Title of Research: 22-3-01

Prediction of internal concentrations of chemicals orally administered using
data-driven pharmacokinetic modeling
Principal Investigator: Prof. Hiroshi Yamazaki, PhD (Showa Pharmaceutical University,
Laboratory of Drug Metabolism and Pharmacokinetics), 3-3165, Higashi-tamagawa Gakuen,
Machida,Tokyo
194-8543,
Japan.
(phone)+81-42-721-1406;(E-mail)hyamazak@ac.shoyaku.ac.jp.
Collaborator: Makiko Shimizu, ibid, (e-mail) shimizu@ac.shoyaku.ac.jp
Summary of Research: Physiologically based pharmacokinetic (PBPK) modelling can beused to evaluate internal exposure in humans without any reference to experimental data.
The input parameters for PBPK models (i.e., fraction absorbed × intestinal availability,absorption rate constants, volumes of the systemic circulation, and hepatic intrinsic
clearances) were estimated for a panel of ~350 chemicals using a light gradient boostingmachine learning algorithm (LightGBM) based on within 30 silico-calculated chemical
descriptors. The parameters for the human and rat PBPK models for a diverse range ofcompounds were successfully estimated using chemical descriptors. Significant inverse
relationships between the hepatic/plasma concentrations of selected lipophilic food chemicals
using forward dosimetry and reported rat hepatic lowest-observed-effect level (LOEL) values
were observed. The output values from rat pharmacokinetic models based on in silico
liver-to-plasma partition coefficient values derived from the primary Poulin and Theil model
can be used to estimate toxicokinetics or internal exposure to substances. This approach topharmacokinetic modeling has the potential for application in computational toxicology and in
the clinical setting for assessing the potential risk of general chemicals.
Timeline: From March 1, 2023 to February 29, 2024
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Adachi K, Nakano H, Sato T, Shimizu M, Yamazaki H. Liver and Plasma Concentrations ofFood Chemicals after Virtual Oral Doses Extrapolated Using in Silico Estimated Input
Pharmacokinetic Parameters to Confirm Reported Liver Toxicity in Rats. Biol Pharm Bull, 46,1133-1140 (2023).
Adachi K, Ohyama K, Tanaka Y, Nakano H, Sato T, Murayama N, Shimizu M, Saito Y,Yamazaki H. Plasma and Hepatic Exposures of Celecoxib and Diclofenac Prescribed Alone inPatients with Cytochrome P450 2C9*3 Modeled after Virtual Oral Administrations and Likely
Associated with Adverse Drug Events Reported in a Japanese Database. Biol Pharm Bull, 46,856-863 (2023).
Adachi K, Utsumi M, Sato T, Nakano H, Shimizu M, Yamazaki H. Modeled Rat Hepatic andPlasma Concentrations of Chemicals after Virtual Administrations Using Two Sets of in Silico
Liver-to-Plasma Partition Coefficients. Biol Pharm Bull, 46, 1316-1323 (2023).
Adachi K, Ohyama K, Tanaka Y, Sato T, Murayama N, Shimizu M, Saito Y, Yamazaki H. Highhepatic and plasma exposures of atorvastatin in subjects harboring impaired cytochrome P450
3A4*16 modeled after virtual administrations and possibly associated with statin intolerance
found in the Japanese adverse drug event report database. Drug Metab Pharmacokinet, 49,100486 (2023).
Shimizu M, Uehara S, Ohyama K, Nishimura H, Tanaka Y, Saito Y, Suemizu H, Yoshida S,Yamazaki H. Pharmacokinetic Models Scaled-up from Humanized-liver Mouse Data Can
Account for Drug Monitoring Results of Atomoxetine and Its 4-Hydroxylated andN-Demethylated Metabolites in Pediatric Patients Genotyped for Cytochrome P450 2D6. DrugMetab Dispos, 52, 35-43 (2024).