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1. Epilepsia. 2012 Mar;53(3):529-38. doi: 10.1111/j.1528-1167.2012.03409.x.

Evaluation of the permeability and P-glycoprotein efflux of carbamazepine and
several derivatives across mouse small intestine by the Ussing chamber technique.

Fortuna A, Alves G, Falcão A, Soares-da-Silva P.

Department of Pharmacology Faculty of Pharmacy, University of Coimbra, Coimbra,
Portugal CNC - Center for Neurosciences and Cell Biology, University of Coimbra,
Coimbra, Portugal CICS-UBI - Health Sciences Research Center, University of Beira
Interior, Covilhã, Portugal Department of Research and Development, BIAL, S.
Mamede do Coronado, Portugal.

Purpose:  The rational discovery and development of new antiepileptic drugs
(AEDs) with safer therapeutic index and better pharmacokinetic properties is
still warranted nowadays. Because the long-term management of epilepsy is
attained by means of orally administered AEDs, investigation of their potential
to be well absorbed at the intestinal level is mandatory. Moreover, involvement
of the efflux transport mediated by P-glycoprotein (P-gp) may compromise the
systemic and central nervous system disposition of AEDs. Therefore, this study
aimed at characterizing mouse jejunal passive transport and the possible active
efflux mediated by P-gp of a series of dibenz[b,f]azepine-5-carboxamide
derivatives (carbamazepine [CBZ], oxcarbazepine [OXC], S-licarbazepine [S-Lic],
R-licarbazepine [R-Lic], carbamazepine-10,11-epoxide [CBZ-E],
10,11-trans-dihydroxy-10,11-dihydro-carbamazepine [trans-diol], and BIA 2-024),
which comprise some AEDs and metabolites. Methods:  Permeation studies were
performed with freshly excised mouse jejunum segments mounted in Ussing chambers.
Absorptive (M-S) and secretive (S-M) transports were analyzed with and without
verapamil, which is a P-gp inhibitor widely recognized. Apparent permeability
coefficients (P(app) ) in both directions and in absence or presence of verapamil
were determined for each test compound. The in vitro method was validated using
five controls that included high and low permeable markers with known absorption
fraction (Fa) and also well-known P-gp substrates. The integrity of intestinal
membrane was guaranteed during the assay by measuring the transepithelial
electrical resistance. Key Findings:  The correlation obtained between P(app)
(M-S) and Fa of references was high (r(2)  = 0.9945), and could be used to
classify the derivatives according to Biopharmaceutical Classification System:
CBZ and OXC were the only classified as highly permeable. The P(app) (S-M) of
OXC, CBZ-E, R-Lic, and BIA 2-024 were significantly higher than their P(app)
(M-S). After verapamil addition, their P(app) (S-M) lowered while P(app) (S-M)
increased, suggesting the involvement of P-gp on the transport of those compounds
across mouse jejunum segments. In opposition, CBZ, S-Lic, and trans-diol
presented no statistical differences between the P(app) values reported in both
directions, with or without verapamil. The results reported herein suggest that
differences in biodisposition of S-Lic and R-Lic might result from their distinct
interaction with P-gp. Significance:  The Ussing chamber model used herein showed
to be useful for predicting Fa of AEDs and the involvement of efflux transport,
namely P-gp, on their absorption. This is an important achievement as compounds
that are not transported by P-gp may offer advantages when used in patients with
pharmacoresistant epilepsy.

Wiley Periodicals, Inc. © 2012 International League Against Epilepsy.

PMID: 22372629 [PubMed - in process]