Abstract
Because modulation of P-glycoprotein (Pgp) through inhibition or induction can lead to drug-drug interactions by altering intestinal, central nervous system, renal, or biliary efflux, it is anticipated that information regarding the potential interaction of drug candidates with Pgp will be a future regulatory expectation. Therefore, to be able to utilize in vitro Pgp inhibition findings to guide clinical drug interaction studies, the utility of five probe substrates (calcein-AM, colchicine, digoxin, prazosin, and vinblastine) was evaluated by inhibiting their Pgp-mediated transport across multidrug resistance-1-transfected Madin-Darby canine kidney cell type II monolayers with 20 diverse drugs having various degrees of Pgp interaction (e.g., efflux ratio, ATPase, and calcein-AM inhibition). Overall, the rank order of inhibition was generally similar with IC50 values typically within 3- to 5-fold of each other. However, several notable differences in the IC50 values were observed. Digoxin and prazosin were the most sensitive probes (e.g., lowest IC50 values), followed by colchicine, vinblastine, and calcein-AM. Inclusion of other considerations such as a large dynamic range, commercially available radiolabel, and a clinically meaningful probe makes digoxin an attractive probe substrate. Therefore, it is recommended that digoxin be considered as the standard in vitro probe to investigate the inhibition profiles of new drug candidates. Furthermore, this study shows that it may not be necessary to generate IC50 values with multiple probe substrates for Pgp as is currently done for cytochrome P450 3A4. Finally, a strategy integrating results from in vitro assays (efflux, inhibition, and ATPase) is provided to further guide clinical interaction studies.
Footnotes
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This work was supported in part by the Academy of Finland (Grants 200582 and 205139), the Finnish Cultural Foundation, and the University of Kuopio (J.R.).
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Article, publication date, and citation information can be found at http://dmd.aspetjournals.org.
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doi:10.1124/dmd.105.008615.
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ABBREVIATIONS: Pgp, P-glycoprotein; FDA, Food and Drug Administration; GF120918, N-(4-[2-(1,2,3,4-tetrahydro-6,7-dimethoxy-2-isoquinolinyl)ethyl]phenyl)-9,10-dihydro-5-methoxy-9-oxo-4-acridine carboxamide; MDR1-MDCK, multidrug resistance-1-transfected Madin-Darby canine kidney; DMSO, dimethyl sulfoxide; A→B, apical to basolateral; B→A, basolateral to apical; LY, Lucifer yellow; K, the concentration of inhibitor required for 50% increase in the prazosin A→B rate; B→A/A→B ratio, Papp B→A/Papp A→B; Papp, apparent permeability.
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↵1 Current affiliation: Department of Pharmaceutical Chemistry, University of Kuopio, Kuopio, Finland.
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↵2 Curren affiliation: Pharmaceutical Research and Development, Merck & Co., Inc., West Point, Pennsylvania.
- Received November 27, 2005.
- Accepted January 31, 2006.
- The American Society for Pharmacology and Experimental Therapeutics
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