Polymorphisms of drug‐metabolizing enzymes (GST, CYP2B6 and CYP3A) affect the pharmacokinetics of thiotepa and tepa

Abstract

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT• Thiotepa is metabolized by oxidative desulphuration by the cytochrome P450 (CYP) enzymes CYP2B6 and CYP3A4 to tepa. • Furthermore, thiotepa and tepa are conjugated to glutathione, which is catalysed by glutathione S-transferase (GST) isoenzymes A1-1 and P1-1. • Polymorphisms in these enzymes could influence exposure to thiotepa and tepa.• Little is known about the influence of polymorphisms in these enzymes on the pharmacokinetics of thiotepa and tepa. WHAT THIS STUDY ADDS• The presently evaluated variant alleles explain only a small part of the substantial interindividual variability in thiotepa and tepa pharmacokinetics.• We show that probably only the GSTP1 C341T variant allele influences thiotepa exposure to a clinically relevant extent. AIMSThiotepa 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. METHODSWhite 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). RESULTSThe 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. CONCLUSIONSThis 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.

Influence of pharmacogenetics on response and toxicity in breast cancer patients treated with doxorubicin and cyclophosphamide

“…For example, the CYP2B6*9 variant has been associated with a decreased clearance of the anti-retroviral reverse transcriptase inhibitor efavirenz (Haas et al, 2004;Ramachandran et al, 2009). Conversely, in a cohort of patients receiving thiotepa as therapy for a range of solid tumours, CYP2B6*5 variant carriers had a lower exposure to the CYP2B6 substrates, thiotepa and tepa, indicating a fast metaboliser phenotype (Ekhart et al, 2009). Given the inconsistencies in the literature and the low frequency of some of the CYP2B6 SNPs investigated in this study, these results should be treated as preliminary and require corroboration in an independent cohort.…”

Influence of CYP2B6 516G>T polymorphism and interoccasion variability (IOV) on the population pharmacokinetics of efavirenz in HIV-infected South African children

“…Intra-individual variability of EFV pharmacokinetics (PK) was shown to be far less with CV% below 30% [21][22][23][24][25]. This variability can be attributed to various factors such as environment (drug-drug interactions, drug-food interactions, recreational drug intake), physiology (gender, age, disease state and pregnancy), non-adherence, difference in dosage bioavailability and genetic polymorphisms [3,[13][14][15][26][27][28].…”

“…The half-life calculated for children (n=48) in Burkina Faso (CL=0.211 l/h/kg; V=4.48 l/kg) was 14.7 h [18] and for children (n=11) in Germany, 12.93 h [19]. The median estimated half-lives in HIV-infected adults genotyped as CYP2B6 516 G/G, G/T and T/T were 23 [interquartile range (IQR) [18][19][20][21][22][23][24][25][26][27][28][29][30][31][32][33][34][35], [27][28][29][30][31] and h respectively [20].…”

Effects of Pregnane X Receptor (NR1I2) and CYP2B6 Genetic Polymorphisms on the Induction of Bupropion Hydroxylation by Rifampin

“…The common allele CYP2B6*6 (c.516GϾT and c.785AϾG) leads to aberrant splicing of pre-mRNA, resulting in reduced expression of functional transcript and protein in human liver (Hofmann et al, 2008). Associations between CYP2B6 genetic polymorphisms and pharmacokinetics have been reported for bupropion (Kirchheiner et al, 2003), thiotepa (Ekhart et al, 2009), and efavirenz (Rotger et al, 2007).…”