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

Abstract

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.

Peripherally Selective Cannabinoid 1 Receptor (CB1R) Agonists for the Treatment of Neuropathic Pain

“…34 Given the very low aqueous solubility of PRCBs, their relative lack of BBB permeability suggests that they may be substrates for active drug efflux transporters such as P-glycoprotein or multidrug resistance proteins. Future studies using selective inhibitors of such transporters (e.g., ref 35) or transporter knockout rodents (e.g., ref 36) should help identify precisely the efflux transporters for which PRCBs serve as substrates.…”

Effect of amyloid beta on ATP-binding cassette transporter expression and activity in porcine brain microvascular endothelial cells

“…(multidrug resistance-related protein 5) and ABCG2 (breast cancer resistance protein) are highly expressed in BBB endothelial cells, and actively transport an array of xenobiotics, including many therapeutic drugs, resulting in reduced CNS penetration [3,4,5]. ABC efflux transporters also transport a variety of endogenous compounds including glucocorticoid, cytokines, bilirubin, cholesterol and lipid [6,7] and, notably, ABCB1 has been reported to transport the amyloid-β (Aβ ) peptide [8].…”

Tracking gastrointestinal transit of solids in aged rats as pharmacological models of chronic dysmotility

“…Loperamide (sold as Imodium â ) treatment was chosen to slow colonic transit because, unlike opiates such as morphine, it does not cross the blood-brain barrier to affect the central nervous system. 12 In rodent studies, it induces constipation when given by subcutaneous [13][14][15] or intra-peritoneal 16 injection at a dose range of 0.2-5 mg/kg. Prucalopride (sold as Resotrans â ) was selected to enhance colonic transit.…”