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Drug Metabolism & Disposition

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Rapid CommunicationShort Communication

Retrospective Analysis of P-Glycoprotein–Mediated Drug-Drug Interactions at the Blood-Brain Barrier in Humans

Hiroshi Sugimoto, Hideki Hirabayashi, Nobuyuki Amano and Toshiya Moriwaki
Drug Metabolism and Disposition April 2013, 41 (4) 683-688; DOI: https://doi.org/10.1124/dmd.112.049577
Hiroshi Sugimoto
Drug Metabolism and Pharmacokinetics Research Laboratories, Pharmaceutical Research Division, Takeda Pharmaceutical Company Limited, Fujisawa, Kanagawa, Japan
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Hideki Hirabayashi
Drug Metabolism and Pharmacokinetics Research Laboratories, Pharmaceutical Research Division, Takeda Pharmaceutical Company Limited, Fujisawa, Kanagawa, Japan
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Nobuyuki Amano
Drug Metabolism and Pharmacokinetics Research Laboratories, Pharmaceutical Research Division, Takeda Pharmaceutical Company Limited, Fujisawa, Kanagawa, Japan
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Toshiya Moriwaki
Drug Metabolism and Pharmacokinetics Research Laboratories, Pharmaceutical Research Division, Takeda Pharmaceutical Company Limited, Fujisawa, Kanagawa, Japan
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Abstract

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/Ki] of 1, where I,unbound is the unbound plasma concentration of P-gp inhibitors. On the basis of 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/Ki]>1 at therapeutic doses. Recently, positron emission tomography studies with P-gp substrates, such as [11C]verapamil, [11C]N-desmethyl loperamide, and [11C]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 multidrug resistance protein 1-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 Ki and unbound plasma concentrations in clinical DDI studies together, the criterion [I,unbound/Ki] 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 in which [I,unbound/Ki] was less than 0.1. This criterion was comparable to the previous IVIVC result in rats.

Footnotes

  • dx.doi.org/10.1124/dmd.112.049577.

  • Received October 10, 2012.
  • Accepted January 22, 2013.
  • Copyright © 2013 by The American Society for Pharmacology and Experimental Therapeutics
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Drug Metabolism and Disposition: 41 (4)
Drug Metabolism and Disposition
Vol. 41, Issue 4
1 Apr 2013
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Rapid CommunicationShort Communication

Retrospective Analysis of P-gp–Mediated DDI at the Human BBB

Hiroshi Sugimoto, Hideki Hirabayashi, Nobuyuki Amano and Toshiya Moriwaki
Drug Metabolism and Disposition April 1, 2013, 41 (4) 683-688; DOI: https://doi.org/10.1124/dmd.112.049577

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Rapid CommunicationShort Communication

Retrospective Analysis of P-gp–Mediated DDI at the Human BBB

Hiroshi Sugimoto, Hideki Hirabayashi, Nobuyuki Amano and Toshiya Moriwaki
Drug Metabolism and Disposition April 1, 2013, 41 (4) 683-688; DOI: https://doi.org/10.1124/dmd.112.049577
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