2. Academic Validation
  3. Prediction of drug-drug interaction risk of P-glycoprotein substrate in drug discovery

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

  • Drug Metab Pharmacokinet. 2024 Jun:56:101008. doi: 10.1016/j.dmpk.2024.101008.
Yasuto Kido 1,  Isamu Nanchi 2,  Takanobu Matsuzaki 3,  Ryosuke Watari 4,  Hayato Kiyohara 5,  Naomi Seki 6,  Tomohiko Okuda 7
Affiliations

Affiliations

  • 1 Laboratory for Drug Discovery and Development, Shionogi & Co., Ltd., Osaka, Japan. Electronic address: [email protected].
  • 2 Laboratory for Bio-Drug Discovery, Shionogi & Co., Ltd., Osaka, Japan. Electronic address: [email protected].
  • 3 Laboratory for Drug Discovery and Development, Shionogi & Co., Ltd., Osaka, Japan. Electronic address: [email protected].
  • 4 Laboratory for Drug Discovery and Development, Shionogi & Co., Ltd., Osaka, Japan. Electronic address: [email protected].
  • 5 Laboratory for Drug Discovery and Development, Shionogi & Co., Ltd., Osaka, Japan. Electronic address: [email protected].
  • 6 Laboratory for Bio-Drug Discovery, Shionogi & Co., Ltd., Osaka, Japan. Electronic address: [email protected].
  • 7 Laboratory for Bio-Drug Discovery, Shionogi & Co., Ltd., Osaka, Japan. Electronic address: [email protected].
PMID: 38663183 DOI: 10.1016/j.dmpk.2024.101008
Abstract

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 (Cplasma) 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 Cplasma 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.

Keywords

Drug discovery; Drug-drug interaction; Knockout mice; P-glycoprotein; Permeability; Prediction; Substrate.

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