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Effect of CYP2C9 Polymorphisms on the Pharmacokinetics of Indomethacin During Pregnancy

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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.

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Authors and Affiliations

  1. Department of Obstetrics and Gynecology, University of Texas Medical Branch, Galveston, TX, 77555, USA

    Mansi Shah, Meixiang Xu, Poonam Shah, Xiaoming Wang, Shannon M. Clark, Maged Costantine, Holly A. West, Tatiana N. Nanovskaya, Mahmoud S. Ahmed, Sherif Z. Abdel-Rahman, Gary D. V. Hankins & Erik Rytting

  2. Magee-Womens Research Institute, University of Pittsburgh, Pittsburgh, PA, 15213, USA

    Raman Venkataramanan & Steve N. Caritis

Authors
  1. Mansi Shah
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  2. Meixiang Xu
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  3. Poonam Shah
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  4. Xiaoming Wang
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Corresponding author

Correspondence to Erik Rytting.

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Funding

The authors are grateful for research support from the Eunice Kennedy Shriver National Institute of Child Health and Human Development (U10HD04789108 and R01HD083003).

Conflict of interest

Authors Mansi Shah, Meixiang Xu, Poonam Shah, Xiaoming Wang, Shannon M. Clark, Maged Costantine, Holly A. West, Tatiana N. Nanovskaya, Mahmoud S. Ahmed, Sherif Z. Abdel-Rahman, Raman Venkataramanan, Steve N. Caritis, Gary D.V. Hankins, and Erik Rytting declare that they have no conflict of interest.

Ethical approval

All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its actual amended version, the International Conference on Harmonization-Good Clinical Practices (ICH-GCP) guidelines.

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Informed consent was obtained from all participants included in this study.

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Shah, M., Xu, M., Shah, P. et al. Effect of CYP2C9 Polymorphisms on the Pharmacokinetics of Indomethacin During Pregnancy. Eur J Drug Metab Pharmacokinet 44, 83–89 (2019). https://doi.org/10.1007/s13318-018-0505-7

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