CYP2C8 and CYP2C9 metabolic profiles and frequency of emergency department visits for sickle cell disease pain management

The CYP2C8 and CYP2C9 variant alleles play a significant role in NSAIDs analgesic effect and toxicity. NSAIDs are used to treat vasoocclusive pain at the prodromal stage in sickle cell disease (SCD) patients. We describe CYP2C8 and CYP2C9 genotypes and phenotypes and frequency of emergency department (ED) visits in an African American SCD patient cohort. DNA from 165 unrelated SCD patients (82 males/83 females, aged from 16 to 61 years) was genotyped for seven CYP2C8 (*1, *2, *3, *4, *5, *7 & *8) alleles and 15 CYP2C9 alleles (*1, *2,*3, *4, *5, *6, *8, *9, *10, *11, *12, *13, *15, *25 & *27) using the iPLEX® ADME PGx multiplexed panel. CYP2C8 *1(0.806),*2(0.164),*3(0.018), and *4 (0.012) alleles were identified. Genotype frequencies were distributed as homozygous wild-type (66.7%), heterozygous (27.8%), and homozygous variant/compound heterozygous (5.4%) respectively. CYP2C9 *1(0.824), *2 (0.027), *3 (0.012), *5 (0.009), *6 (0.009), *8 (0.042), *9 (0.061), and *11(0.015) were observed with extensive (68.5%), intermediate (18.1%) and poor predicted metabolizers (0.6%) respectively. Ten of twelve of the combined alleles of the CYP2C8 and CYP2C9 enzymes identified in our cohort contribute to deficient metabolic genotypes. Fifty-two subjects had at least one variant CYP2C9 allele associated with either the intermediate metabolizer, poor, or indeterminate phenotype. Fifty-five subjects had at least one CYP2C8 variant allele that contributes to impaired metabolic genotypes. Unlike the CYP2C9 (p= 0.0515), the distribution of CYP2C8 phenotypes was not significantly different in high and low ED users (p= 0.1668); but some CYP2C8 and CYP2C9 allelic combinations observed in 15.2% (25) of the cohort are associated with higher risks for analgesic failure or exacerbation of SCD related morbidity. Data on the association of NSAIDs treatment with analgesic failure are limited for SCD patients. CYP2C8 and CYP2C9 preemptive genotyping may facilitate early prediction of efficacy of NSAID treatment outcomes. Abstract source