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 pharm...

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Published in:Clinical pharmacology and therapeutics 2007-11, Vol.82 (5), p.579-585
Main Authors: Jin, Y, Wang, Y‐H, Miao, J, Li, L, Kovacs, R J, Marunde, R, Hamman, M A, Phillips, S, Hilligoss, J, Hall, S D
Format: Article
Language:English
Subjects:
Adult
Anti-Arrhythmia Agents - pharmacology
Biological and medical sciences
Calcium Channel Blockers - administration & dosage
Calcium Channel Blockers - blood
Calcium Channel Blockers - pharmacokinetics
Calcium Channel Blockers - pharmacology
Cytochrome P-450 CYP3A
Cytochrome P-450 Enzyme System - genetics
Electrocardiography
Female
Genotype
Heart Conduction System - drug effects
Humans
Isoenzymes
Male
Medical sciences
Metabolic Clearance Rate
Pharmacology. Drug treatments
Polymorphism, Genetic
Prospective Studies
Reference Values
Vasodilator Agents - pharmacology
Verapamil - administration & dosage
Verapamil - blood
Verapamil - pharmacokinetics
Verapamil - pharmacology
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Summary: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
ISSN:0009-9236
1532-6535
DOI:10.1038/sj.clpt.6100208