Effects of CYP2C19 and CYP2C9 genetic polymorphisms on the disposition of and blood glucose lowering response to tolbutamide in humans

Ji Hong Shon, Young Ran Yoon, Kyoung Ah Kim, Young Chae Lim, Kwang Jae Lee, Ji Young Park, In June Cha, David A. Flockhart, Jae Gook Shin

Research output: Contribution to journalArticle

86 Citations (Scopus)

Abstract

Several recent in-vitro data have revealed that CYP2C19, in addition to CYP2C9, is also involved in the 4-methylhydroxylation of tolbutamide. We evaluated the relative contribution of CYP2C9 and CYP2C19 genetic polymorphisms on the disposition of blood glucose lowering response to tolbutamide in normal healthy Korean subjects in order to reappraise tolbutamide as a selective in-vivo probe substrate of CYP2C9 activity. A single oral dose of tolbutamide (500 mg) or placebo was administered to 18 subjects in a single-blind, randomized, crossover study with a 2-week washout period. Twelve subjects (of whom six were CYP2C19 extensive metabolizer (EM) and six were CYP2C19 poor metabolizer (PM) genotype) were of the homozygous wild-type CYP2C9* 1 genotype; the other six subjects were of the CYP2C9* 1/* 3 and CYP2C19 EM genotype. Pharmacokinetic parameters were estimated from plasma and urine concentrations of tolbutamide and 4-hydroxytolbutamide. Serum glucose concentrations were measured before and after oral intake of 100 g dextrose. In subjects heterozygous for the CYP2C9* 3 allele, Cmax and AUC of tolbutamide were significantly greater and the plasma half-life significantly longer than those in homozygous CYP2C9* 1 subjects. No pharmacokinetic differences were found between CYP2C19 EM and PM genotype subjects. The estimated AUC of the increase in serum glucose after oral intake of 100 g dextrose was 2.7-fold higher in subjects with the wild-type CYP2C9 genotype than in those with CYP2C9* 1/* 3, but CYP2C19 genetic polymorphism did not alter the blood glucose lowering effect of tolbutamide. The plasma AUC of 4-hydroxytolbutamide and the ratio of 4-hydroxytolbutamide/tolbutamide did not differ significantly between CYP2C19 PM and EM genotype subjects, while these parameters were about twice as high in subjects with the wild-type CYP2C9 genotype than in heterozygous CYP2C9* 3 subjects (P <0.05). Our results strongly suggest that the disposition and hypoglycemic effect of tolbutamide are affected mainly by CYP2C9 genetic polymorphism, but not by CYP2C19 polymorphism. The in-vivo contribution of CYP2C19 to tolbutamide 4-methylhydroxylation appears to be minor in humans. This suggests that, at least in vivo, tolbutamide remains a selective probe for measuring CYP2C9 activity in humans.

Original languageEnglish (US)
Pages (from-to)111-119
Number of pages9
JournalPharmacogenetics
Volume12
Issue number2
DOIs
StatePublished - 2002
Externally publishedYes

Fingerprint

Tolbutamide
Genetic Polymorphisms
Blood Glucose
Genotype
Area Under Curve
Glucose
Cytochrome P-450 CYP2C19
Cytochrome P-450 CYP2C9
Pharmacokinetics
Serum
Hypoglycemic Agents
Human Activities
Cross-Over Studies
Half-Life
Healthy Volunteers

Keywords

  • CYP2C19
  • CYP2C9
  • Genetic polymorphism
  • Pharmacodynamics
  • Pharmacokinetics
  • Tolbutamide

ASJC Scopus subject areas

  • Genetics
  • Pharmacology, Toxicology and Pharmaceutics(all)

Cite this

Effects of CYP2C19 and CYP2C9 genetic polymorphisms on the disposition of and blood glucose lowering response to tolbutamide in humans. / Shon, Ji Hong; Yoon, Young Ran; Kim, Kyoung Ah; Lim, Young Chae; Lee, Kwang Jae; Park, Ji Young; Cha, In June; Flockhart, David A.; Shin, Jae Gook.

In: Pharmacogenetics, Vol. 12, No. 2, 2002, p. 111-119.

