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The remarkable properties of pristine B 3 O 3 nanosheet as a nanocarrier for adsorption and desorption of TEPA anticancer drug for designing potential drug delivery platform were investigated using periodic DFT calculations. We studied the adsorption energy of all stable complexes formed between the drug molecule and B 3 O 3 in gas and aqueous phases along with electronic structure analysis of complexes. Different adsorption configurations were studied for drug/B 3 O 3 complexes, including the interaction of the C atom of the triangular ring, O atom in the TEPA drug with the B atom in B 3 O 3 , and indirect drug interaction the middle of the R1 ring cavity of the B 3 O 3 nanosheet. The take-up of TEPA prompts a substantial change of 68.13% in the band gap (E g ) of the B 3 O 3 nanosheet in the most stable complex. The present study results affirmed the application of B 3 O 3 nanosheet as a potential vehicle for TEPA drugs in the treatment of cancerous tissues., (© 2021. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Aims: Thiotepa is widely used in high-dose chemotherapy. Previous studies have shown relations between exposure and severe organ toxicity. Thiotepa is metabolized by cytochrome P450 and glutathione S-transferase enzymes. Polymorphisms of these enzymes may affect elimination of thiotepa and tepa, its main metabolite. The purpose of this study was to evaluate effects of known allelic variants in CYP2B6, CYP3A4, CYP3A5, GSTA1 and GSTP1 genes on pharmacokinetics of thiotepa and tepa., Methods: White patients (n = 124) received a high-dose regimen consisting of cyclophosphamide, thiotepa and carboplatin as intravenous infusions. Genomic DNA was analysed using polymerase chain reaction and sequencing. Plasma concentrations of thiotepa and tepa were determined using validated GC and LC-MS/MS methods. Relations between allelic variants and elimination pharmacokinetic parameters were evaluated using nonlinear mixed effects modelling (nonmem)., Results: The polymorphisms CYP2B6 C1459T, CYP3A4*1B, CYP3A5*3, GSTA1 (C-69T, G-52A) and GSTP1 C341T had a significant effect on clearance of thiotepa or tepa. Although significant, most effects were generally not large. Clearance of thiotepa and tepa was predominantly affected by GSTP1 C341T polymorphism, which had a frequency of 9.3%. This polymorphism increased non-inducible thiotepa clearance by 52% [95% confidence interval (CI) 41, 64, P < 0.001] and decreased tepa clearance by 32% (95% CI 29, 35, P < 0.001) in heterozygous patients, which resulted in an increase in combined exposure to thiotepa and tepa of 45% in homozygous patients., Conclusions: This study indicates that the presently evaluated variant alleles explain only a small part of the substantial interindividual variability in thiotepa and tepa pharmacokinetics. Patients homozygous for the GSTP1 C341T allele may have enhanced exposure to thiotepa and tepa.

A sensitive assay for the determination of N,N',N"-triethylenethiophosphoramide (thioTEPA) and its metabolite N,N',N"-triethylenephosphoramide (TEPA) in micro-volumes human plasma and urine has been developed. ThioTEPA and TEPA were analysed using gas chromatography with selective nitrogen-phosphorus detection or mass spectrometry after extraction with a mixture of 1-propanol-chloroform from the biological matrix. Diphenylamine was used as internal standard. The limit of detection was 1.5 ng/ml for thioTEPA and 2.5 ng/ml for TEPA, using 100 microl of biological sample; recoveries ranged between 70 and 90% and both accuracy and precision were less than 10%. Linearity was accomplished in the range of 10-1000 ng/ml for plasma and 100-10000 ng/ml for urine using thermionic nitrogen-phosphorus detection. With mass spectrometry a linear range of 100-25000 ng/ml TEPA in plasma or urine was obtained. For thioTEPA a second-order polynomial function describes the relationship between the analyte concentration in the range of 500-25000 ng/ml and detection response. TEPA proved to be stable in plasma and urine for at least 10 weeks at -80 degrees C. ThioTEPA and TEPA plasma concentrations of two patients treated with thioTEPA are presented demonstrating the applicability of the assay for clinical samples.

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.

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.