Effect of CYP2C9 Polymorphisms on the Pharmacokinetics of Indomethacin During Pregnancy

Mansi Shah, Meixiang Xu, Poonam Shah, Xiao-Ming Wang, Shannon Clark, Maged Costantine, Holly A. West, Tatiana Nanovskaya, Mahmoud Ahmed, Sherif Abdel-Rahman, Raman Venkataramanan, Steve N. Caritis, Gary Hankins, Erik Rytting

Research output: Contribution to journalArticle

Abstract

Background and Objective: Cytochrome P450 (CYP) 2C9 catalyzes the biotransformation of indomethacin to its inactive metabolite O-desmethylindomethacin (DMI). The aim of this work was to determine the effect of CYP2C9 polymorphisms on indomethacin metabolism in pregnant women. Methods: Plasma concentrations of indomethacin and DMI at steady state were analyzed with a validated LC–MS/MS method. DNA was isolated from subject blood and buccal smear samples. Subjects were grouped by genotype for comparisons of pharmacokinetic parameters. Results: For subjects with the *1/*2 genotype, the mean steady-state apparent oral clearance (CL/Fss) of indomethacin was 13.5 ± 7.7 L/h (n = 4) and the mean metabolic ratio (AUCDMI/AUCindomethacin) was 0.291 ± 0.133. For subjects with the *1/*1 genotype, these values were 12.4 ± 2.7 L/h and 0.221 ± 0.078, respectively (n = 14). Of note, we identified one subject who was a carrier of both the *3 and *4 alleles, resulting in an amino acid change (I359P) which has not been reported previously. This subject had a metabolic ratio of 0.390 and a CL/Fss of indomethacin (24.3 L/h) that was nearly double the wild-type clearance. Conclusion: Although our results are limited by sample size and are not statistically significant, these data suggest that certain genetic polymorphisms of CYP2C9 may lead to an increased metabolic ratio and an increase in the clearance of indomethacin. More data are needed to assess the impact of CYP2C9 genotype on the effectiveness of indomethacin as a tocolytic agent.

Original languageEnglish (US)
JournalEuropean Journal of Drug Metabolism and Pharmacokinetics
DOIs
StateAccepted/In press - Jan 1 2018

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Indomethacin
Pharmacokinetics
Pregnancy
Genotype
Tocolytic Agents
Cheek
Genetic Polymorphisms
Biotransformation
Cytochrome P-450 CYP2C9
Sample Size
Cytochrome P-450 Enzyme System
Pregnant Women
Alleles
Amino Acids
DNA

ASJC Scopus subject areas

  • Pharmacology
  • Pharmacology (medical)

Cite this

Effect of CYP2C9 Polymorphisms on the Pharmacokinetics of Indomethacin During Pregnancy. / Shah, Mansi; Xu, Meixiang; Shah, Poonam; Wang, Xiao-Ming; Clark, Shannon; Costantine, Maged; West, Holly A.; Nanovskaya, Tatiana; Ahmed, Mahmoud; Abdel-Rahman, Sherif; Venkataramanan, Raman; Caritis, Steve N.; Hankins, Gary; Rytting, Erik.

In: European Journal of Drug Metabolism and Pharmacokinetics, 01.01.2018.

Research output: Contribution to journalArticle

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abstract = "Background and Objective: Cytochrome P450 (CYP) 2C9 catalyzes the biotransformation of indomethacin to its inactive metabolite O-desmethylindomethacin (DMI). The aim of this work was to determine the effect of CYP2C9 polymorphisms on indomethacin metabolism in pregnant women. Methods: Plasma concentrations of indomethacin and DMI at steady state were analyzed with a validated LC–MS/MS method. DNA was isolated from subject blood and buccal smear samples. Subjects were grouped by genotype for comparisons of pharmacokinetic parameters. Results: For subjects with the *1/*2 genotype, the mean steady-state apparent oral clearance (CL/Fss) of indomethacin was 13.5 ± 7.7 L/h (n = 4) and the mean metabolic ratio (AUCDMI/AUCindomethacin) was 0.291 ± 0.133. For subjects with the *1/*1 genotype, these values were 12.4 ± 2.7 L/h and 0.221 ± 0.078, respectively (n = 14). Of note, we identified one subject who was a carrier of both the *3 and *4 alleles, resulting in an amino acid change (I359P) which has not been reported previously. This subject had a metabolic ratio of 0.390 and a CL/Fss of indomethacin (24.3 L/h) that was nearly double the wild-type clearance. Conclusion: Although our results are limited by sample size and are not statistically significant, these data suggest that certain genetic polymorphisms of CYP2C9 may lead to an increased metabolic ratio and an increase in the clearance of indomethacin. More data are needed to assess the impact of CYP2C9 genotype on the effectiveness of indomethacin as a tocolytic agent.",
author = "Mansi Shah and Meixiang Xu and Poonam Shah and Xiao-Ming Wang and Shannon Clark and Maged Costantine and West, {Holly A.} and Tatiana Nanovskaya and Mahmoud Ahmed and Sherif Abdel-Rahman and Raman Venkataramanan and Caritis, {Steve N.} and Gary Hankins and Erik Rytting",
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AU - Shah, Mansi