Research output: Contribution to journalArticle

Shon, JH, Yoon, YR, Kim, KA, Lim, YC, Lee, KJ, Park, JY, Cha, IJ, Flockhart, DA & Shin, JG 2002, 'Effects of CYP2C19 and CYP2C9 genetic polymorphisms on the disposition of and blood glucose lowering response to tolbutamide in humans', Pharmacogenetics, vol. 12, no. 2, pp. 111-119. https://doi.org/10.1097/00008571-200203000-00005
Shon, Ji Hong ; Yoon, Young Ran ; Kim, Kyoung Ah ; Lim, Young Chae ; Lee, Kwang Jae ; Park, Ji Young ; Cha, In June ; Flockhart, David A. ; Shin, Jae Gook. / Effects of CYP2C19 and CYP2C9 genetic polymorphisms on the disposition of and blood glucose lowering response to tolbutamide in humans. In: Pharmacogenetics. 2002 ; Vol. 12, No. 2. pp. 111-119.
@article{5daa9a0858614f3698b2857450e99a21,
title = "Effects of CYP2C19 and CYP2C9 genetic polymorphisms on the disposition of and blood glucose lowering response to tolbutamide in humans",
abstract = "Several recent in-vitro data have revealed that CYP2C19, in addition to CYP2C9, is also involved in the 4-methylhydroxylation of tolbutamide. We evaluated the relative contribution of CYP2C9 and CYP2C19 genetic polymorphisms on the disposition of blood glucose lowering response to tolbutamide in normal healthy Korean subjects in order to reappraise tolbutamide as a selective in-vivo probe substrate of CYP2C9 activity. A single oral dose of tolbutamide (500 mg) or placebo was administered to 18 subjects in a single-blind, randomized, crossover study with a 2-week washout period. Twelve subjects (of whom six were CYP2C19 extensive metabolizer (EM) and six were CYP2C19 poor metabolizer (PM) genotype) were of the homozygous wild-type CYP2C9* 1 genotype; the other six subjects were of the CYP2C9* 1/* 3 and CYP2C19 EM genotype. Pharmacokinetic parameters were estimated from plasma and urine concentrations of tolbutamide and 4-hydroxytolbutamide. Serum glucose concentrations were measured before and after oral intake of 100 g dextrose. In subjects heterozygous for the CYP2C9* 3 allele, Cmax and AUC of tolbutamide were significantly greater and the plasma half-life significantly longer than those in homozygous CYP2C9* 1 subjects. No pharmacokinetic differences were found between CYP2C19 EM and PM genotype subjects. The estimated AUC of the increase in serum glucose after oral intake of 100 g dextrose was 2.7-fold higher in subjects with the wild-type CYP2C9 genotype than in those with CYP2C9* 1/* 3, but CYP2C19 genetic polymorphism did not alter the blood glucose lowering effect of tolbutamide. The plasma AUC of 4-hydroxytolbutamide and the ratio of 4-hydroxytolbutamide/tolbutamide did not differ significantly between CYP2C19 PM and EM genotype subjects, while these parameters were about twice as high in subjects with the wild-type CYP2C9 genotype than in heterozygous CYP2C9* 3 subjects (P <0.05). Our results strongly suggest that the disposition and hypoglycemic effect of tolbutamide are affected mainly by CYP2C9 genetic polymorphism, but not by CYP2C19 polymorphism. The in-vivo contribution of CYP2C19 to tolbutamide 4-methylhydroxylation appears to be minor in humans. This suggests that, at least in vivo, tolbutamide remains a selective probe for measuring CYP2C9 activity in humans.",
keywords = "CYP2C19, CYP2C9, Genetic polymorphism, Pharmacodynamics, Pharmacokinetics, Tolbutamide",
author = "Shon, {Ji Hong} and Yoon, {Young Ran} and Kim, {Kyoung Ah} and Lim, {Young Chae} and Lee, {Kwang Jae} and Park, {Ji Young} and Cha, {In June} and Flockhart, {David A.} and Shin, {Jae Gook}",
year = "2002",
doi = "10.1097/00008571-200203000-00005",
language = "English (US)",
volume = "12",
pages = "111--119",
journal = "Pharmacogenetics and Genomics",
issn = "1744-6872",
publisher = "Lippincott Williams and Wilkins",
number = "2",

}

TY - JOUR

T1 - Effects of CYP2C19 and CYP2C9 genetic polymorphisms on the disposition of and blood glucose lowering response to tolbutamide in humans

AU - Shon, Ji Hong

AU - Yoon, Young Ran

AU - Kim, Kyoung Ah

AU - Lim, Young Chae

AU - Lee, Kwang Jae

AU - Park, Ji Young

AU - Cha, In June

AU - Flockhart, David A.

