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The Effect of Loperamide and Fentanyl on the Distribution Kinetics of Verapamil in the Lung and Brain in Sprague Dawley Rats

Verapamil has been shown to inhibit fentanyl uptake in vitro and is a potent P-glycoprotein inhibitor. Tissue partitioning of loperamide, a commercially available opioid, is closely controlled by the P-gp efflux transporter. The following studies were designed to evaluate the effect of opioids on verapamil partitioning in the lung and brain, in vivo. Opioid (fentanyl or loperamide) was administered by intravenous infusion to Sprague Dawley rats alone or in combination with verapamil and plasma, with lung and brain tissues were collected at 1, 5, 6, 8, 10 and 60 minutes. Drug dispositions were modeled by recirculatory pharmacokinetic models. Fentanyl slightly increased the verapamil lung (PL) partition coefficient yet decreased the brain (PB) partition coefficient. Furthermore, loperamide significantly increased PLand PB. Fentanyl reduced the verapamil volume of distribution (V1) and verapamil elimination clearance (ClE). Fentanyl decreased verapamil brain partitioning, yet increased verapamil lung partitioning. Also, loperamide increased lung and brain partitioning in vivo. These results suggest that verapamil and fentanyl may be substrates of an unidentified inward transporter in brain tissue and confirm that verapamil and loperamide are substrates of the efflux transporter P-gp. Keywords—efflux transporter, elimination clearance, partition coefficient, verapamil.