[Evaluation and Clarification of Enterohepatic Interactions in Pharmacokinetics]

The evaluation and prediction of pharmacokinetics in humans is important in the field of drug discovery and development. Generally, human pharmacokinetics is predicted using physiologically based pharmacokinetic models that include physiological and physicochemical (drug) parameters obtained from in vitro assays. Specific organ dysfunction, such as liver disease, also affects the functions of other organs, causing unexpected pharmacokinetic fluctuations. I investigated the effect of cholestasis on intestinal drug absorption in mice subjected to bile duct ligation (BDL). The intestinal absorption and permeability of imatinib was decreased in BDL mice compared with sham-operated mice, and this may be attributed to the up-regulation of the efflux transporter, breast cancer resistance protein. However, a single-organ experimental system cannot predict such pharmacokinetic changes. To overcome this challenge, I investigated a microphysiological system (MPS) equipped with intestinal and hepatic cells for pharmacokinetic evaluation. The glucuronidation of triazolam was significantly increased in an enterohepatic MPS compared with a single-culture system. These results suggested that the elucidation of organ interactions requires the use of an MPS loaded with human cells in combination with laboratory animal studies. In this review, I present the results of my evaluation of organ interactions using animal models and MPSs in the Award for Young Scientists from the Pharmaceutical Society of Japan, Hokuriku Branch.