PT  - JOURNAL ARTICLE
AU  - Jarkko Rautio
AU  - Joan E. Humphreys
AU  - Lindsey O. Webster
AU  - Anand Balakrishnan
AU  - John P. Keogh
AU  - Jeevan R. Kunta
AU  - Cosette J. Serabjit-Singh
AU  - Joseph W. Polli
TI  - IN VITRO P-GLYCOPROTEIN INHIBITION ASSAYS FOR ASSESSMENT OF CLINICAL DRUG INTERACTION POTENTIAL OF NEW DRUG CANDIDATES: A RECOMMENDATION FOR PROBE SUBSTRATES
AID  - 10.1124/dmd.105.008615
DP  - 2006 May 01
TA  - Drug Metabolism and Disposition
PG  - 786--792
VI  - 34
IP  - 5
4099  - http://dmd.aspetjournals.org/content/34/5/786.short
4100  - http://dmd.aspetjournals.org/content/34/5/786.full
SO  - Drug Metab Dispos2006 May 01; 34
AB  - 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. The American Society for Pharmacology and Experimental Therapeutics