Predictability of human pharmacokinetics of drugs that undergo hepatic organic anion transporting polypeptide (OATP)-mediated transport using single-species allometric scaling in chimeric mice with humanized liver: integration with hepatic drug metabolism
Creators: name: Sanoh, Seigo
name: Naritomi, Yoichi
name: Kitamura, Satoshi
name: Shinagawa, Akihiko
name: Kakuni, Masakazu
name: Chise Tateno
name: Ohta, Shigeru
Publisher: name: Taylor & Francis
Year: 2020
Subjects: subject: Biochemistry
subject: Microbiology
subject: FOS: Biological sciences
subject: FOS: Biological sciences
subject: Cell Biology
subject: Genetics
subject: Physiology
subject: Pharmacology
subject: 39999 Chemical Sciences not elsewhere classified
subject: FOS: Chemical sciences
subject: FOS: Chemical sciences
subject: Cancer
subject: 111714 Mental Health
subject: FOS: Health sciences
subject: FOS: Health sciences
subject: 110309 Infectious Diseases
subject: 60506 Virology
subject: Computational Biology

description: We previously reported a prediction method for human pharmacokinetics (PK) using single species allometric scaling (SSS) and the complex Dedrick plot in chimeric mice with humanized liver to predict the total clearance (CL<sub>t</sub>), distribution volumes in steady state (Vd<sub>ss</sub>) and plasma concentration-time profiles of several drugs metabolized by cytochrome P450 (P450) and non-P450 enzymes. In the present study, we examined eight compounds (bosentan, cerivastatin, fluvastatin, pitavastatin, pravastatin, repaglinide, rosuvastatin, valsartan) as typical organic anion transporting polypeptide (OATP) substrates and six compounds metabolized by P450 and non-P450 enzymes to evaluate the predictability of CL<sub>t</sub>, Vd<sub>ss</sub> and plasma concentration-time profiles after intravenous administration to chimeric mice.The predicted CL<sub>t</sub> and Vd<sub>ss</sub> of drugs that undergo OATP-mediated uptake and P450/non-P450-mediated metabolism reflected the observed data from humans within a threefold error range.We also examined the possibility of predicting plasma concentration-time profiles of drugs that undergo OATP-mediated uptake using the complex Dedrick plot in chimeric mice. Most profiles could be superimposed with observed profiles from humans within a two- to threefold error range.PK prediction using SSS and the complex Dedrick plot in chimeric mice can be useful for evaluating drugs that undergo both OATP-mediated uptake and P450/non-P450-mediated metabolism. We previously reported a prediction method for human pharmacokinetics (PK) using single species allometric scaling (SSS) and the complex Dedrick plot in chimeric mice with humanized liver to predict the total clearance (CL<sub>t</sub>), distribution volumes in steady state (Vd<sub>ss</sub>) and plasma concentration-time profiles of several drugs metabolized by cytochrome P450 (P450) and non-P450 enzymes. In the present study, we examined eight compounds (bosentan, cerivastatin, fluvastatin, pitavastatin, pravastatin, repaglinide, rosuvastatin, valsartan) as typical organic anion transporting polypeptide (OATP) substrates and six compounds metabolized by P450 and non-P450 enzymes to evaluate the predictability of CL<sub>t</sub>, Vd<sub>ss</sub> and plasma concentration-time profiles after intravenous administration to chimeric mice. The predicted CL<sub>t</sub> and Vd<sub>ss</sub> of drugs that undergo OATP-mediated uptake and P450/non-P450-mediated metabolism reflected the observed data from humans within a threefold error range. We also examined the possibility of predicting plasma concentration-time profiles of drugs that undergo OATP-mediated uptake using the complex Dedrick plot in chimeric mice. Most profiles could be superimposed with observed profiles from humans within a two- to threefold error range. PK prediction using SSS and the complex Dedrick plot in chimeric mice can be useful for evaluating drugs that undergo both OATP-mediated uptake and P450/non-P450-mediated metabolism.