3Xenobiotic transporters play key roles in disposition of a certain therapeutic agents although limited information is available on their roles other than pharmacokinetic issues. Here, suppressive effect of multispecific organic cation transporter OCTN1/SLC22A4 on liver fibrosis was proposed in liver injury models. After injection of hepatotoxins such as dimethylnitrosamine (DMN) or concanavalin A, hepatic fibrosis and oxidative stress, evaluated in terms of Sirius red and 4-hydroxy-2-nonenal staining, respectively, were more severe in liver of octn1/slc22a4 gene knockout (octn1 -/-) mice than that in wild-type mice. DMN treatment markedly increased α-smooth muscle actin

Objectives Carnitine/organic cation transporter 1 (OCTN1) is involved in gastrointestinal absorption and mitochondrial toxicity of biguanides in rodents, but its pharmacokinetic roles in humans are largely unknown. The purpose of this study was to clarify the transport activities of two major OCTN1 variants, L503F and I306T, for gabapentin and three biguanide drugs, metformin, buformin and phenformin. Methods HEK293 cells were transfected with OCTN1 gene, its variants, or vector alone, and the uptake and cytotoxicity of each drug were examined. Key findings Buformin was identified to be an OCTN1 substrate. Uptake of biguanides, especially metformin, mediated by OCTN1 variant L503F, which is commonly found in Caucasians, was much higher than that by the wild‐type transporter (WT‐OCTN1). Cytotoxicity of metformin was also greater in HEK293 cells expressing the L503F variant, compared with WT‐OCTN1. Uptake of gabapentin mediated by OCTN1 variant I306T, which is commonly found in both Asians and Caucasians, was lower than that by WT‐OCTN1, although uptake of the typical OCTN1 substrate ergothioneine was similar. Conclusion Organic cation transporter 1 variant L503F transports biguanides, especially metformin, more efficiently than WT‐OCTN1, whereas the I306T variant transports gabapentin less efficiently than WT‐OCTN1, suggesting that the common OCTN1 variants may alter pharmacokinetics of these drugs.

Polymorphism c.421C>A in the gene is thought to reduce the activity of breast cancer resistance protein (BCRP), a xenobiotic transporter, although it is not clear which organ(s) contributes to the polymorphism-associated pharmacokinetic change. The aim of the present study was to estimate quantitatively the influence of c.421C>A on intestinal and hepatic BCRP activity using a physiologically based pharmacokinetic (PBPK) model of rosuvastatin developed from clinical data and several in vitro studies. Simultaneous fitting of clinical data for orally and intravenously administered rosuvastatin, obtained in human subjects without genotype information, was first performed with the PBPK model to estimate intrinsic clearance for hepatic elementary process. The fraction of BCRP activity in 421CA and 421AA (f and f values, respectively) with respect to that in 421CC subjects was then estimated based on extended clearance concepts and simultaneous fitting to oral administration data for the three genotypes (421CC, 421CA, and 421AA). On the assumption that c.421C>A affects both intestinal and hepatic BCRP, clinical data in each genotype were well reproduced by the model, and the estimated terminal half-life was compatible with the observed values. The assumption that c.421C>A affects only either intestinal or hepatic BCRP gave poorer agreement with observed values. The f values obtained on the former assumption were 0.48-0.54. Thus, PBPK model analysis enabled quantitative evaluation of alteration in BCRP activity owing to c.421C>A, and BCRP activity in 421AA was estimated as half that in 421CC.

Quantitative assessment of drug-drug interactions (DDIs) via organic anion transporting polypeptide (OATP) 1B1 is one of the key issues in drug development. Although OATP1B1 inhibition exhibits unique characteristics, including preincubation dependence for some inhibitors, a limited approach has been attempted based on the static model that considers such preincubation dependence in the prediction of DDIs via OATP1B1. The present study aimed to establish the prediction of DDIs via OATP1B1 using preincubationdependent inhibitors based on the static model and incorporating both inactivation and recovery of OATP1B1 activity. Cyclosporine A was selected as a preincubation-dependent inhibitor, as well as five substrates that include probes and pharmaceuticals. The inhibition ratio (R value) calculated on the basis of a conventional static model, considering inhibition of OATP1B1 and contribution ratio of OATP1B1 to the overall hepatic uptake, was much lower than the reported AUC ratio, even when IC 50 values were estimated after preincubation conditions. Conversely, the R value that was estimated by considering inactivation and recovery parameters was closer to the AUC ratio. The R value that was calculated assuming the complete contribution of OATP1B1 was much higher than the AUC ratio, avoiding false-negative prediction. The R value estimated by considering inactivation and recovery for another combination of a preincubation-dependent inhibitor, asunaprevir, and substrate drug, rosuvastatin, was also closer to the AUC ratio. Thus, R values calculated based on such OATP1B1 kinetics would be potential alternative indexes for the quantitative prediction of OATP1B1-mediated DDIs using preincubation-dependent inhibitors, although this prediction is affected by estimation of the contribution ratio of substrates. SIGNIFICANCE STATEMENTStatic model-based quantitative prediction of organic anion transporting polypeptide 1B1-mediated drug-drug interactions induced by preincubation-dependent inhibitors was newly proposed to avoid false-negative prediction.

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