Metformin, a biguanide that has been used to treat type 2 diabetes mellitus, is reportedly transported into human hepatocytes by human organic cation transporter 1 (hOCT1). The objective of this study was to investigate differences in the hepatic uptake of metformin and phenformin, a biguanide derivative similar to metformin. Special focus was on the role of active transport into cells. Experiments were therefore performed using human cryopreserved hepatocytes and hOCT1 expressing oocytes. Both biguanides proved to be good substrates for hOCT1. However, phenformin exhibited a much higher affinity and transport activity, with a marked difference in uptake kinetics compared with metformin. Both biguanides were transported actively by hOCT1, with the active transport components much greater than passive transport components in both cases, suggesting that functional changes in hOCT1 might affect the transport of both compounds to the same degree. This study for the first time produced detailed comparative findings for uptake profiles of metformin and phenformin in human hepatocytes and hOCT1 expressing oocytes. It is considered that hOCT1 may not be the only key factor that determines the frequency of metformin and phenformin toxicity, considering the major contribution of this transporter to the total hepatic uptake and comparable width of their therapeutic concentrations.

A quantitative structure-activity relationship (QSAR) model of the fetal-maternal blood concentration ratio (F/M ratio) of chemicals was developed to predict the placental transfer in humans. Data on F/M ratio of 55 compounds found in the literature were separated into training (75%, 41 compounds) and testing sets (25%, 14 compounds). The training sets were then subjected to multiple linear regression analysis using the descriptors of molecular weight (MW), topological polar surface area (TopoPSA), and maximum E-state of hydrogen atom (Hmax). Multiple linear regression analysis and a cross-validation showed a relatively high adjusted coefficient of determination (R a 2 ) (0.73) and cross-validated coefficient of determination (Q 2 ) (0.71), after removing three outliers. In the external validation, R 2 for external validation (R 2 pred ) was calculated to be 0.51. These results suggested that the QSAR model developed in this study can be considered reliable in terms of its robustness and predictive performance. Since it is difficult to examine the F/M ratio in humans experimentally, this QSAR model for prediction of the placental transfer of chemicals in humans could be useful in risk assessment of chemicals in humans.Key words placental transfer; human; quantitative structure-activity relationship; fetal-maternal blood concentration ratioThe placental transfer of chemicals is crucial for toxicity assessment of fetus, because chemicals that do not penetrate the placenta are considered safe for fetus.1) Therefore, investigations of many drugs that are transferred from mother to fetus through the placenta have been performed.Since it is difficult to measure the placental transfer of chemicals in humans ethically, in vitro and ex vivo methods have been developed and used for the evaluation of human placental transfer.2) In in vitro methods, cell lines from human placenta, such as BeWo, JAr, and JEG cells, have been commonly used as models of the placental barrier.3) In ex vivo methods, the human placenta is perfused to investigate the transfer of chemicals from maternal to fetal compartment. Although this system has been validated in many studies, and therefore this system is considered reliable, there are difficulties in conducting this evaluation method. 2,4)Quantitative structure-activity relationship (QSAR) models are useful tools for predicting the biological activity of chemicals. Descriptors of chemicals such as molecular weight and log P, are needed to develop QSAR prediction, and those are determined by experiments, calculation, or predicted using software. In the field of pharmacokinetics, QSAR models have been developed and reported in areas such as oral bioavailability, Caco-2 permeability, and metabolism. 5-7)QSAR models for predicting the placental transfer of chemicals using ex vivo data have already been reported. 8,9) However, to our knowledge, this is the first report that indicates prediction of the fetal-maternal blood concentration ratio (F/M ratio) of chemicals using in vivo data. To predict t...

The plasma concentration profile, urinary excretion rate and diuretic response were studied in anaesthetized dogs after an intravenous administration of torasemide or furosemide. The urinary excretion rate of furosemide decreased rapidly after administration. The plasma concentration, which is related to the urinary excretion profile, also decreased rapidly. The diuretic response, which reflected the excretion rate, occurred rapidly after administration but lasted for a short time. The urinary excretion rate of torasemide was much lower than that of furosemide and decreased slowly after administration. The plasma concentration also decreased slowly. The diuretic response to torasemide occurred more slowly but lasted longer than the response to furosemide. These results suggest that the diuretic response profile of either diuretic depends on their urinary excretion rate, and that the difference in the diuretic response between torasemide and furosemide may be explained by the different transfer rate of the drugs from the plasma to the nephron.

Incubation of inverted plasma membrane vesicles from rat liver with micromolar concentrations of Sdinitrophenylglutathione (DNP-SG) in the presence of ATP resulted in the uptake of DNP-SG into the vesicles. ATP-dependent DNP-SG accumulation was half-maximal with 9 PM DNP-SG, while the K,,, for ATP was 320 PM. Glutathione disulfide (GSSG), but not reduced glutathione, inhibited the ATP-dependent accumulation of DNP-SG by the vesicles, suggesting that the same, ATP-dependent transport system is responsible for the extrusion of glutathione conjugates and GSSG from liver