Quantitative prediction of P‐glycoprotein‐mediated drug–drug interactions and intestinal absorption using humanized mice

• Published in: British journal of pharmacology 2021-11, Vol.178 (21), p.4335-4351
• Main Authors: Miyake, Taiji, Tsutsui, Haruka, Haraya, Kenta, Tachibana, Tatsuhiko, Morimoto, Kayoko, Takehara, Shoko, Ayabe, Miho, Kobayashi, Kaoru, Kazuki, Yasuhiro
• Format: Article
• Language: English
• Subjects: Artificial chromosomes; ATP binding cassette transporter subfamily B member 1; Chromosomes; Digoxin; Drug interaction; drug interactions; Fexofenadine; Glycoproteins; humanized animal models; Intestinal absorption; Intestine; mathematical modeling; MDR1 protein; Multidrug resistance; Oral administration; Pharmacokinetics; Substrate specificity
• ISSN: 0007-1188; 1476-5381
• DOI: 10.1111/bph.15612

Background and Purpose P‐glycoprotein (P‐gp) exhibits a broad substrate specificity and affects pharmacokinetics, especially intestinal absorption. However, prediction, in vivo, of P‐gp‐mediated drug–drug interaction (DDI) and non‐linear absorption at the preclinical stage, is challenging. Here we evaluate the use of human MDR1 mouse artificial chromosome (hMDR1‐MAC) mice carrying human P‐gp and lacking their own murine P‐gp to quantitatively predict human P‐gp‐mediated DDI and non‐linear absorption. Experimental Approach The P‐gp substrates (aliskiren, betrixaban, celiprolol, digoxin, fexofenadine and talinolol) were administered orally to wild‐type, Mdr1a/b‐knockout (KO) and hMDR1‐MAC mice, and their plasma concentrations were measured. We calculated the ratio of area under the curve (AUCR) in mice (AUCMdr1a/b‐KO/AUCwild‐type or AUCMdr1a/b‐KO/AUChMDR1‐MAC) estimated as attributable to complete P‐gp inhibition and the human AUCR with and without P‐gp inhibitor administration. The correlations of AUCRhuman with AUCRwild‐type and AUCRhMDR1‐MAC were investigated. For aliskiren, betrixaban and celiprolol, the Km and Vmax values for P‐gp in hMDR1‐MAC mice and humans were optimized from different dosing studies using GastroPlus. The correlations of Km and Vmax for P‐gp between human and hMDR1‐MAC mice were investigated. Key Results A better correlation between AUCRhuman and AUCRhMDR1‐MAC (R2 = 0.88) was observed. Moreover, good relationships of Km (R2 = 1.00) and Vmax (R2 = 0.98) for P‐gp between humans and hMDR1‐MAC mice were observed. Conclusions and Implications These results suggest that P‐gp‐mediated DDI and non‐linear absorption can be predicted using hMDR1‐MAC mice. These mice are a useful in vivo tool for quantitatively predicting P‐gp‐mediated disposition in drug discovery and development.