CYP3A5 genetic variability influences sildenafil and metabolite in pulmonary hypertension

Interindividual variability in sildenafil response among pulmonary hypertension patients (PH) may be influenced by CYP3A5 polymorphisms. CYP3A5*3 allele reduces CYP3A5 activity and affects sildenafil metabolism. This study investigated the associations between CYP3A5 genotype and plasma concentrations of sildenafil and N-desmethyl sildenafil, as well as clinical outcomes, in PH.

A cross-sectional study of 92 patients with PH was conducted. Blood samples were collected at trough and 1 h after sildenafil administration (C1h). Plasma concentrations were quantified by HPLC, and CYP3A5 genotypes were determined by real-time PCR with TaqMan probes.

Thirteen (14.13%) patients carried the CYP3A5 *1/*1 genotype, and 79 (85.87%) carried the CYP3A5*3 allele. CYP3A5*3 allele carriers had a significantly higher mean C1h sildenafil concentration-to-dose (C/D) ratio than CYP3A5*1/*1 carriers (3.61 ± 2.69 vs. 2.66 ± 1.20 ng/mL/mg; p = 0.043). The mean C1h of sildenafil, trough sildenafil concentration and trough sildenafil C/D ratio were higher in CYP3A5*3 carriers, but not statistically significant. The trough and C1h of N-desmethyl sildenafil and their corresponding C/D ratios were lower in CYP3A5*3 carriers but did not reach statistical significance. CYP3A5*3 allele carriers showed greater improvement in 6-min walk distance (33.74 ± 43.46 m vs. -5.58 ± 44.52 m; p = 0.005), WHO functional class (32.00% vs. 15.39%; p = 0.042) and EmPHasis-10 scores (-4.15 ± 6.46 vs. 1.08 ± 3.80; p = 0.009).

The CYP3A5*3 allele is associated with higher sildenafil exposure and superior clinical outcomes. Therefore, CYP3A5 genotyping may facilitate personalized assessment of sildenafil efficacy and clinical outcomes.