Abstract
It is essential to predict the pharmacokinetics (PK) of drugs in the process of drug development. Thus, to accurately predict the human PK before starting the clinical studies, the concept of in vitro-in vivo extrapolation (IVIVE) has been utilized. Since PK is determined as an output from detoxification system consisting of multiple metabolic enzymes and uptake/efflux transporters, it is difficult to predict the PK without in vitro experimental systems which maintain the expression of all the PK-related genes. Moreover, species differences in expression/function of those genes have to be considered. Therefore, it is very effective to use human-derived tissue samples for IVIVE. We have been involving many researches to clarify the impact of transporters on the in vivo PK with the use of human cryopreserved hepatocytes and kidney slices. We demonstrated that in vitro uptake clearances of transporter substrate drugs into human hepatocytes and kidney slices were well correlated with in vivo human hepatic (non-renal) and renal clearances, respectively. Moreover, by the use of probe substrates and inhibitors for each transporter isoform, we succeeded in the estimation of the relative contribution of each transporter to the tissue uptake of drugs. Regarding the prediction of drug interactions, though the decrease in the renal secretion clearance by the coadministration of cimetidine was believed to be due to the inhibition of organic cation transporter (OCT) 2, we proposed that the inhibition of renal efflux transporter, multidrug and toxin extrusion (MATE), should be a true target for drug interaction with cimetidine.
