Premium
Effect of cytochrome P450 3A5*3 genotype on the stereoselective pharmacokinetics of amlodipine in healthy subjects
Author(s) -
Kim KyoungAh,
Park PilWhan,
Park JiYoung
Publication year - 2009
Publication title -
chirality
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.43
H-Index - 77
eISSN - 1520-636X
pISSN - 0899-0042
DOI - 10.1002/chir.20588
Subject(s) - amlodipine , pharmacokinetics , cyp3a5 , chemistry , stereoselectivity , cyp3a , pharmacology , enantiomer , genotype , medicine , cytochrome p450 , stereochemistry , metabolism , biochemistry , blood pressure , gene , catalysis
Abstract Amlodipine is a racemic mixture composed of S ‐ and R ‐form and metabolized stereoselectively. Cytochrome P450 3A (CYP3A) including CYP3A5 are involved in the metabolism of amlodipine and it was reported that polymorphic CYP3A5 genotype modulates the plasma levels of amlodipine and thus affect its pharmacokinetics. This study was conducted to find whether stereoselective pharmacokinetics of amlodipine was affected by the polymorphic CYP3A5 genotype. Seventeen healthy subjects were genotyped for CYP3A5*3 variant. After a single dose of 10‐mg amlodipine, enantiomers of amlodipine were analyzed using HPLC‐MS/MS equipped with an AGP column. Amlodipine showed stereoselective pharmacokinetics. S ‐amlodipine exhibited higher plasma levels than R ‐amlodipine in both genotype groups. S ‐amlodipine showed 15% higher mean peak plasma concentrations ( C max ) in CYP3A5*1/*3 carriers (3.28 ng/ml) than CYP3A5*3/*3 carriers (2.85 ng/ml) ( P = 0.194) and R ‐amlodipine also showed 21% higher C max in CYP3A5*1/*3 carriers (3.33 ng/ml) than CYP3A5*3/*3 carriers (2.75 ng/ml) ( P = 0.114). CYP3A5*1/*3 carriers also have 23 and 12% higher mean area under the time versus concentration curve of R ‐amlodipine and S ‐amlodipine than CYP3A5*3/*3 carriers, respectively (for R ‐amlodipine, 147.1 ng*h/ml for CYP3A5*1/*3 carriers versus 121.8 ng*h/ml for CYP3A5*3/*3 carriers, P = 0.234; for S‐amlodipine, 161.6 ng*h/ml for CYP3A5*1/*3 carriers vs. 144.2 ng*h/ml for CYP3A5*3/*3 carriers, P = 0.353). Other pharmacokinetic parameters also showed no significant difference between them. In conclusion, the present study showed that despite the evidence that amlodipine is stereoselectively metabolized, CYP3A5*3 genotype did not affect stereoselective disposition of amlodipine. It provides the evidence that CYP3A5*3 genotype plays a minor role in the interindividual variability of stereoselective disposition of amlodipine in humans. Chirality, 2009. © 2008 Wiley‐Liss, Inc.