancer patients. TEPA was present in serum as of 5 min after drug administration, and its concentration rapidly reached a plateau in the range of 50-100 ng/ml. After about 3 h the serum concentration of TEPA exceeded that of thio-TEPA, and in five of the six patients the metabolite persisted longer than the parent drug in serum. AUCs of thio-TEPA and TEPA were 822 +/- 83 and 1,084 +/- 234 ng h/ml, respectively. The great interindividual variation encountered in the serum pharmacokinetics of TEPA may be of clinical importance and represents a further indication that pharmacokinetically guided dosing of thio-TEPA could be valuable. Urinary recoveries of both thio-TEPA and TEPA were low, together constituting less than 2% of the delivered dose. A substantial gap existed between this and the total urinary alkylating activity, which averaged 13% of the dose in terms of thio-TEPA equivalents. This gap strongly indicates the presence of other unknown metabolites.

Adult↗
PubMed1990

ThioTEPA pharmacokinetics during intravesical chemotherapy and the influence of Tween 80.

A pharmacokinetic study of randomised crossover design was carried out in which eight patients with recurrent stage pTa or pT1 transitional cell carcinoma of the bladder were given thioTEPA (30 mg) in distilled water or in 10% (v/v) Tween 80 (30 ml) intravesically for 2 h, followed 3 months later by the alternative treatment. ThioTEPA and its primary metabolite, TEPA, were measured in plasma and urine using a sensitive and specific chromatographic assay. Large differences between patients were observed in the proportion of thioTEPA absorbed, ranging from 20%-78%. Peak plasma levels of thioTEPA were observed within 1 h of intravesical administration. By 2 h after administration the plasma levels of TEPA were similar to those of thioTEPA and, in contrast to those of the parent compound, remained at a similar level over the next 4 h. The rate of absorption of thioTEPA was not influenced by Tween 80, but it did cause statistically significant increases in mean peak plasma levels (from 101 to 154 ng/ml) and mean AUC values (from 0.376 to 0.496 micrograms h per ml) and a decrease in the mean half-life (from 1.83 to 1.25 h). To obtain plasma levels similar to those achieved after instillation with thioTEPA alone, the dose should be reduced with Tween 80.

Absorption↗
PubMed1991

Pharmacokinetics of thio-TEPA and TEPA in the conventional dose-range and its correlation to myelosuppressive effects.

A total of 13 patients with ovarian cancer were studied during the initial two courses of i.v. thio-TEPA treatment they underwent after primary surgery. Following an increase in the dose from 60 to 80 mg for the second course, no sign of saturation of thio-TEPA elimination processes or of formation of the metabolite TEPA occurred, indicating dose-independent pharmacokinetics. Myelosuppression after courses was registered by serial measurements of platelets and leukocytes. The time to platelet nadir was quite uniformly 3 weeks and tended to be longer than that of leukocytes, which averaged 2 weeks but showed greater interindividual variation. Linear regression analyses of pharmacokinetic parameters versus myelosuppression revealed statistically significant correlations between thio-TEPA pharmacokinetics and the percentage of reductions in leukocytes and platelets at their mean nadirs. In contrast, no such correlation could be demonstrated for TEPA despite its greater exposure to the body in terms of AUC. We advocate further investigation of this pharmacokinetic-pharmacodynamic relationship so as to establish individualized dosing of thio-TEPA.

Aged↗