Cytochrome P 450 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. Clinical Pharmacology & Therapeutics (2007) 82 , 579–585; doi: 10.1038/sj.clpt.6100208 ; published online 18 April 2007