Widely used as anti-cancer and immunosuppressive agents, thiopurines have narrow therapeutic indices due to frequent toxicities, partly explained by TPMT genetic polymorphisms. Recent studies identified germline NUDT15 variation as another critical determinant of thiopurine intolerance, but the underlying molecular mechanisms and its clinical implications remain unknown. In 270 children enrolled in clinical trials for acute lymphoblastic leukemia in Guatemala, Singapore, and Japan, we identified 4 NUDT15 coding variants (p.Arg139Cys, p.Arg139His, p.Val18Ile, p.Val18_Val19insGlyVal) that resulted in 74.4%–100% loss of nucleotide diphosphatase activity. Loss-of-function NUDT15 diplotypes were consistently associated with thiopurine intolerance across three cohorts (P=0.021, 2.1×10−5, and 0.0054, respectively; meta-analysis P=4.45×10−8, allelic effect size=−11.5). Mechanistically, NUDT15 inactivated thiopurine metabolites and decreased its cytotoxicity in vitro, and patients with defective NUDT15 alleles showed excessive thiopurine active metabolites and toxicity. Taken together, our results indicate that a comprehensive pharmacogenetic model integrating NUDT15 variants may inform personalized thiopurine therapy.
DPYD, TYMS, and MTHFR play a limited role for FU related toxicity but a pronounced DPYD gene/sex-interaction increases prediction rate for male patients. Toxicity risk assessment should include sex, mode of administration, and folinic acid as additional predictive factors.
Aims The C3435T polymorphism in the human MDR1 gene is associated with lower intestinal P-glycoprotein expression, reduced protein function in peripheral blood cells and higher plasma concentrations of the P-glycoprotein substrate digoxin. Using fexofenadine, a known P-glycoprotein substrate, the hypothesis was tested whether this polymorphism also affects the disposition of other drugs in humans. Methods Ten Caucasian subjects homozygous for the wild-type allele at position 3435 (CC) and 10 individuals homozygous for T at position 3435 participated in this study. A single oral dose of 180 mg fexofenadine HCl was administered. Plasma and urine concentrations of fexofenadine were measured up to 72 h using a sensitive LC/MS method. In addition, P-glycoprotein function was assessed using efflux of the P-glycoprotein substrate rhodamine 123 from CD56 + cells.Results Fexofenadine plasma concentrations varied considerably among the study population. However, fexofenadine disposition was not significantly different between the CC and TT groups (e.g. AUC(0,?) CC vs TT: 3567.1t1535.5 vs 3910.1t1894.8 ng ml x1 h, NS; 95% CI on the difference x1364.9, 2050.9).In contrast, P-glycoprotein function was significantly decreased in CD56 + cells of the TT compared with the CC group (rhodamine fluorescence CC vs TT: 45.6t7.2% vs 61.1t12.3%, P<0.05; 95% CI on the difference 5.6, 25.5).Conclusions In spite of MDR1 genotype-dependent differences in P-glycoprotein function in peripheral blood cells, there was no association of the C3435T polymorphism with the disposition of the P-glycoprotein substrate fexofenadine in this German Caucasian study population. These data indicate that other mechanisms including uptake transporter function are likely to play a role in fexofenadine disposition.
Metformin, an oral insulin-sensitizing drug, is actively transported into cells by organic cation transporters (OCT) 1, 2, and 3 (encoded by SLC22A1, SLC22A2, or SLC22A3), which are tissue specifically expressed at significant levels in various organs such as liver, muscle, and kidney. Because metformin does not undergo hepatic metabolism, drug-drug interaction by inhibition of OCT transporters may be important. So far, comprehensive data on the interaction of proton pump inhibitors (PPIs) with OCTs are missing although PPIs are frequently used in metformin-treated patients. Using in silico modeling and computational analyses, we derived pharmacophore models indicating that PPIs (i.e. omeprazole, pantoprazole, lansoprazole, rabeprazole, and tenatoprazole) are potent OCT inhibitors. We then established stably transfected cell lines expressing the human uptake transporters OCT1, OCT2, or OCT3 and tested whether these PPIs inhibit OCT-mediated metformin uptake in vitro. All tested PPIs significantly inhibited metformin uptake by OCT1, OCT2, and OCT3 in a concentration-dependent manner. Half-maximal inhibitory concentration values (IC50) were in the low micromolar range (3–36 µM) and thereby in the range of IC50 values of other potent OCT drug inhibitors. Finally, we tested whether the PPIs are also transported by OCTs, but did not identify PPIs as OCT substrates. In conclusion, PPIs are potent inhibitors of the OCT-mediated metformin transport in vitro. Further studies are needed to elucidate the clinical relevance of this drug-drug interaction with potential consequences on metformin disposition and/or efficacy.
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