Abstract
The magnitude of P-glycoprotein [(P-gp)/multidrug resistance protein 1 (MDR1)]-mediated drug-drug interaction (DDI) at the blood-brain barrier (BBB) in rats was estimated by in vitro-in vivo correlation (IVIVC). In in vitro studies, rat Mdr1a-expressing LLC-PK1 cells were examined for the evaluation of P-gp inhibitory activity using digoxin as a P-gp probe substrate. The in vitro Ki value was calculated using a modified corrected flux ratio that reflects the P-gp function. In in vivo studies, digoxin with or without P-gp inhibitors was administered to rats by constant intravenous infusion to evaluate the effect of P-gp inhibition on digoxin transport to the brain under steady-state conditions. In the presence of elacridar, the brain-to-plasma concentration ratio (Kp,brain) of digoxin was approximately 14 times the control value. However, no significant change in the Kp,brain was observed in the presence of clinically used P-gp inhibitors, with the exception of cyclosporine A. A positive correlation was found between the in vivo Kp,brain of digoxin and [I,unbound/Ki] (where I,unbound is the unbound plasma concentration of P-gp inhibitors). Compounds with [I,unbound/Ki] values of >1 increased Kp,brain of digoxin in rats. In summary, we used a quantitative approach to evaluate the impact of P-gp-mediated DDI at the rat BBB. We successfully established the IVIVC, which indicated the potential DDI in the presence of potent P-gp inhibitors. On the basis of the IVIVC in rats and Ki values in human MDR1, we speculated that clinically used P-gp inhibitors do not cause DDI at the human BBB, because none of the compounds studied showed [I,unbound/Ki] values of >1 at therapeutic doses.
Footnotes
- Received August 6, 2010.
- Accepted October 20, 2010.
Article, publication date, and citation information can be found at http://dmd.aspetjournals.org.
doi:10.1124/dmd.110.035774.
ABBREVIATIONS:
- P-gp
- P-glycoprotein
- BBB
- blood-brain barrier
- DDI
- drug-drug interaction
- IVIVC
- in vitro-in vivo correlation
- CFR
- corrected flux ratio
- FR
- flux ratio
- MDR1
- multidrug resistance protein 1
- MCFR
- modified corrected flux ratio
- I,unbound
- unbound plasma concentration of P-gp inhibitors
- LY
- lucifer yellow
- UFLC
- ultrafast liquid chromatograph
- LC/MS/MS
- liquid chromatography with triple quad mass spectrometric detection
- MS/MS
- tandem mass spectrometry
- MS
- mass spectrometry
- Kp,brain
- brain-to-plasma concentration ratio
- OATP
- organic anion transport peptide.
- Copyright © 2011 by The American Society for Pharmacology and Experimental Therapeutics
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