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Population Pharmacokinetics of Sulindac and Genetic Polymorphisms of FMO3 and AOX1 in Women with Preterm Labor

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Abstract

Purpose

This prospective study aimed to evaluate the effects of genetic polymorphisms in sulindac-related metabolizing enzyme genes including FMO3 and AOX1 on the population pharmacokinetics of sulindac in 58 pregnant women with preterm labor.

Methods

Plasma samples were collected at 1.5, 4, and 10 h after first oral administration of sulindac. Plasma concentrations of sulindac and its active metabolite (sulindac sulfide) were determined, and pharmacokinetic analysis was performed with NONMEM 7.3.

Results

The mean maternal and gestational ages at the time of dosing were 32.5 ± 4.4 (range, 20–41) years and 27.4 ± 4.4 (range, 16.4–33.4) weeks, respectively. In the population pharmacokinetic analysis, one depot compartment model of sulindac with absorption lag time best described the data. The metabolism of sulindac and sulindac sulfide was described using Michaelis-Menten kinetics. In stepwise modeling, gestational age impacted volume of distribution (Vc), and FMO3 rs2266782 was shown by the Michaelis constant to affect conversion of sulindac sulfide to sulindac (KM32); these were retained in the final model.

Conclusions

Genetic polymorphisms of FMO3 and AOX1 could affect the pharmacokinetics of sulindac in women who undergo preterm labor. The results of this study could help clinicians develop individualized treatment plans for administering sulindac.

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Abbreviations

AOX :

Aldehyde oxidase

CWRES:

Conditional weighted residuals

FMO3 :

Flavin-containing monooxygenase 3

HWE :

Hardy-Weinberg equilibrium

OFV:

Objective function value

SNP :

Single nucleotide polymorphism

SCM:

Stepwise covariate model

VPC:

Visual predictive check

References

  1. Simhan HN, Caritis SN. Prevention of preterm delivery. N Engl J Med. 2007;357:477–87.

    Article  CAS  Google Scholar 

  2. Miyazaki C, Moreno GR, Ota E, Swa T, Oladapo OT, Mori R. Tocolysis for inhibiting preterm birth in extremely preterm birth, multiple gestations and in growth-restricted fetuses: a systematic review and meta-analysis. Reprod Health. 2016;13:4.

    Article  Google Scholar 

  3. Davies NM, Watson MS. Clinical pharmacokinetics of sulindac. A dynamic old drug. Clin Pharmacokinet. 1997;32:437–59.

    Article  CAS  Google Scholar 

  4. Eriksson LO, Bostrom H. Deactivation of sulindac-sulphide by human renal microsomes. Pharmacol Toxicol. 1988;62:177–83.

    Article  CAS  Google Scholar 

  5. Duggan DE, Hooke KF, Hwang SS. Kinetics of the tissue distributions of sulindac and metabolites. Relevance to sites and rates of bioactivation. Drug Metab Dispos. 1980;8:241–6.

    CAS  PubMed  Google Scholar 

  6. Miller MJ, Bednar MM, McGiff JC. Renal metabolism of sulindac: functional implications. J Pharmacol Exp Ther. 1984;231:449–56.

    CAS  PubMed  Google Scholar 

  7. Ratnayake JH, Hanna PE, Anders MW, Duggan DE. Sulfoxide reduction. In vitro reduction of sulindac by rat hepatic cytosolic enzymes. Drug Metab Dispos. 1981;9:85–7.

    CAS  PubMed  Google Scholar 

  8. Brunell D, Sagher D, Kesaraju S, Brot N, Weissbach H. Studies on the metabolism and biological activity of the Epimers of Sulindac. Drug Metab Dispos. 2011;39:1014–21.

    Article  CAS  Google Scholar 

  9. Kuehl GE, Lampe JW, Potter JD, Bigler J. Glucuronidation of nonsteroidal anti-inflammatory drugs: identifying the enzymes responsible in human liver microsomes. Drug Metab Dispos. 2005;33:1027–35.

    Article  CAS  Google Scholar 

  10. Duggan DE, Hare LE, Ditzler CA, Lei BW, Kwan KC. The disposition of sulindac. Clin Pharmacol Ther. 1977;21:326–35.

    Article  CAS  Google Scholar 

  11. Dujovne C, Pitterman A, Vincek W, Dobrinska M. Enerohepatic circulation of sulindac and metabolites. Clin Pharmcol Ther. 1983;33:172–7.

    Article  CAS  Google Scholar 

  12. Kitamura S, Ohashi KNK, Sugihara K, Hosokawa R, Akagawa Y, Ohta S. Extremely high drug-reductase activity based on aldehyde oxidase in monkey liver. Biol Pharm Bull. 2001;24:856–9.

    Article  CAS  Google Scholar 

  13. Hisamuddin IM, Yang VW. Genetic polymorphisms of human flavin-containing monooxygenase 3: implications for drug metabolism and clinical perspectives. Pharmacogenomics. 2007;8:635–43.

    Article  CAS  Google Scholar 

  14. Shimizu M, Yano H, Nagashima S, Murayama N, Zhang J, Cashman JR, et al. Effect of genetic variants of the human flavin-containing monooxygenase 3 on N- and S-oxygenation activities. Drug Metab Dispos. 2007;35:328–30.

    Article  CAS  Google Scholar 

  15. Park S, Lee NR, Lee KE, Park JY, Kim YJ, Gwak HS. Effects of single-nucleotide polymorphisms of FMO3 and FMO6 genes on pharmacokinetic characteristics of sulindac sulfide in premature labor. Drug Metab Dispos. 2014;42:40–3.