AU - Xu, Meixiang

AU - Shah, Poonam

AU - Wang, Xiao-Ming

AU - Clark, Shannon

AU - Costantine, Maged

AU - West, Holly A.

AU - Nanovskaya, Tatiana

AU - Ahmed, Mahmoud

AU - Abdel-Rahman, Sherif

AU - Venkataramanan, Raman

AU - Caritis, Steve N.

AU - Hankins, Gary

AU - Rytting, Erik

PY - 2018/1/1

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N2 - Background and Objective: Cytochrome P450 (CYP) 2C9 catalyzes the biotransformation of indomethacin to its inactive metabolite O-desmethylindomethacin (DMI). The aim of this work was to determine the effect of CYP2C9 polymorphisms on indomethacin metabolism in pregnant women. Methods: Plasma concentrations of indomethacin and DMI at steady state were analyzed with a validated LC–MS/MS method. DNA was isolated from subject blood and buccal smear samples. Subjects were grouped by genotype for comparisons of pharmacokinetic parameters. Results: For subjects with the *1/*2 genotype, the mean steady-state apparent oral clearance (CL/Fss) of indomethacin was 13.5 ± 7.7 L/h (n = 4) and the mean metabolic ratio (AUCDMI/AUCindomethacin) was 0.291 ± 0.133. For subjects with the *1/*1 genotype, these values were 12.4 ± 2.7 L/h and 0.221 ± 0.078, respectively (n = 14). Of note, we identified one subject who was a carrier of both the *3 and *4 alleles, resulting in an amino acid change (I359P) which has not been reported previously. This subject had a metabolic ratio of 0.390 and a CL/Fss of indomethacin (24.3 L/h) that was nearly double the wild-type clearance. Conclusion: Although our results are limited by sample size and are not statistically significant, these data suggest that certain genetic polymorphisms of CYP2C9 may lead to an increased metabolic ratio and an increase in the clearance of indomethacin. More data are needed to assess the impact of CYP2C9 genotype on the effectiveness of indomethacin as a tocolytic agent.

AB - Background and Objective: Cytochrome P450 (CYP) 2C9 catalyzes the biotransformation of indomethacin to its inactive metabolite O-desmethylindomethacin (DMI). The aim of this work was to determine the effect of CYP2C9 polymorphisms on indomethacin metabolism in pregnant women. Methods: Plasma concentrations of indomethacin and DMI at steady state were analyzed with a validated LC–MS/MS method. DNA was isolated from subject blood and buccal smear samples. Subjects were grouped by genotype for comparisons of pharmacokinetic parameters. Results: For subjects with the *1/*2 genotype, the mean steady-state apparent oral clearance (CL/Fss) of indomethacin was 13.5 ± 7.7 L/h (n = 4) and the mean metabolic ratio (AUCDMI/AUCindomethacin) was 0.291 ± 0.133. For subjects with the *1/*1 genotype, these values were 12.4 ± 2.7 L/h and 0.221 ± 0.078, respectively (n = 14). Of note, we identified one subject who was a carrier of both the *3 and *4 alleles, resulting in an amino acid change (I359P) which has not been reported previously. This subject had a metabolic ratio of 0.390 and a CL/Fss of indomethacin (24.3 L/h) that was nearly double the wild-type clearance. Conclusion: Although our results are limited by sample size and are not statistically significant, these data suggest that certain genetic polymorphisms of CYP2C9 may lead to an increased metabolic ratio and an increase in the clearance of indomethacin. More data are needed to assess the impact of CYP2C9 genotype on the effectiveness of indomethacin as a tocolytic agent.

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