Increased drug delivery to the brain by P‐glycoprotein inhibition

@article{Sadeque2000IncreasedDD,
  title={Increased drug delivery to the brain by P‐glycoprotein inhibition},
  author={Abu Sadeque and Christoph Wandel and H B He and Selina Shah and Alastair J. J. Wood},
  journal={Clinical Pharmacology \& Therapeutics},
  year={2000},
  volume={68}
}
Although the antidiarrheal loperamide is a potent opiate, it does not produce opioid central nervous system effects at usual doses in patients. On the basis of in vitro studies demonstrating that loperamide is a substrate for the adenosine triphosphate–dependent efflux membrane transporter P‐glycoprotein, we postulated that inhibition of P‐glycoprotein with quinidine would increase entry of loperamide into the central nervous system with resultant respiratory depression. 

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

This study searched the literature for papers containing data on drug–drug interactions of loperamide‐containing products in humans and 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.

Ritonavir increases loperamide plasma concentrations without evidence for P‐glycoprotein involvement

Itraconazole, a potent inhibitor of P‐glycoprotein, moderately increases plasma concentrations of oral morphine

Evaluated whether itraconazole, which is a potent inhibitor of P‐glycoprotein and CYP3A4, would change the pharmacokinetics or the pharmacodynamics of oral morphine.

Role of P‐glycoprotein in the intestinal absorption and clinical effects of morphine

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

This study aimed to investigate whether cyclosporin A (CsA), a P‐gp inhibitor, potentiates EPS induced by DOM.

Effect of P‐glycoprotein inhibition on methadone analgesia and brain distribution in the rat

P‐gp plays a critical role in the evolution of the methadone analgesic effect and in its brain uptake, independent of the administration route, and is identified the most relevant site via dual oral and intravenous (i.v.) experiments.

Loperamide and P‐glycoprotein modulator in opioid detoxification

The successful use of a new opioid withdrawal protocol using over‐the‐counter medications loperamide and P‐glycoprotein inhibitor (omeprazole) is discussed in a case series.

pH Dependent Uptake of Loperamide Across the Gastrointestinal Tract: An In Vitro Study

In vitro studies determined that drugs used to decrease acid secretion in the stomach could result in higher plasma loperamide levels based on the in vitro system reflecting the in vivo environment, and showed that P‐gp was not affected by pH conditions.

Tariquidar, a Selective P-glycoprotein Inhibitor, Does Not Potentiate Loperamide’s Opioid Brain Effects in Humans despite Full Inhibition of Lymphocyte P-glycoprotein

The results suggest that despite full inhibition of lymphocyte P-glycoprotein, the selective P- glycoprotein inhibitor tariquidar does not potentiate loperamide’s opioid brain effects in humans.

Effect of a P‐glycoprotein inhibitor, cyclosporin A, on the disposition in rodent brain and blood of the 5‐HT1A receptor radioligand, [11C](R)‐(––)‐RWAY

Small animal positron emission tomography is used to investigate how P‐gp and its blockade with Cyclosporin A (CsA) affect rodent brain uptake of [11C](R)‐(−)‐RWAY, a radioligand for brain 5‐HT1A receptors.
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