Laboratory of Pharmaceutics

Japanese

Quantitative understanding of the pharmacokinetics of drugs to facilitate drug development and to realize the proper use of drugs in the clinics

“Biopharmaceutics”is the research field to understand the mechanisms that govern the drug movement inside the body after drugs are administered. The pharmacokinetics (PK) of drugs in the body is determined by multiple processes of so-called "ADME"; Absorption, Distribution, Metabolism, and Excretion. In recent years, it has been elucidated that the ADME properties of drugs are dominated not only by their simple physicochemical properties but also by the functions of various PK-related molecules (metabolic enzymes, transporters) in a drug-selective manner. In addition, the functions of these molecules are modified by multiple intrinsic and extrinsic factors such as genetic polymorphisms, drug-drug interactions and pathophysiological conditions. Finally, various functional modifications of each function results in the inter-individual differences in the pharmacokinetics of drugs and subsequently their pharmacological/toxicological effects.
　We are studying to clarify the factors controlling pharmacokinetics and their quantitative contributions, and to predict in vivo pharmacokinetics based on the results of in vitro experiments.

Research Content

Our Research Mission

To clarify the transport characteristics of drug transporters that affect the absorption, distribution, metabolism and excretion (ADME) of drugs/endogenous substances, and to explore the factors that affect the transport activity, leading to a quantitative understanding of inter-individual variability in human clinical pharmacokinetics.

Research on basic characterization of transport via folate transporter (PCFT) (Dr. Narawa)

Folic acid, one of the most important vitamins, is efficiently taken up into cells despite its extremely hydrophilicity, and the importance of transporter in the transport of folic acid has been clarified. In particular, PCFT (proton-coupled folate transporter) plays a major role in the intestinal absorption of folic acid. In order to clarify the basic characteristics of PCFT-mediated transport and the factors that cause inter-individual variation in PCFT transport in clinical situation, we are conducting research on stereoselectivity of substrates, interactions between drugs and food-derived components, and variation in transport caused by genetic mutations.

Research on basic characterization of transport of organic anions via OATP2B1 (Dr. Takano)

OATP (organic anion transporting polypeptide) 2B1 is a transporter that recognizes a wide variety of anionic drugs and is expressed in the gastrointestinal tract, suggesting that it may contribute to the enhancement of intestinal absorption of substrate drugs. In order to clarify the basic characteristics of OATP2B1-mediated transport and the factors that cause inter-individual variability in OATP2B1-mediated transport in the clinical situation, we are conducting research on interactions between drugs and food-derived components and variability in transport caused by genetic mutations.

Establishment of a culture system for intestinal epithelial stem cells and studies on species difference and regional difference in intestinal drug absorption/expression of gastrointestinal toxicity in differentiated cells (Dr. Maeda)

Due to differences in the expression profiles of metabolic enzymes and transporters, there is no cell system that can accurately predict intestinal absorption in humans. There are many difference In this study, we are developing a 3D stable culture system of gastrointestinal stem cells as a starting point for predicting gastrointestinal absorption in humans by using appropriately differentiated human and animal absorption epithelial cells. In addition, this cell system maintains the genetic profile of the original cell location from which the cells were harvested, making it possible to examine differences in the gastrointestinal tract that were previously impossible to evaluate in vitro. In addition, since the same cell line can be established from animals with almost the same protocol, it is also possible to study species differences in vitro, and we hope to demonstrate the usefulness of this cell line as an alternative method for animal experiments in the future.

Studies on modulators of intracellular dynamics that determine the potency of middle-size compounds (Dr. Tomabechi)

Modalities such as middle-size cyclic peptides inhibiting intracellular protein–protein interactions and proteolysis-targeting chimeras (PROTACs) degrading a target protein by harnessing the ubiquitin-proteasome system have recently been attracting significant interest from many researchers. However, membrane permeability of middle-size compounds is assumed to be quite low due to their physicochemical properties including molecular size and polar surface area. We are conducting research to understand the intracellular dynamics of middle-size compounds up to exertion of their biological effect, and to identify and clarify the molecular entities regulating the intracellular dynamics in host cells. Based on findings in this study, we aim to establish a methodology for efficient delivery of middle-size compounds to the cytoplasm.