Cytochrome P450 3A5 genotype is associated with verapamil response in healthy subjects.
We hypothesized that CYP3A5 genotype contributes to the interindividual variability in verapamil response. Healthy subjects (n=26) with predetermined CYP3A5 genotypes were categorized as expressers (at least one CYP3A5(*)1 allele) and nonexpressers (subjects without a CYP3A5(*)1 allele). Verapamil pharmacokinetics and pharmacodynamics were determined after 7 days of dosing with 240 mg daily. There was a significantly higher oral clearance of R-verapamil (165.1+/-86.4 versus 91.2+/-36.5 l/h; P=0.009) and S-verapamil (919.4+/-517.4 versus 460.2+/-239.7 l/h; P=0.01) in CYP3A5 expressers compared to nonexpressers. Consequently, CYP3A5 expressers had significantly less PR-interval prolongation (19.5+/-12.3 versus 44.0+/-19.4 ms; P=0.0004), and had higher diastolic blood pressure (69.2+/-7.5 versus 61.6+/-5.1 mm Hg; P=0.036) than CYP3A5 nonexpressers after 7 days dosing with verapamil. CYP3A5 expressers display a greater steady-state oral clearance of verapamil and may therefore experience diminished pharmacological effect of verapamil due to a greater steady state oral clearance.
Jin
Y
Y
Division of Clinical Pharmacology, Department of Medicine, Indiana University, School of Medicine, Indianapolis, Indiana, USA.
Wang
Y-H
YH
Miao
J
J
Li
L
L
Kovacs
R J
RJ
Marunde
R
R
Hamman
M A
MA
Philips
S
S
Phillips
S
S
Hilligoss
J
J
Hall
S D
SD
D000328:Adult; D000889:Anti-Arrhythmia Agents / Q000494:pharmacology; D002121:Calcium Channel Blockers / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics / Q000494:pharmacology*; D051544:Cytochrome P-450 CYP3A; D003577:Cytochrome P-450 Enzyme System / Q000235:genetics*; D004562:Electrocardiography; D005260:Female; D005838:Genotype; D006329:Heart Conduction System / Q000187:drug effects; D006801:Humans; D007527:Isoenzymes; D008297:Male; D008657:Metabolic Clearance Rate; D011110:Polymorphism, Genetic; D011446:Prospective Studies; D012016:Reference Values; D014665:Vasodilator Agents / Q000494:pharmacology; D014700:Verapamil / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics / Q000494:pharmacology*
D000889:Anti-Arrhythmia Agents; D002121:Calcium Channel Blockers; D007527:Isoenzymes; D014665:Vasodilator Agents; D003577:Cytochrome P-450 Enzyme System; D014700:Verapamil; C510164:CYP3A5 protein, human; D051544:Cytochrome P-450 CYP3A