Abstracts

The pharmacokinetics of carbamazepine (CBZ) and valproic acid (VPA) exhibit significant interindividual variation. CBZ and VPA undergo extensive metabolism and the genes coding for these metabolizing enzymes exhibit polymorphism variation. To begin to understand the genetic contributions underlying the pharmacokinetic variability, we first examined allele frequencies, genotype distributions and racial differences of recognized polymorphisms in genes coding for CBZ and VPA metabolizing enzymes. DNA was isolated from peripheral blood from 546 individuals from the Greater Cincinnati area with a racial distribution approximating the 2000 Population Census of the area. Identification of normal alleles and functionally significant polymorphic variants of genes CYP1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP3A4, and EPHX1 was performed by PCR amplification followed by detection using either Third Wave Technology or TaqMan[reg]Pre-Developed Assay Reagents. Two alleles, CYP2A6*3 and CYP3A4*2 were deleted from further population analysis, because no positive control DNA was available. To ensure satisfactory data, 23 subjects were excluded for incompleteness, defined as having incomplete genotype data for more than one-third of the assays. Of the remaining 523 study subjects, 49% were female, 79% were Caucasian, 16% were African American, and 5% were other race. Allele frequency differences were assessed between African Americans and Caucasians using Mann-Whitney tests with Bonferroni-adjusted p-values to control for multiple testing. Frequencies for the major allele for each gene ranged from 73% to 100% and homozygosity for the major allele genotypes ranged from 46% (CYP1A2*1F) to 99% (CYP2C19*3). Significant differences in genotypic distributions between African Americans and Caucasians were identified for CYP1A2*1C, CYP3A4*1B and CYP2C8*2 at the 0.001 level and for markers CYP2C8*3-399, CYP2C9*2, and CYP2C9*3 at the 0.05 level. No differences were identified for CYP1A2*1F, EPHX1-113, EPHX1-139, CYP2A6*2, CYP2B6*5, CYP2C8*3-139, CYP2C19*2, or CYP2C19*3. Due to low counts, differences among the other racial categories were not estimated. Among genes coding for CBZ and VPA metabolizing enzymes, frequencies of alleles and genotypic distributions varied by marker. Significant differences in genotypic distributions exist between African Americans and Caucasians for many of the markers. These results are being used in ongoing CBZ and VPA pharmacogenetic studies. (Supported by The Epilepsy Foundation[apos]s Partnership for Pediatric Epilepsy Research.)