Effect of Cytochrome P450 3A5*3 genotype on the stereoselective pharmacokinetics of amlodipine in healthy subjects

Kyoung Ah Kim, Pil Whan Park, Ji-Young Park

Research output: Contribution to journalArticle

10 Citations (Scopus)

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 (Cmax) in CYP3A5*1/ *3 carriers (3.28 ng/ml) than CYP3A5*3/*3 carriers (2.85 ng/ml) (P 5 0.194) and R-amlodipine also showed 21% higher Cmax in CYP3A5*1/*3 carriers (3.33 ng/ml) than CYP3A5*3/*3 carriers (2.75 ng/ml) (P 5 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 5 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 5 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.

Original languageEnglish
Pages (from-to)485-491
Number of pages7
JournalChirality
Volume21
Issue number5
DOIs
Publication statusPublished - 2009 Aug 12

Fingerprint

Cytochrome P-450 CYP3A
Amlodipine
Pharmacokinetics
Healthy Volunteers
Genotype
Plasmas
Enantiomers

Keywords

  • Amlodipine
  • CYP3A5*3
  • Cytochrome P450 3A5
  • Stereoselectivity

ASJC Scopus subject areas

  • Analytical Chemistry
  • Catalysis
  • Pharmacology
  • Drug Discovery
  • Spectroscopy
  • Organic Chemistry

Cite this

Effect of Cytochrome P450 3A5*3 genotype on the stereoselective pharmacokinetics of amlodipine in healthy subjects. / Kim, Kyoung Ah; Park, Pil Whan; Park, Ji-Young.

In: Chirality, Vol. 21, No. 5, 12.08.2009, p. 485-491.

Research output: Contribution to journalArticle

@article{2e1d0817a0354e9facbee232c6797138,
title = "Effect of Cytochrome P450 3A5*3 genotype on the stereoselective pharmacokinetics of amlodipine in healthy subjects",
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 (Cmax) in CYP3A5*1/ *3 carriers (3.28 ng/ml) than CYP3A5*3/*3 carriers (2.85 ng/ml) (P 5 0.194) and R-amlodipine also showed 21{\%} higher Cmax in CYP3A5*1/*3 carriers (3.33 ng/ml) than CYP3A5*3/*3 carriers (2.75 ng/ml) (P 5 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 5 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 5 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.",
keywords = "Amlodipine, CYP3A5*3, Cytochrome P450 3A5, Stereoselectivity",
author = "Kim, {Kyoung Ah} and Park, {Pil Whan} and Ji-Young Park",
year = "2009",
month = "8",
day = "12",
doi = "10.1002/chir.20588",
language = "English",
volume = "21",
pages = "485--491",
journal = "Chirality",
issn = "0899-0042",
publisher = "Wiley-Liss Inc.",
number = "5",

}

TY - JOUR

T1 - Effect of Cytochrome P450 3A5*3 genotype on the stereoselective pharmacokinetics of amlodipine in healthy subjects

AU - Kim, Kyoung Ah

AU - Park, Pil Whan

AU - Park, Ji-Young

PY - 2009/8/12

Y1 - 2009/8/12

N2 - 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 (Cmax) in CYP3A5*1/ *3 carriers (3.28 ng/ml) than CYP3A5*3/*3 carriers (2.85 ng/ml) (P 5 0.194) and R-amlodipine also showed 21% higher Cmax in CYP3A5*1/*3 carriers (3.33 ng/ml) than CYP3A5*3/*3 carriers (2.75 ng/ml) (P 5 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 5 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 5 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.

AB - 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 (Cmax) in CYP3A5*1/ *3 carriers (3.28 ng/ml) than CYP3A5*3/*3 carriers (2.85 ng/ml) (P 5 0.194) and R-amlodipine also showed 21% higher Cmax in CYP3A5*1/*3 carriers (3.33 ng/ml) than CYP3A5*3/*3 carriers (2.75 ng/ml) (P 5 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 5 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 5 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.

KW - Amlodipine

KW - CYP3A53

KW - Cytochrome P450 3A5

KW - Stereoselectivity

UR - http://www.scopus.com/inward/record.url?scp=68249157017&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=68249157017&partnerID=8YFLogxK

U2 - 10.1002/chir.20588

DO - 10.1002/chir.20588

M3 - Article

C2 - 18752284

AN - SCOPUS:68249157017

VL - 21

SP - 485

EP - 491

JO - Chirality

JF - Chirality

SN - 0899-0042

IS - 5

ER -