Impact of P-glycoprotein and breast cancer resistance protein on the brain distribution of antiepileptic drugs in knockout mouse models

Refractory epilepsy is reportedly associated with an overexpression of ATP-binding cassette transporters such as P-glycoprotein (Pgp) and breast cancer resistance protein (Bcrp). In this study, we examined the contribution of Pgp and Bcrp to the brain distribution of 12 antiepileptic drugs (AEDs) in Mdrlallb(-/-) and Mdrlallb(-/-)1Bcrp(-/-) mice within a therapeutic concentration range. The blood concentrations were sequentially determined, and the brain concentrations were measured at 60 min after intravenous administration. The plasma concentration profiles for each AED in the Mdrlallb(-/-) mice were equivalent to those in the wild-type mice. In contrast, the plasma concentration profiles of phenytoin, lamotrigine, topiramate, tiagabine, and levetiracetam in the Mdrlallb(-/-)1Bcrp(-/-) mice were significantly lower than the corresponding ones in the wild-type mice. The brain-to-plasma concentration ratio (Kpbram) values of phenytoin, topiramate, and tiagabine in the Mdrlallb(-/-) mice were significantly higher than the corresponding ones in the wild-type mice. In contrast, the Kpbram values of phenobarbital, clobazam, zonisamide, gabapentin, tiagabine, and levetiracetam in the Mdrlallb(-/-)1Bcrp(-I-) mice were significantly higher than the corresponding ones in Mdrlallb (-/-) mice. The Kpbram values of the 12 AEDs in the Mdrlallb(-/-)IBcrp(-/-) mice, but not wild-type mice, significantly correlated with the corresponding molecular weight values. These findings suggest that both Pgp and Bcrp restrict brain access for several AEDs. Taken together, information on the contribution of each transporter may be useful in the development of strategic treatments of refractory epilepsy. 0 2013 Elsevier By. All rights reserved.