PT - JOURNAL ARTICLE AU - Edna F. Choo AU - Daniel Kurnik AU - Mordechai Muszkat AU - Tadashi Ohkubo AU - Sheila D. Shay AU - James N. Higginbotham AU - Hartmut Glaeser AU - Richard B. Kim AU - Alastair J. J. Wood AU - Grant R. Wilkinson TI - Differential in Vivo Sensitivity to Inhibition of P-glycoprotein Located in Lymphocytes, Testes, and the Blood-Brain Barrier AID - 10.1124/jpet.105.099648 DP - 2006 Jun 01 TA - Journal of Pharmacology and Experimental Therapeutics PG - 1012--1018 VI - 317 IP - 3 4099 - http://jpet.aspetjournals.org/content/317/3/1012.short 4100 - http://jpet.aspetjournals.org/content/317/3/1012.full SO - J Pharmacol Exp Ther2006 Jun 01; 317 AB - A major functional component of the blood-brain barrier is P-glycoprotein. In principle, inhibition of this efflux transporter would permit greater distribution of its substrates into the brain and increased central effects. Tariquidar and elacridar, potent and selective P-glycoprotein inhibitors, were investigated in this regard using the opioid loperamide as an in vivo probe in mice. Pretreatment with both inhibitors converted intravenous loperamide from a drug without central effects to one producing antinociception. Radiolabeled loperamide tissue distribution studies indicated that inhibition was associated with increased uptake into brain and testes in the absence of changes in plasma levels, along with enhanced efflux of rhodamine 123 from CD3e+ T-lymphocytes. However, with tariquidar, the loperamide dose-response curves for testes/plasma and brain/plasma concentration ratios were shifted 6- (p = 0.07) and 25-fold (p < 0.01) to the right, respectively (ED50 = 1.48 and 5.65 mg/kg), compared with the rhodamine 123 efflux curve (ED50 0.25 mg/kg). Less pronounced shifts were noted with elacridar where the brain/plasma ratio was shifted only 2-fold relative to the rhodamine 123 efflux data (ED50 = 2.36 versus 1.34 mg/kg, respectively; p 0.01). These results indicate that the P-glycoprotein localized in the blood-brain barrier and, to a lesser extent, the testes-blood barrier is more resistant to inhibition than at other tissue sites such as the lymphocyte; moreover, the extent of this effect depends on the inhibitor. Such resistance can be overcome by a sufficiently high dose of an inhibitor; however, whether this is safely attainable in the clinical situation remains to be determined. The American Society for Pharmacology and Experimental Therapeutics