Prediction of drug-drug interaction risk of P-glycoprotein substrate in drug discovery.

Autor: Kido Y; Laboratory for Drug Discovery and Development, Shionogi & Co., Ltd., Osaka, Japan. Electronic address: yasuto.kido@shionogi.co.jp., Nanchi I; Laboratory for Bio-Drug Discovery, Shionogi & Co., Ltd., Osaka, Japan. Electronic address: isamu.nanchi@shionogi.co.jp., Matsuzaki T; Laboratory for Drug Discovery and Development, Shionogi & Co., Ltd., Osaka, Japan. Electronic address: takanobu.matsuzaki@shionogi.co.jp., Watari R; Laboratory for Drug Discovery and Development, Shionogi & Co., Ltd., Osaka, Japan. Electronic address: ryosuke.watari@shionogi.co.jp., Kiyohara H; Laboratory for Drug Discovery and Development, Shionogi & Co., Ltd., Osaka, Japan. Electronic address: hayato.kiyohara@shionogi.co.jp., Seki N; Laboratory for Bio-Drug Discovery, Shionogi & Co., Ltd., Osaka, Japan. Electronic address: naomi.seki@shionogi.co.jp., Okuda T; Laboratory for Bio-Drug Discovery, Shionogi & Co., Ltd., Osaka, Japan. Electronic address: tomohiko.okuda@shionogi.co.jp.
Jazyk: angličtina
Zdroj: Drug metabolism and pharmacokinetics [Drug Metab Pharmacokinet] 2024 Jun; Vol. 56, pp. 101008. Date of Electronic Publication: 2024 Mar 11.
DOI: 10.1016/j.dmpk.2024.101008
Abstrakt: We aimed at predicting the drug-drug interaction (DDI) risk of P-glycoprotein (P-gp) substrates by using P-gp expressing LLC-PK1 cells and its knockout mice (KO). The area under the curve (AUC) of 16 marketed drugs and plasma concentration (C plasma ) of 207 screening compounds, with corrected efflux ratio (CER) ≥ 2, were compared between P-gp KO mice and wild type mice (WT). At permeability (Papp) ≥ 10 × 10 -6  cm/s in parent LLC-PK1 cells, AUC ratios (KO/WT) and C plasma ratios (KO/WT) of these compounds were within 3-fold. AUC ratios (KO/WT) of clinical P-gp substrates, with human AUC ratios with and without P-gp inhibitor administration ≥2, were higher than 8.7. These observations led us to establish a work-flow of P-gp substrate assessment with the threshold AUC ratio (KO/WT) ≥ 9 leading to a DDI risk of AUC ratio (human) ≥ 2. A screening compound showing high CER (=57.6) was found, but its AUC ratio (KO/WT) was 3.7, had been presumed to be a weak risk and its AUC ratio (human) was 1.2 in a later clinical DDI study. Our proposed workflow should be useful for predicting the DDI risk of P-gp substrates in drug discovery.
Competing Interests: Declaration of competing interest The authors declare no conflict of interest.
(Copyright © 2024 The Japanese Society for the Study of Xenobiotics. Published by Elsevier Ltd. All rights reserved.)
Databáze: MEDLINE
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