Pharmacogenetic Expression of CYP2C19 in a Pediatric Population

Abstract

Genetic variability in CYP2C19 may be associated with both lack of efficacy and toxicity of drugs due to its different metabolic status based on the presence of particular alleles. This literature review summarizes current knowledge relative to the association or treatment adaptation based on CYP2C19 genetics in a pediatric population receiving drugs metabolized by CYP2C19, such as voriconazole, antidepressants, clopidogrel and proton pump inhibitors. Additionally, we also presented one of the approaches that we developed for detection of variant alleles in the CYP2C19 gene. A total of 25 articles on PubMed were retained for the study. All studies included pediatric patients (age up to 21 years) having benefited from an assessment of CYP2C19. CYP2C19 poor and intermediate metabolizers exhibit a higher trough plasma concentration of voriconazole, and PPIs compared to the rapid and ultra-rapid metabolizers. The pharmacogenetic data relative to CYP2C19 and clopidogrel in the pediatric population are not yet available. CYP2C19 poor metabolizers have a higher trough plasma concentration of antidepressants compared to the rapid and the ultra-rapid metabolizers. Modification of allele-specific PCR through the introduction of artificial mismatch is presented. CYP2C19 genotyping remains a powerful tool needed to optimize the treatment of children receiving voriconazole, PPIs, and anti-depressants.

Keywords: CYP2C19; anti-depressants; clopidogrel; genotyping; metabolizer; pediatrics; proton pump inhibitors; trough plasma concentration; voriconazole.

Figure 1

Allele-specific PCR for CYP2C19 alleles. Illustrative example of genotypes obtained by modification of allele-specific PCR through destabilizing mismatches, distinguishing 3 possible genotypes of CYP2C19 polymorphisms whose minor alleles define variant *2 (upper panels) and *17 (lower panel) with decreased and increased enzyme activity, respectively. (Left panels), PCR specific for major alleles; (Right panel), PCR specific for minor alleles, genotypes are indicated at the top of the panels. Denaturation, annealing, and elongation steps of PCR amplification are 30 s in duration each and were performed at 94, 60, and 72 °C, respectively, for a total of 35 cycles. The PCR product was visualized by electrophoresis on a 2% agarose gel.