Abstracts

Rationale: Carbamazepine (CBZ) is a substrate of CYP3A4 and CYP3A5 drug metabolizing enzymes and weak substrate of p-glycoprotein (Pgp) efflux transporter. Multiple functional variants in CYP3A5 and ABCB1 (encoding Pgp)genes may contribute to variability in CBZ exposure. We investigated the association of CYP3A5 and ABCB1 variants with area under the curve (AUC) of CBZ after an oral dose. Methods: Datasets of 37 unrelated adult Caucasian and 16 African American epileptic patients on CBZ maintenance therapy were tested. Candidate functional variants including ABCB1 (c.3435C>T), CYP3A5*3 A (g.6986A>G), CYP3A5*6 (g.14690G>A) and CYP3A5*7 (g.27131_27132insT) were genotyped by using TaqMan assay. The twenty-four hour steady-state AUC was determined. Multiple regression analysis was used to test for association of variants with AUC/dose. ANCOVA was used to compare adjusteded means (adjusted for age and weight).Results: Association of low AUC/dose was seen with Caucasian race (r= -0.453, p=0.001), CYP3A5*3/*3 (r= -0.532, p< 0.001) and ABCB1 T/T (r= -0.258, p=0.049). Whereas, association of high AUC/dose was seen with CYP3A5*7/*7 (r= 0.343, p=0.013) and CYP3A5 wt/*3 (r= 0.299, p=0.027). Adjusted mean of AUC/dose ± S.E. for Caucasians was 0.76±0.09 and for Africans was 1.38±0.14 mg hr/L/mg (p<0.001). In the regression model, CYP3A5*3/*3 was an independent predictor for CBZ AUC/dose (β= -0.532, p<0.001). In Caucasians, the T allele frequency of ABCB1c.3435C>