AU - Shin, Jae Gook

PY - 2002

Y1 - 2002

N2 - Several recent in-vitro data have revealed that CYP2C19, in addition to CYP2C9, is also involved in the 4-methylhydroxylation of tolbutamide. We evaluated the relative contribution of CYP2C9 and CYP2C19 genetic polymorphisms on the disposition of blood glucose lowering response to tolbutamide in normal healthy Korean subjects in order to reappraise tolbutamide as a selective in-vivo probe substrate of CYP2C9 activity. A single oral dose of tolbutamide (500 mg) or placebo was administered to 18 subjects in a single-blind, randomized, crossover study with a 2-week washout period. Twelve subjects (of whom six were CYP2C19 extensive metabolizer (EM) and six were CYP2C19 poor metabolizer (PM) genotype) were of the homozygous wild-type CYP2C9* 1 genotype; the other six subjects were of the CYP2C9* 1/* 3 and CYP2C19 EM genotype. Pharmacokinetic parameters were estimated from plasma and urine concentrations of tolbutamide and 4-hydroxytolbutamide. Serum glucose concentrations were measured before and after oral intake of 100 g dextrose. In subjects heterozygous for the CYP2C9* 3 allele, Cmax and AUC of tolbutamide were significantly greater and the plasma half-life significantly longer than those in homozygous CYP2C9* 1 subjects. No pharmacokinetic differences were found between CYP2C19 EM and PM genotype subjects. The estimated AUC of the increase in serum glucose after oral intake of 100 g dextrose was 2.7-fold higher in subjects with the wild-type CYP2C9 genotype than in those with CYP2C9* 1/* 3, but CYP2C19 genetic polymorphism did not alter the blood glucose lowering effect of tolbutamide. The plasma AUC of 4-hydroxytolbutamide and the ratio of 4-hydroxytolbutamide/tolbutamide did not differ significantly between CYP2C19 PM and EM genotype subjects, while these parameters were about twice as high in subjects with the wild-type CYP2C9 genotype than in heterozygous CYP2C9* 3 subjects (P <0.05). Our results strongly suggest that the disposition and hypoglycemic effect of tolbutamide are affected mainly by CYP2C9 genetic polymorphism, but not by CYP2C19 polymorphism. The in-vivo contribution of CYP2C19 to tolbutamide 4-methylhydroxylation appears to be minor in humans. This suggests that, at least in vivo, tolbutamide remains a selective probe for measuring CYP2C9 activity in humans.

AB - Several recent in-vitro data have revealed that CYP2C19, in addition to CYP2C9, is also involved in the 4-methylhydroxylation of tolbutamide. We evaluated the relative contribution of CYP2C9 and CYP2C19 genetic polymorphisms on the disposition of blood glucose lowering response to tolbutamide in normal healthy Korean subjects in order to reappraise tolbutamide as a selective in-vivo probe substrate of CYP2C9 activity. A single oral dose of tolbutamide (500 mg) or placebo was administered to 18 subjects in a single-blind, randomized, crossover study with a 2-week washout period. Twelve subjects (of whom six were CYP2C19 extensive metabolizer (EM) and six were CYP2C19 poor metabolizer (PM) genotype) were of the homozygous wild-type CYP2C9* 1 genotype; the other six subjects were of the CYP2C9* 1/* 3 and CYP2C19 EM genotype. Pharmacokinetic parameters were estimated from plasma and urine concentrations of tolbutamide and 4-hydroxytolbutamide. Serum glucose concentrations were measured before and after oral intake of 100 g dextrose. In subjects heterozygous for the CYP2C9* 3 allele, Cmax and AUC of tolbutamide were significantly greater and the plasma half-life significantly longer than those in homozygous CYP2C9* 1 subjects. No pharmacokinetic differences were found between CYP2C19 EM and PM genotype subjects. The estimated AUC of the increase in serum glucose after oral intake of 100 g dextrose was 2.7-fold higher in subjects with the wild-type CYP2C9 genotype than in those with CYP2C9* 1/* 3, but CYP2C19 genetic polymorphism did not alter the blood glucose lowering effect of tolbutamide. The plasma AUC of 4-hydroxytolbutamide and the ratio of 4-hydroxytolbutamide/tolbutamide did not differ significantly between CYP2C19 PM and EM genotype subjects, while these parameters were about twice as high in subjects with the wild-type CYP2C9 genotype than in heterozygous CYP2C9* 3 subjects (P <0.05). Our results strongly suggest that the disposition and hypoglycemic effect of tolbutamide are affected mainly by CYP2C9 genetic polymorphism, but not by CYP2C19 polymorphism. The in-vivo contribution of CYP2C19 to tolbutamide 4-methylhydroxylation appears to be minor in humans. This suggests that, at least in vivo, tolbutamide remains a selective probe for measuring CYP2C9 activity in humans.

KW - CYP2C19

KW - CYP2C9

KW - Genetic polymorphism

KW - Pharmacodynamics

KW - Pharmacokinetics

KW - Tolbutamide

UR - http://www.scopus.com/inward/record.url?scp=0036217595&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=0036217595&partnerID=8YFLogxK

U2 - 10.1097/00008571-200203000-00005

DO - 10.1097/00008571-200203000-00005

M3 - Article

C2 - 11875365

AN - SCOPUS:0036217595

VL - 12

SP - 111

EP - 119

JO - Pharmacogenetics and Genomics

JF - Pharmacogenetics and Genomics

SN - 1744-6872

IS - 2

ER -