Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.6.3.44 (P-glycoprotein)
 13,344 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Delivery to the CNS via the nasal cavity has been pursued as a means to circumvent the blood-brain barrier (BBB), yet the mechanism of drug transport across this novel route is not well understood. Hydroxyzine and triprolidine have been reported to readily reach the CNS following nasal administration, whereas no measurable amounts of chlorcyclizine or chlorpheniramine, structurally similar antihistamines, were observed in the CSF. The permeation of chlorpheniramine and chlorcyclizine in vitro across the bovine olfactory mucosa was studied to investigate the biological and physicochemical characteristics that contribute to the limited CNS disposition of these compounds following nasal administration. The submucosal to mucosal fluxes (J(s-m)) of chlorcyclizine and chlorpheniramine across the olfactory mucosa were significantly greater than the mucosal to submucosal fluxes (J(m-s)). Moreover, the submucosal-mucosal permeability of both compounds was temperature dependent and saturable. In the presence of metabolic inhibitors (ouabain and 2,4-dinitrophenol) and P-glycoprotein (P-gp)/multidrug resistance protein 1 (MRP1) inhibitors (quinidine and verapamil), the J(m-s) increased and J(s-m) decreased significantly. These results indicate that chlorpheniramine and chlorcyclizine are effluxed from the olfactory mucosa by efflux transporters such as P-gp and MRP1. Transport studies across inert polymeric membranes demonstrated that the permeability of chlorpheniramine and chlorcyclizine decreased at donor concentrations higher than 3 mM suggesting that physicochemical properties such as self-aggregation also play a role in the reduced olfactory mucosal permeability of these compounds at higher concentrations.
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PMID:Carrier mediated transport of chlorpheniramine and chlorcyclizine across bovine olfactory mucosa: implications on nose-to-brain transport. 1566 93

Nasal administration as a means of delivering therapeutic agents preferentially to the brain has gained significant recent interest. While some substrates appear to be delivered directly to the brain via this route, the mechanisms governing overall brain uptake and exposure remain unclear. Some substrates utilize the olfactory nerve tract and gain direct access to the brain, thus bypassing the blood-brain barrier (BBB). However, most agents of pharmacologic interest likely gain access to the brain via the olfactory epithelium, which represents a more direct route of uptake. While the traditional BBB is not present at the interface between nasal epithelium and brain, P-glycoprotein (and potentially other barrier transporters) is expressed at this interface. In addition, work in this laboratory has demonstrated that P-glycoprotein throughout the brain can be modulated with nasal administration of appropriate inhibitors. The potential for targeted central nervous system delivery via this route is discussed.
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PMID:Nasal drug administration: potential for targeted central nervous system delivery. 1585 50

We attempted to assess regional differences in cerebral P-glycoprotein (P-gp) function by performing paired positron emission tomography (PET) scans with the P-gp substrate (R)-[(11)C]verapamil in five healthy subjects before and after i.v. infusion of tariquidar (2 mg/kg). Comparison of tariquidar-induced changes in distribution volumes (DVs) in 42 brain regions of interest (ROIs) failed to detect significant differences among brain ROIs. Statistical parametric mapping analysis of parametric DV images visualized symmetrical bilateral clusters with moderately higher DV increases in response to tariquidar administration in cerebellum, parahippocampal gyrus, olfactory gyrus, and middle temporal lobe and cortex, which might reflect moderately decreased P-gp function and expression.
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PMID:Assessment of regional differences in tariquidar-induced P-glycoprotein modulation at the human blood-brain barrier. 2001 Sep 57

The main objective of this study was to evaluate comparative biodistribution and pharmacokinetics of cyclosporine-A (CsA) following intranasal (IN) administration versus intravenous (IV) administration in Sprague-Dawley rats using an oil-in-water nanoemulsion delivery system. CsA, a hydrophobic peptide that is also a substrate for P-glycoprotein, is a well-known immunosuppressive agent. In the brain, CsA has been shown to be a potent anti-inflammatory and neuroprotective agent. CsA nanoemulsions (CsA-NE) and solution formulations (CsA-S) were prepared using an ultrasonication method and were characterized for drug content, encapsulation efficiency, globule size, and zeta potential. We compared the uptake of CsA-NE and CsA-S in brain regions and peripheral organs following IN and IV administration using LC-MS/MS based bioanalytical method. CsA-NE IN resulted in the highest accumulation compared to that with any other treatment and route of administration; this was consistent for all three regions of brain that were evaluated (olfactory bulbs, mid brain, and hind brain). The brain/blood exposure ratios of 4.49, 0.01, 0.33, and 0.03 for CsA-NE (IN), CsA-NE (IV), CsA-S (IN), and CsA-S (IV), respectively, indicated that CsA-NE is capable of direct nose-to-brain transport, bypassing the blood-brain barrier. Furthermore, CsA-NE administration reduces nontarget organ exposure. These studies show that IN delivery of CsA-NE is an effective way of brain targeting compared to that of other treatment strategies. This approach not only enhances the brain concentration of the peptide but also significantly limits peripheral exposure and the potential for off-target toxicity.
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PMID:Comparative Biodistribution and Pharmacokinetic Analysis of Cyclosporine-A in the Brain upon Intranasal or Intravenous Administration in an Oil-in-Water Nanoemulsion Formulation. 2578 92

P-glycoprotein (P-gp) plays a pivotal role in cellular defense, aimed at reducing xenobiotic accumulation. As a member of the ABC family of proteins, expression of this protein confers the multixenobiotic resistant (MXR) phenotype in aquatic organisms, including fish. To identify tissues protected by or contributing to the elimination of xenobiotics via P-gp, tissue-specific P-gp isoforms abcb1a and abcb1b transcript expression were measured in rainbow trout (Oncorhynchus mykiss). Tissues investigated included the proximal and distal intestines, liver, head kidney, gills, gonads, and 5 regions of the brain: olfactory lobe, cerebrum, optic lobe, cerebellum and medulla. Abcb1a transcript was more widely expressed across tissues and generally showed higher transcript expression than abcb1b. Deviation from this trend occurred in the gills, cerebrum and head kidney, where transcript levels were relatively equal between abcb1a and abcb1b. Intestinal tissues had greater abcb1a expression than abcb1b (3 orders of magnitude). Abcb1b was absent from liver tissue indicating that abcb1a is relied upon for hepatic defense. This study suggests that abcb1b acts to protect sensitive organs from compounds in the systemic circulation (brain and gonad), whereas abcb1a acts primarily in an elimination role in organs such as liver and intestine. To determine if P-gp induction alters transcript responses, the antifungal mammalian Pregnane-X-Receptor (PXR) agonist clotrimazole (CTZ) was used. CTZ-treated rainbow trout showed significantly increased abcb1b transcript expression in the optic lobe and distal intestine, providing evidence that trout PXR exhibits a similar substrate base as mammalian PXR, albeit selectively in regions of the brain and intestine.
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PMID:Short communication: Tissue-specific transcript expression of P-glycoprotein isoforms abcb1a and abcb1b in rainbow trout (Oncorhynchus mykiss) following induction with clotrimazole. 3322 21