Evaluation of drug efflux transporter liabilities of darifenacin in cell culture models of the blood–brain and blood–ocular barriers

✍ Scribed by Donald W. Miller; Martha Hinton; Fang Chen

• Publisher: John Wiley and Sons
• Year: 2011
• Tongue: English
• Weight: 232 KB
• Volume: 30
• Category: Article
• ISSN: 0733-2467
• DOI: 10.1002/nau.21110

✦ Synopsis

Abstract

Aims

The objective of the present study was to evaluate drug efflux transporter interactions of darifenacin and examine the impact of such transporter interactions on darifenacin permeability in an in vitro model of the blood–brain barrier (BBB) and blood–ocular barrier (BOB).

Methods

Cell membranes expressing human P‐glycoprotein (P‐gp), multidrug resistance‐associated protein (MRP), and breast cancer resistance protein (BCRP) were examined for ATPase activity following darifenacin exposure (0–10 µM). Primary cultured bovine brain microvessel endothelial cells (BBMEC) and P‐gp transfected Manin–Darby canine kidney epithelial cells (MDCK__MDR1__) were used to examine darifenacin permeability and drug efflux transporter responses.

Results

Concentration‐dependent increases in ATPase activity was observed in P‐gp membranes following darifenacin exposure. Both MRP and BCRP membrane preparations were unresponsive to darifenacin. Studies in both BBMEC and MDCK__MDR1__ monolayers confirmed a P‐gp interaction for darifenacin and significantly greater efflux (basolateral to apical) permeability for darifenacin that was reduced by the P‐gp inhibitor, elacridar.

Conclusions

Darifenacin is a substrate for the P‐gp drug efflux transporter present in both BBB and BOB. The P‐gp drug efflux transporter liabilities of darifenacin may limit its penetration into brain and ocular tissue thereby reducing side effect potential. Neurourol. Urodynam. Neurourol. Urodynam. 30: 1633–1638, 2011. © 2011 Wiley Periodicals, Inc.