Organic cation transporter (OCT) 2, multidrug and toxin extrusion protein (MATE) 1, and MATE2K mediate the renal secretion of various cationic drugs and can serve as the loci of drug-drug interactions (DDI). To support the evaluation of cynomolgus monkey as a surrogate model for studying human organic cation transporters, monkey genes were cloned and shown to have a high degree of amino acid sequence identity versus their human counterparts (93.7, 94.7, and 95.4% for OCT2, MATE1, and MATE2K, respectively). Subsequently, the three transporters were individually stably expressed in human embryonic kidney (HEK) 293 cells and their properties (substrate selectivity, time course, pH dependence, and kinetics) were found to be comparable to the corresponding human form. For example, six known human cation transporter inhibitors, including pyrimethamine (PYR), showed generally similar IC 50 values against the monkey transporters (within sixfold). Consistent with the in vitro inhibition of metformin (MFM) transport by PYR (IC 50 for cynomolgus OCT2, MATE1, and MATE2K; 1.2 6 0.38, 0.17 6 0.04, and 0.25 6 0.04 mM, respectively), intravenous pretreatment of monkeys with PYR (0.5 mg/kg) decreased the clearance (54 6 9%) and increased in the area under the plasma concentration-time curve of MFM (AUC ratio versus control = 2.23; 90% confidence interval of 1.57 to 3.17). These findings suggest that the cynomolgus monkey may have some utility in support of in vitroin vivo extrapolations (IVIVEs) involving the inhibition of renal OCT2 and MATEs. In turn, cynomolgus monkey-enabled IVIVEs may inform human DDI risk assessment. IntroductionIt is widely appreciated that renal elimination of cations, drug, toxin, or endogenous metabolite related, is achieved not only by glomerular filtration but also by active transport processes that facilitate their tubular secretion and reabsorption. Indeed, the mechanisms governing the renal elimination of organic cations have been studied in detail, and the transporters facilitating their tubular uptake and extrusion have been identified (Okuda et al., 1996;Otsuka et al., 2005;Masuda et al., 2006).Secretion of organic cations in renal proximal tubules involves at least two distinct transporters, located in the basolateral and apical membranes of proximal tubule cells (Motohashi et al., 2002Masuda et al., 2006). Specifically, organic cations, like metformin (MFM), 1-methyl-4-phenylpyridinium (MPP + ), tetraethylammonium (TEA), and cimetidine (CMD), are taken up from the circulation by organic cation transporter 2 (OCT2) expressed on the basolateral domain of renal proximal tubular cells. In turn, uptake is followed by efflux into the tubular fluid by multidrug and toxin extrusion protein (MATE) 1 and MATE2K expressed on the apical domain of the same cells. Therefore, OCT2 and MATEs function coordinately to mediate vectorial transport of certain cationic drugs, from blood to tubular fluid, which represents the tubular secretion clearance component of total renal clearance. Perturbation of c...

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Despite a recent expansion in the recognition of the potential utility of coproporphyrin (CP) as an endogenous biomarker of organic anion-transporting polypeptide (OATP) 1B activity, there have been few detailed studies of CP's pharmacokinetic behavior and an overall poor understanding of its pharmacokinetic fate from tissues and excretion. Here, we describe the pharmacokinetics of octadeuterium-labeled coproporphyrin I (CPI-d8) in cynomolgus monkeys following oral and intravenous administration. CPI-d8 has a half-life and bioavailability of 7.6 hours and 3.2%, respectively. Cynomolgus monkeys received oral cyclosporin A (CsA) at 4, 20, and 100 mg/kg which yielded maximum blood concentrations (C max ) and area under the plasma concentration-time curve (AUC) values of 0.