Development of the quantitative prediction method of pharmacokinetics with considering the function of metabolic enzymes and transporters

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The purpose of this study is to clarify the cooperative roles of metabolic enzymes and transporters expressed in liver, kidney and intestine in the drug absorption and excretion quantitatively. Regarding the transporters in kidney, we constructed the OAT1- or OAT3-expressing LLC-PK1 cells and observed the transcellular transport of several compounds in this cell line, suggesting the involvement of apical efflux transporters. We also clarified the involvement of Mrp4 in the apical efflux of adefovir and ceftizoxime in kidney by using Mrp4 knockout mice and gene expression systems. As for the liver, we established the methodology for the prediction of the change in the clearance by the induction of metabolic enzymes in humans and showed the good prediction of the pharmacokinetics of substrates of CYP3A4 when CYP3A4 was induced by coadministered drugs Moreover, we first clarified that Mrp3 expressed in basal membrane is involved in the pharmacokinetics of fexofenadine and methotrexate (un … More changed form) by using knockout mice. In the small intestine, we found that both BCRP and SULT are expressed more at the lower part compared to the upper part, and that intestinal secretion of 4-MUS and minoxidil sulfate to luminal side at the lower part was higher than that at the upper part in small intestine in mice, indicating that SUIT and BCRP cooperatively work for the efficient detoxification. We clarified that BCRP also works as a efflux transporter for the limit of the distribution of several drugs (dantrolene, prazosin) and carcinogenic compounds (MelQx, PhIP in brain and testis. In these tissues, the relative contribution of P-gp and BCRP to the overall efflux is determined by the physicochemical properties of compounds. Also, we established the methodology for the quantitative prediction of drug-drug interaction mediated by CYP3A4 in the small intestine and demonstrated the good prediction of drug-drug interaction between midazolam and ketoconazole in the small intestine by using apparent intestinal volume. Less