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P-glycoprotein Inhibitor (p-glycoprotein + inhibitor)

Distribution by Scientific Domains
Medical Sciences100%

Selected Abstracts

Loperamide and P-glycoprotein inhibition: assessment of the clinical relevance

JOURNAL OF PHARMACY AND PHARMACOLOGY: AN INTERNATI ONAL JOURNAL OF PHARMACEUTICAL SCIENCE, Issue 4 2010
Joris Vandenbossche
Abstract Objectives Loperamide is a peripherally acting , opioid receptor agonist and an avid substrate for P-glycoprotein. This may give rise to drug,drug interactions and increased risk for central adverse effects. The objective of this study was to re-evaluate the predictability of non-clinical data using loperamide as a probe P-glycoprotein substrate. We searched the literature for papers containing data on drug,drug interactions of loperamide-containing products in humans. We also reviewed the internal worldwide safety database of Johnson & Johnson for spontaneous case reports suggestive of a central opioid effect after coadministration of loperamide with a P-glycoprotein inhibitor or substrate. Key findings Only one of the ten studies in our review supported the finding that inhibition of P-glycoprotein is associated with clinically relevant signs or symptoms of central nervous system (CNS) depression/opioid toxicity of loperamide. None of the 25 spontaneous case reports of interest were suggestive of signs or symptoms of CNS depression/opioid toxicity due to coadministration of loperamide and a P-glycoprotein inhibitor or substrate. Summary Based on a review of the literature and a cumulative review of the sponta-neous case reports, there is insufficient evidence that an interaction between loperamide and a P-glycoprotein inhibitor or substrate is associated with clinical symptoms of CNS depression/opioid toxicity when loperamide is taken at the recommended dose. [source]

Potentiation of domperidone-induced catalepsy by a P-glycoprotein inhibitor, cyclosporin A

BIOPHARMACEUTICS AND DRUG DISPOSITION, Issue 3 2003
Kenji Tsujikawa
Abstract The distribution of domperidone (DOM), a peripheral dopamine D2 receptor antagonist, to the brain is restricted by P-glycoprotein (P-gp) at the blood,brain barrier (BBB) and for this reason, DOM rarely causes parkinsonian symptoms, such as extrapyramidal side effects (EPS), unlike other dopamine D2 antagonists. In this study, we aimed to investigate whether cyclosporin A (CsA), a P-gp inhibitor, potentiates EPS induced by DOM. The intensity of EPS was assessed in terms of the duration of catalepsy in mice. D1, D2 and mACh receptor occupancies at the striatum were measured in vivo and in vitro. Moreover, the distribution of DOM to the brain was investigated by using an in situ brain perfusion technique. The intensity of DOM-induced catalepsy was significantly potentiated by the coadministration of CsA. The in vivo occupancies of D1, D2 and mACh receptors, as well as the brain distribution of DOM, were increased by CsA. These results suggest that CsA increases the brain distribution of DOM by inhibiting P-gp at the BBB, and potentiates catalepsy by increasing the occupancies of the D1 and D2 receptors. The risk of DOM-induced parkinsonism may be enhanced by the coadministration of CsA. Copyright © 2003 John Wiley & Sons, Ltd. [source]

The effects of the cyclosporin A, a P-glycoprotein inhibitor, on the pharmacokinetics of baicalein in the rat: a microdialysis study

BRITISH JOURNAL OF PHARMACOLOGY, Issue 8 2002
T H Tsai
Baicalein is a bioactive flavonoid isolated from the root of Scutellaria baicalensis Georgi, a medicinal herb that has been used since ancient times to treat bacterial infections. As little is known concerning its pharmacokinetics, this study focussed on its pharmacokinetics as well as the possible roles of the multidrug transporter P-glycoprotein on its distribution and disposition. Three microdialysis probes were simultaneously inserted into the jugular vein, the hippocampus and the bile duct of male Sprague,Dawley rats for sampling in biological fluids following the administration of baicalein (10, 30 and 60 mg kg,1) through the femoral vein. The P-glycoprotein inhibitor cyclosporin A was used to help delineate its roles. The study design consisted of two groups of six rats in parallel: control rats which received baicalein alone and the cyclosporin A treated-group in which the rats were injected cyclosporin A, a P-glycoprotein inhibitor, 10 min prior to baicalein administration. Cyclosporin A treatment resulted in a significant increase in elimination half-life, mean residence time and area under the concentration versus time curve (AUC) of unbound baicalein in the brain. However, AUC in the bile was decreased. The decline of baicalein in the hippocampus, blood and bile suggested that there was rapid exchange and equilibration between the peripheral compartment and the central nervous system. In addition, the results indicated that baicalein was able to penetrate the blood,brain barrier as well as undergoing hepatobiliary excretion. Although no direct transport studies were undertaken and multiple factors may affect BBB penetration and hepatobiliary excretion, strong association of the involvement of P-glycoprotein in these processes is indicated. British Journal of Pharmacology (2002) 137, 1314,1320. doi:10.1038/sj.bjp.0704959 [source]