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

Neurourology and Urodynamics - Tập 30 Số 8 - Trang 1633-1638 - 2011
Donald W. Miller1, Martha Hinton1, Fang Chen1
1Department of Pharmacology and Therapeutics, University of Manitoba, Winnipeg, Manitoba, Canada

Tóm tắt

AbstractAimsThe 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).MethodsCell 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 (MDCKMDR1) were used to examine darifenacin permeability and drug efflux transporter responses.ResultsConcentration‐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 MDCKMDR1 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.ConclusionsDarifenacin 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.

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Thông tin xuất bản

Neurourology and Urodynamics

Tập 30 Số 8

1633-1638

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