P-Glycoprotein-Based Loperamide–Cyclosporine Drug Interaction at the Rat Blood–Brain Barrier: Prediction from <i>In Vitro</i> Studies and Extrapolation to Humans

Hsiao, Peng; Unadkat, Jashvant D.

doi:10.1021/mp200563a

Cited by 28 publications

(34 citation statements)

References 22 publications

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“…This study was carried out using a rat model, which is a promising model to predict P-gp-based drug-drug interactions at the human BBB (Hsiao and Unadkat, 2012). The choice of loperamide as a P-gp substrate and its dose was based on its opiate-like behavior, which provides an efficient means with which to ascertain the blockage of the P-gp (Elkiweri et al, 2009).…”

Section: Methodsmentioning

confidence: 99%

“…The blood and brains were first sampled 1 hour after dosing because, according to the literature, loperamide reaches a pseudoequilibrium between the brain and the plasma at this time (Hsiao and Unadkat, 2012). The subsequent time points up to 24 hours were selected to determine possible drug-drug interactions and a possible extension of the P-gp modulation at the BBB.…”

Section: Methodsmentioning

confidence: 99%

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Coadministration of P-Glycoprotein Modulators on Loperamide Pharmacokinetics and Brain Distribution

et al. 2014

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The efflux transporter P-glycoprotein, expressed at high levels at the blood-brain barrier, exerts a profound effect on the disposition of various therapeutic compounds in the brain. A rapid and efficient modulation of this efflux transporter could enhance the distribution of its substrates and thereby improve central nervous system pharmacotherapies. This study explored the impact of the intravenous coadministration of two P-glycoprotein modulators, tariquidar and elacridar, on the pharmacokinetics and brain distribution of loperamide, a P-glycoprotein substrate probe, in rats. After 1 hour postdosing, tariquidar and elacridar, both at a dose of 1.0 mg/kg, increased loperamide levels in the brain by 2.3-and 3.5-fold, respectively. However, the concurrent administration of both P-glycoprotein modulators, each at a dose of 0.5 mg/kg, increased loperamide levels in the brain by 5.8-fold and resulted in the most pronounced opioid-induced clinical signs. This phenomenon may be the result of a combined noncompetitive modulation by tariquidar and elacridar. Besides, the simultaneous administration of elacridar and tariquidar did not significantly modify the pharmacokinetic parameters of loperamide. This observation potentially allows the concurrent use of low but therapeutic doses of P-gp modulators to achieve full inhibitory effects.

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Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Coadministration of P-Glycoprotein Modulators on Loperamide Pharmacokinetics and Brain Distribution

et al. 2014

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“…Unfortunately, interaction studies at the BBB in humans are few. Cyclosporin is the most potent P-gp inhibitor on the market, doubling the brain concentrations of verapamil and loperamide (Sasongko et al 2005;Hsiao and Unadkat 2012). Quinidine also inhibits P-gp in humans, causing a 20 % reduction in the response to CO 2 (opiate-induced respiratory depression) when administered with loperamide (Sadeque et al 2000).…”

Section: Drug Interactions At the Bbbmentioning

confidence: 99%

Pharmacokinetic Concepts in Brain Drug Delivery

Hammarlund‐Udenaes

2013

Drug Delivery to the Brain

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This chapter presents the pharmacokinetic principles of blood-brain barrier (BBB) transport and the intra-brain distribution of drugs in order to provide a basis for understanding drug delivery to the brain from a clinically relevant perspective. The most important concentrations to measure when determining drug distribution are those of the unbound drug, because it is the unbound drug that causes the pharmacological effect by interacting with the target. Therefore, this chapter also discusses the pharmacokinetic basis, the kind of information provided, and the in vivo relevance of the methods used to obtain reliable, therapeutically useful estimates of brain drug delivery. The main factors governing drug distribution to the brain are the permeability of the BBB to the drug (influx clearance), the extent of nonspecific binding to brain tissue, and the efflux clearance of the drug. The ratio of the influx and efflux clearances provides an estimation of the extent of drug equilibration across the BBB, described by K p,uu,brain . This parameter is important, as active uptake and/or efflux transporters influence the absolute brain concentrations of unbound drug in relation to those in plasma. The advantage of using K p,uu,brain during the drug discovery process lies in its ability to predict the potential success of drugs intended for action within the brain or, conversely, of those with few or no side effects in the brain.

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“…28 Similarly, an excellent correlation was reported between the CsA-induced increase of 11 C-loperamide levels in the two species. 29 Similar to experimentation in rats, for testing in vivo-in vitro correlation, an in vitro mouse BBB model (pMBMEC monolayer) was also observed. Astrocyte co-culture was included to mimic the brain microenvironment.…”

Section: Discussionmentioning

confidence: 85%

The Use of Microdialysis Techniques in Mice to Study P-gp Function at the Blood-Brain Barrier

et al. 2013

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An integrated assay system involving dual/triple-probe microdialysis techniques in rats was developed earlier for testing interactions with P-glycoprotein (P-gp) at the blood-brain barrier using quinidine/PSC-833 as a P-gp substrate/inhibitor combination. The aim of the present study was to expand our assay system to mice using microdialysis with simultaneous sampling of blood and brain and to compare the result with a primary mouse brain endothelial cell monolayer (pMBMEC) assay. Brain penetration of quinidine was dose dependent in both anesthetized and awake mice after intraperitoneal drug administration. PSC-833 pretreatment caused a 2.5-to 3.4-fold increase in quinidine levels of brain dialysate samples in anesthetized or awake animals, after single or repeated administration of PSC-833. In pMBMEC, a 2.0-to 2.5-fold efflux ratio was observed in the transcellular transport of quinidine. The P-gp-mediated vectorial transport of quinidine was eliminated by PSC-833. These results indicate that quinidine with PSC-833 is a good probe substrate-reference inhibitor combination for testing drug-drug interactions with P-gp in the in vivo and in vitro mouse systems. With increasing number of humanized transgenic mice, a test system with mouse microdialysis experimentation becomes more important to predict drug-drug interactions in humans.

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P-Glycoprotein-Based Loperamide–Cyclosporine Drug Interaction at the Rat Blood–Brain Barrier: Prediction from In Vitro Studies and Extrapolation to Humans

Cited by 28 publications

References 22 publications

Coadministration of P-Glycoprotein Modulators on Loperamide Pharmacokinetics and Brain Distribution

Coadministration of P-Glycoprotein Modulators on Loperamide Pharmacokinetics and Brain Distribution

Pharmacokinetic Concepts in Brain Drug Delivery

The Use of Microdialysis Techniques in Mice to Study P-gp Function at the Blood-Brain Barrier

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