Differential in Vivo Sensitivity to Inhibition of P-glycoprotein Located in Lymphocytes, Testes, and the Blood-Brain Barrier

Abstract

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 ϩ T-lymphocytes. However, with tariquidar, the loperamide dose-response curves for testes/plasma and brain/ plasma concentration ratios were shifted 6-(p ϭ 0.07) and 25-fold (p Ͻ 0.01) to the right, respectively (ED 50 ϭ 1.48 and 5.65 mg/kg), compared with the rhodamine 123 efflux curve (ED 50 ϭ 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 (ED 50 ϭ 2.36 versus 1.34 mg/kg, respectively; p Ͻ 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.

In vivo dose finding of tariquidar using (R)-[11C]verapamil μPET

“…TQD inhibited P-gp-mediated efflux of VPM across the BBB with an apparent half-maximum effective dose (ED 50 ) of 6.6 mg/kg (95% confidence interval: 4.9-8.2 mg/kg) which was in good agreement with previous data reported in mice for another P-gp substrate (loperamide, ED 50 : 5.7 mg/kg) [1]. Brain-to-plasma radioactivity ratios after 0 and 15 mg/kg of TQD were 0.23 and 3.15, respectively.…”

Valproic Acid Is Not a Substrate for P-glycoprotein or Multidrug Resistance Proteins 1 and 2 in a Number of in Vitro and in Vivo Transport Assays

“…The efficacy of drug transport by efflux transporters in a tissue depends on a number of factors, such as the nature and physical state of the surrounding lipids, interactions with other tissue-specific proteins, and tissue-specific regulation of the transporters (Löscher and Potschka, 2005a). Furthermore, it has been demonstrated recently in in vitro assays, including LLC-MDR1 cells and a mouse in vivo model, that Pgp in the BBB differs strikingly in its sensitivity to Pgp inhibitors from Pgp in other tissues (Choo et al, 2006). Thus, despite the negative in vitro results with VPA in kidney cell lines, we decided to examine the in vivo role of Pgp and MRPs in efflux of VPA from the brain.…”

If the KI Is Defined by the Free Energy of Binding to P-Glycoprotein, Which Kinetic Parameters Define the IC50 for the Madin-Darby Canine Kidney II Cell Line Overexpressing Human Multidrug Resistance 1 Confluent Cell Monolayer?

“…Choo et al (2006) found that the tariquidar dose in mice needed to increase the tissue penetration of […”

“…We expect k 1 to be roughly cell-and tissue-independent because it depends mostly on lipid lateral diffusion in the inner plasma membrane, although this has not yet been proven. In contrast, the value of the membrane concentration of efflux active P-gp can be changed in the simulations, as this parameter can differ between cultured cells (Polli et al, 2001;Tang et al, 2002) and between tissues (Choo et al, 2006;Kurnik et al, 2008).…”