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Retrospective Analysis of P-glycoprotein-mediated Drug-drug Interactions at the Blood-brain Barrier in Humans.

Drug Metab Dispos. 2013 Jan 22;

Authors: Sugimoto H, Hirabayashi H, Amano N, Moriwaki T


To date, the in vitro-in vivo correlation (IVIVC) of P-glycoprotein (P-gp)-mediated drug-drug interaction (DDI) at the blood-brain barrier (BBB) in rats indicated that the cutoff value to significantly affect the brain penetration of digoxin was [I,(unbound)/K(i)] of 1, where I,(unbound) is the unbound plasma concentration of P-gp inhibitors. Based on the IVIVC in rats, we speculated that clinically used P-gp inhibitors do not cause DDI at the human BBB, because none of the compounds studied was [I,(unbound)/K(i)]>1 at therapeutic doses. Recently, positron emission tomography studies with P-gp substrates such as [(11)C]verapamil, [(11)C]N-desmethyl loperamide, and [(11)C]loperamide together with potent P-gp inhibitors have indicated that increases in the influx rate constant for brain entry were observed in humans. Therefore, we aimed to retrospectively analyze the results of P-gp-mediated DDIs with in vitro P-gp inhibition assays and to confirm the appropriate cutoff value. In vitro P-gp inhibition assays using verapamil, N-desmethyl loperamide, and loperamide as P-gp probe substrates were performed in human MDR1-expressing LLC-PK1 cells. The efflux ratios decreased in the presence of P-gp inhibitors and the Ki of tariquidar was 10 nmol/L regardless of probe substrates. Taking the in vitro K(i) and unbound plasma concentrations in clinical DDI studies together, the criterion [I,(unbound)/K(i)] of 1 was an appropriate cutoff limit to observe significant P-gp-mediated DDI at the BBB in humans. On the other hand, no significant DDI was observed in cases where [I,(unbound)/K(i)] was less than 0.1. This criterion was comparable to the previous IVIVC result in rats.

PMID: 23340958 [PubMed - as supplied by publisher]