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Genetic variability of UGT2B7, CYP3A4, CYP3A5 and CYP2B6 DMETs in a sickle cell disease patient cohort

key information

source: The Journal of Pain

year: 2016

authors: C. Jaja, M. Lyon, N. Patel, A. Kutlar

summary/abstract:

Interindividual variability in analgesic effects of opioids prescribed for sickle cell disease (SCD) pain is attributed to polymorphisms in drug metabolizing enzymes and transporters (DMET). We describe UGT2B7, CYP3A4, CYP3A5, and CYP2B6 allelic variants characterized in opioid pharmacokinetic and pharmacodynamic pathways for determination of potential suboptimal opioid exposure in SCD patients. DNA from 165 unrelated SCD patients was genotyped for 2 UGT2B7 alleles, 4 CYP3A4 alleles, 6 CYP3A5 alleles, and 7 CYP2B6 alleles using the iPLEX ADME PGx multiplexed panel. We reported genotype frequencies as homozygous wild-type, heterozygous, and homozygous variant/compound heterozygous; and predicted phenotypes as extensive, intermediate, ultra-rapid, and poor metabolizers. Four CYP2B6 alleles were detected in the cohort. The most common alleles were *1 (0.482) and *6 (0.442). Phenotypes were distributed into EM (21.8%), IM (72%), and UNK (6%).The CYP3A4 *1 frequency was 0.994 and the *20 was 0.006. The phenotypes were distributed as EM (98.8) and IM (1.2%). For the CYP3A5*1, allelic frequency was 0.461. The combined frequency for the *3, *6 & *7 was 0.539. Phenotypically, 23% of the cohort were EM, 30% were PM, and 46.1% were IM. The UGT2BT*1 frequency was 0.785 and the *2 was 0.215. The phenotypes were EM (64.2%), UM/EM (28.5%), and UM (7.3%) respectively. Our study provides important data on the pattern of the UGT2B7, CYP3A4, CYP3A5, and CYP2B6 allelic variants for the first time in an African American SCD cohort. For SCD pain, preemptive genotyping of selected DMETs variants could empower clinicians to communicate pharmacologic risk and drug response prediction with SCD patients using biological evidence as opposed to explaining statistical risk without biological significance. Additional pharmacokinetic studies are necessary to determine the genotype – metabolic phenotype concordance in SCD patients due to the influence of disease state on DMETs expression.

organization: University of Cincinnati, Cincinnati

DOI: 10.1016/j.jpain.2016.01.187

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