Carbamazepine is not a substrate for P-glycoprotein

Aims To determine whether the anticonvulsant carbamazepine (CBZ), a known C YP3A4 substrate, is also a substrate for the multidrug efflux transporter P -glycoprotein (Pgp). Methods The role of Pgp in the transport of CBZ was assessed in three syste ms: (a) in mdr1a/1b(-/-) and wild-type mice after administration of 2 mg kg (-1) and 20 mg kg(-1), which served as a model for brain penetration; (b) i n CAco-2 cells, an in vitro model of the intestinal epithelium that is know n to express high Pgp levels; and (c) by flow cytometry in lymphocytes usin g rhodamine 123, a fluorescent substrate for PgP. Results Brain penetration of both doses of CBZ at 1 h and 4 h was comparabl e in wild-type and mdr1a/1b(-/-) mice. Transport across the Caco-2 cell mon olayer was Pgp-independent, and was not affected by the Pgp inhibitor PSC-8 33. CBZ had no effect on rhodamine 123 efflux from lymphocytes, in contrast to verapamil, which increased fluorescence intensity fivefold. Conclusion CBZ is not a substrate for Pgp. Its efficacy is unlikely to be a ffected by Pgp over-expression in the brain. Furthermore, the interaction o f CBZ with drugs that modulate both CYP3A4 and Pgp function such as verapam il is probably due to inhibition of CYP3A4 and not Pgp.