Increased drug delivery to the brain by P‐glycoprotein inhibition

  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},
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.



Inhibition of P-glycoprotein-mediated drug transport: A unifying mechanism to explain the interaction between digoxin and quinidine [seecomments].

The in vivo data strongly support the hypothesis that inhibition of P-glycoprotein-mediated digoxin elimination plays an important role in the increase of plasma digoxin concentration occurring with quinidine coadministration in wild-type mice and thus support a similar mechanism in humans.

P-glycoprotein and cytochrome P-450 3A inhibition: dissociation of inhibitory potencies.

Results demonstrate that, although many P-gp inhibitors are potent inhibitors of CYP3A, a varying degree of selectivity is present and the development and use of P-GP inhibitors with minimal or absent CYP2A inhibitory effects should decrease the impact of drug interactions on the therapeutic use of such compounds.

Differential effects of quinidine on the disposition of nifedipine, sparteine, and mephenytoin in humans

The interaction between quinidine and nifedipine supports the involvement of a common P450 (P450IIIA4) in the metabolism of the two drugs.

P-glycoprotein in the blood-brain barrier of mice influences the brain penetration and pharmacological activity of many drugs.

It is shown here that the drugs loperamide, domperidone, and ondansetron are transported substrates for the mouse mdr1a P-GP and its human homologue MDR1, and the possible role that the drug-transporting P- GP(s) may play in the clinical use of many drugs, especially those with potential targets in the central nervous system.

The drug transporter P-glycoprotein limits oral absorption and brain entry of HIV-1 protease inhibitors.

It is demonstrated that P-glycoprotein limits the oral bioavailability and penetration of these agents into the brain and raises the possibility that higher HIV-1 protease inhibitor concentrations may be obtained by targeted pharmacologic inhibition of P- glycoprotein transport activity.

In vitro and in vivo drug interactions involving human CYP3A.

Cytochrome P4503A (CYP3A) is importantly involved in the metabolism of many chemically diverse drugs administered to humans and makes it a major contributor to presystemic elimination following oral drug administration.

Mechanism of the cardiotoxic actions of terfenadine.

In vitro cardiac electrophysiologic studies found that terfenadine is equipotent to quinidine as a blocker of the delayed rectifier potassium current in isolated feline myocytes, which indicates that episodes of torsades de pointes are most likely the result of a quinidinelike action of the parent drug and of factors that impair the normally rapid metabolism of terfenADine.

The role of human cytochrome P450 enzymes in the metabolism of anticancer agents: implications for drug interactions.

Although cyclosporin and calcium channel blockers may influence the pharmacokinetics of certain anticancer agents by inhibiting their CYP3A mediated metabolism, it is more likely that these P-glycoprotein inhibitors inhibit P- glycoprotein mediated drug elimination.

Impact of ethnic origin and quinidine coadministration on codeine's disposition and pharmacodynamic effects.

Comparing the pharmacokinetics and pharmacodynamics of codeine with and without quinidine between Caucasian and Chinese extensive metabolizers of debrisoquin found Chinese produce less morphine from codeine, exhibit reduced sensitivity to that morphine, and therefore might experience reduced analgesic effect in response to codeine.

Identification of rifampin-inducible P450IIIA4 (CYP3A4) in human small bowel enterocytes.

The identification of inducible P450IIIA4 in enterocytes may in part account for drug interactions characteristic of P450 IIIA4 substrates and suggests a strategy for controlling entry into the body of a major class of xenobiotics.