Abstract
Aim
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.
Methods
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.
Results
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).
Conclusions
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.