Tariquidar (TAR, XR‐9576) selectively inhibits P‐glycoprotein (P‐gp) in t‐lymphocytes compared to that in the blood‐brain barrier (BBB)

Background Modulation of P‐gp in humans has been hampered by the lack of potent and selective inhibitors. TAR does not have these limitations, thus, certain of its in vivo effects were investigated. Methods A double‐blind, placebo controlled study was performed in 9 healthy subjects following an initial dose‐finding/safety study with oral loperamide (LOP). Intravenous TAR (150 mg over 30 min) or placebo was given on different days followed 30 min later by oral LOP (32 mg). Pupil diameter was determined prior to and every 30 min for 12 hr; serial plasma samples for measurement of LOP levels and the ex vivo efflux of the fluorescent dye DiOC 2 (3) were obtained over the same period. Results TAR had no effect on LOP's plasma levels, however, it rapidly produced over 90% inhibition of P‐gp mediated efflux of DiOC 2 (3) in T‐lymphocytes that was maintained over the study period. Considerable interindividual variability in LOP's effect on the change in pupil diameter was observed which appeared to be related to the opioid's plasma level. Even in “responders”, however, TAR did not change the extent of the pupillary effect. Conclusions Despite producing nearly complete inhibition of P‐gp function in T‐lymphocytes, TAR had negligible effect on the BBB and brain uptake of LOP. The reason(s) for such selectivity is unknown, but suggests that modulation of brain uptake of P‐gp substrates may be more difficult than previous animal studies suggest. Clinical Pharmacology & Therapeutics (2005) 77 , P39–P39; doi: 10.1016/j.clpt.2004.12.041