Differential in Vivo Sensitivity to Inhibition of P-glycoprotein Located in Lymphocytes, Testes, and the Blood-Brain Barrier
| Autor: | James N. Higginbotham, Mordechai Muszkat, Hartmut Glaeser, Sheila Shay, Daniel Kurnik, Grant R. Wilkinson, Alastair J. J. Wood, Richard B. Kim, Edna F. Choo, Tadashi Ohkubo |
|---|---|
| Rok vydání: | 2006 |
| Předmět: |
Male
Loperamide T-Lymphocytes Tariquidar Pain Mice Inbred Strains Pharmacology Blood–brain barrier Rhodamine 123 Mice chemistry.chemical_compound In vivo Tetrahydroisoquinolines Testis medicine Animals Tissue Distribution ATP Binding Cassette Transporter Subfamily B Member 1 ED50 P-glycoprotein Mice Knockout Analgesics Dose-Response Relationship Drug biology medicine.anatomical_structure chemistry Blood-Brain Barrier Quinolines biology.protein Acridines Molecular Medicine Efflux medicine.drug |
| Zdroj: | Journal of Pharmacology and Experimental Therapeutics. 317:1012-1018 |
| ISSN: | 1521-0103 0022-3565 |
| DOI: | 10.1124/jpet.105.099648 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|