Title:
Importance of transporters in drug disposition: species and interindividual differences
Speaker:
Hiroyuki Kusuhara, PhD
The University of Tokyo, Graduate School of Pharmaceutical Sciences, Department of Pharmaceutical Technology
Abstract:
Transporters with multispecificity to xenobiotics are considered drug transporters that mediate the cellular uptake or efflux of drugs; thus, they play indispensable roles in the disposition of oral drugs in the body, such as the efficacy of intestinal absorption, clearance pathways, and tissue distribution. Drug-transport activities and the inhibition potency of new chemical entities are routinely assessed in drug development to optimize their pharmacokinetic properties. We developed a prediction method for pharmacokinetics and drug–drug interactions based on in vitro data, in addition to a clinical evaluation method for drug-transporter activities using PET imaging and metabolomics to identify the factors causing interindividual differences in drug pharmacokinetics, such as genetic mutations, and drugs that can act as inhibitors at their therapeutic doses. This presentation will introduce our recent progress in drug-transporter research for drug development.
References:
1.Takehara I, Watanabe N, Mori D, Ando O, Kusuhara H. Effect of Rifampicin on the Plasma Concentrations of Bile Acid-O-Sulfates in Monkeys and Human Liver-Transplanted Chimeric Mice With or Without Bile Flow Diversion. J Pharm Sci. 2019 Aug;108(8):2756-2764.
2.Mori D, Kashihara Y, Yoshikado T, Kimura M, Hirota T, Matsuki S, Maeda K, Irie S, Ieiri I, Sugiyama Y, Kusuhara H. Effect of OATP1B1 Genotypes on Plasma Concentrations of Endogenous OATP1B1 Substrates and Drugs, and Their Association in Healthy Volunteers. Drug Metab Pharmacokinet. 2019 Feb;34(1):78-86.
3.Yoshikado T, Toshimoto K, Maeda K, Kusuhara H, Kimoto E, Rodrigues AD, Chiba K, Sugiyama Y. PBPK Modeling of Coproporphyrin I as an Endogenous Biomarker for Drug Interactions Involving Inhibition of Hepatic OATP1B1 and OATP1B3. CPT Pharmacometrics Syst Pharmacol. 2018 Nov;7(11):739-747.
4.Yoshida K, Maeda K, Konagaya A, Kusuhara H. Accurate Estimation of In Vivo Inhibition Constants of Inhibitors and Fraction Metabolized of Substrates with Physiologically Based Pharmacokinetic Drug-Drug Interaction Models Incorporating Parent Drugs and Metabolites of Substrates with Cluster Newton Method. Drug Metab Dispos. 2018 Nov;46(11):1805-1816.
5.Kaneko K, Tanaka M, Ishii A, Katayama Y, Nakaoka T, Irie S, Kawahata H, Yamanaga T, Wada Y, Miyake T, Toshimoto K, Maeda K, Cui Y, Enomoto M, Kawamura E, Kawada N, Kawabe J, Shiomi S, Kusuhara H, Sugiyama Y, Watanabe Y. A Clinical Quantitative Evaluation of Hepatobiliary Transport of [11C]Dehydropravastatin in Humans Using Positron Emission Tomography. Drug Metab Dispos. 2018 May;46(5):719-728.
6.Mizuno T, Kinoshita S, Ito T, Maedera S, Kusuhara H. Development of Orthogonal Linear Separation Analysis (OLSA) to Decompose Drug Effects into Basic Components. Sci Rep. 2019 Feb 12;9(1):1824.
