Although OATP1B1 is not expressed in the kidney, polymorphisms in SLCO1B1 have been associated with methotrexate clearance or toxicity. This unexpected pharmacogenetic association may reflect remote communication between liver and kidney transporters. This study confirms the pharmacogenetic association with methotrexate toxicity in adult patients with hematological malignancies. Using a targeted urinary metabolomics approach, we identified 38 and 34 metabolites which were differentially excreted between wildtype and carriers of the c.388A>G or c.521T>C variant alleles, respectively, half of them being associated with methotrexate toxicity. These metabolites mainly consisted of fatty acid derivatives and microbiota catabolites, including glycine conjugates and other uremic toxins, all known OATs substrates. These results suggest that dysfunction of a transporter affects the excretion profile of endogenous or exogenous substrates, possibly through metabolite-mediated interactions involving other transport systems, even in distant organs. This opens the way for better comprehension of complex pharmacokinetics and transporter-mediated drug-drug or nutrient-drug interactions.

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Clinical Therapeutics e28 Volume 39 Number 8S and 26% analgesics. 85% of NPs prescribed paracetamol, 76% omeprazole, 71% amoxicillin or amoxicillin with clavulanic acid, 68% salbutamol, 68% flucloxacillin, 67% prednisone, 67% loratidine, 65% ibuprofen, and 64% aspirin. The primary care scope of practice NPs prescribed a median (IQR) of 198 (140 to 285) unique medications. Conclusions: NPs prescribe a very broad range of medications for a wide variety of health conditions. Patients often live in deprived communities.

Urine metabolomic profiling can identify biochemical alterations resulting from various injuries affecting the graft outcome after renal transplantation. Here, we aimed to describe in depth the metabolite content of urines of renal transplant patients and to link it with the major injury factors acting at critical stages following transplantation. Morning urine samples were prospectively collected from 38 kidney transplant patients at 7 days (D7), 3 months (M3) and 12 months (M12) after transplantation. Twenty-five patients were treated with tacrolimus (Tac) and thirteen patients with cyclosporine (CsA). (1)H-NMR (proton nuclear magnetic resonance) and gas chromatography-mass spectrometry (GC-MS) were used to examine the overall metabolomic signature of each sample. Multivariate analysis was performed to study the changes in the metabolic profile over time and their dependency on the type of calcineurin inhibitor (CNI) administered to patients. Biological pathways affected by transplantation were identified using a metabolomics pathway analysis (MetPA) web-tool. The metabolic profile of urine samples clearly varied with time. Markers of medullary injury, tubule cell oxidative metabolism and impaired tubular reabsorption or secretion were present at D7. Differences in metabolic profiles became less marked as time passed on, urine content being quite similar at M3 and M12. The metabolite profile tended to differ between patients receiving Tac and those receiving CsA but no clear discriminating profiles can be found. The combination of (1)H-NMR and GC-MS for the analysis of urine metabolomic profiles is a very useful method to study patho-physiological alterations in kidney transplant patients over time.

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