    Article  CAS  Google Scholar 

  16. Lee SC, Renwick AG. Sulphoxide reduction by rat and rabbit tissues in vitro. Biochem Pharmacol. 1995;49:1557–65.

    Article  CAS  Google Scholar 

  17. Gabriel SB, Schaffner SF, Nguyen H, Moore JM, Roy J, Blumenstiel B, et al. The structure of haplotype blocks in the human genome. Science. 2002;296:2225–9.

    Article  CAS  Google Scholar 

  18. Park CS, Kang JH, Chung WG, Yi HG, Pie JE, Park DK, et al. Ethnic differences in allelic frequency of two flavin-containing monooxygenase 3 (FMO3) polymorphisms: linkage and effects on in vivo and in vitro FMO activities. Pharmacogenetics. 2002;12:77–80.

    Article  CAS  Google Scholar 

  19. Koukouritaki SB, Poch MT, Henderson MC, Siddens LK, Krueger SK, VanDyke JE, et al. Identification and functional analysis of common human flavin-containing monooxygenase 3 genetic variants. J Pharmacol Exp Ther. 2007;320:266–73.

    Article  CAS  Google Scholar 

  20. Lattard V, Zhang J, Tran Q, Furnes B, Schlenk D, Cashman JR. Two new polymorphisms of the FMO3 gene in Caucasian and African-American populations: comparative genetic and functional studies. Drug Metab Dispos. 2003;31:854–60.

    Article  CAS  Google Scholar 

  21. Berg AK, Mandrekar SJ, Ziegler KL, Carlson EC, Szabo E, Ames MM, et al. Population pharmacokinetic model for cancer chemoprevention with sulindac in healthy subjects. J Clin Pharmacol. 2013;53:403–12.

    Article  Google Scholar 

  22. Tang Y, Hu K, Huang W, Wang C, Liu Z, Chen Y, et al. Effects of FMO3 polymorphisms on pharmacokinetics of sulindac in Chinese healthy male volunteers. Biomed Res Int. 2017;4189678.

  23. Anderson GD. Pregnancy-induced changes in pharmacokinetics: a mechanistic-based approach. Clin Pharmacokinet. 2005;44:989–1008.

    Article  CAS  Google Scholar 

  24. Davison JM, Dunlop W. Renal hemodynamics and tubular function normal human pregnancy. Kidney Int. 1980;18:152–61.

    Article  CAS  Google Scholar 

  25. Davison JM, Dunlop W, Ezimokhai M. 24-hour creatinine clearance during the third trimester of normal pregnancy. Br J Obstet Gynaecol. 1980;87:106–9.

    Article  CAS  Google Scholar 

  26. Tasnif Y, Morado J, Hebert MF. Pregnancy-related pharmacokinetic changes. Clin Pharmacol Ther. 2016;100:53–62.

    Article  CAS  Google Scholar 

  27. Hytten FE, Paintin DB. Increase in plasma volume during normal pregnancy. J Obstet Gynaecol Br Emp. 1963;70:402–7.

    Article  CAS  Google Scholar 

  28. Stormer E, Roots I, Brockmoller J. Benzydamine N-oxidation as an index reaction reflecting FMO activity in human liver microsomes and impact of FMO3 polymorphisms on enzyme activity. Br J Clin Pharmacol. 2000;50:553–61.

    Article  CAS  Google Scholar 

  29. Wang L, Christopher LJ, Cui D, Li W, Iyer R, Humphreys WG, et al. Identification of the human enzymes involved in the oxidative metabolism of dasatinib: an effective approach for determining metabolite formation kinetics. Drug Metab Dispos. 2008;36:1828–39.

    Article  CAS  Google Scholar 

  30. Lickteig AJ, Riley R, Melton RJ, Reitz BA, Fischer HD, Stevens JC. Expression and characterization of functional dog flavin-containing monooxygenase 3. Drug Metab Dispos. 2009;37:1987–90.

    Article  CAS  Google Scholar 

  31. Manevski N, Balavenkatraman KK, Bertschi B, Swart P, Walles M, Camenisch G, et al. Aldehyde oxidase activity in fresh human skin. Drug Metab Dispos. 2014;42:2049–57.

    Article  Google Scholar 

  32. Al-Salmy HS. Individual variation in hepatic aldehyde oxidase activity. IUBMB Life. 2001;51:249–53.

    Article  CAS  Google Scholar 

  33. Hernandez D, Addou S, Lee D, Orengo C, Shephard EA, Phillips IR. Trimethylaminuria and a human FMO3 mutation database. Hum Mutat. 2003;22:209–13.

    Article  CAS  Google Scholar 

  34. Hines RN, Cashman JR, Philpot RM, Williams DE, Ziegler DM. The mammalian flavin-containing monooxygenases: molecular characterization and regulation of expression. Toxicol Appl Pharmacol. 1994;125:1–6.

    Article  CAS  Google Scholar 

  35. Mayatepek E, Flock B, Zschocke J. Benzydamine metabolism in vivo is impaired in patients with deficiency of flavin-containing monooxygenase 3. Pharmacogenetics. 2004;14:775–7.

    Article  CAS  Google Scholar 

  36. Hisamuddin IM, Wehbi MA, Schmotzer B, Easley KA, Hylind LM, Giardiello FM, et al. Genetic polymorphisms of flavin monooxygenase 3 in sulindac-induced regression of colorectal adenomas in familial adenomatous polyposis. Cancer Epidemiol Biomark Prev. 2005;14:2366–9.

    Article  CAS  Google Scholar 

  37. Hisamuddin IM, Wehbi MA, Chao A, Wyre HW, Hylind LM, Giardiello FM, et al. Genetic polymorphisms of human flavin monooxygenase 3 in sulindac-mediated primary chemoprevention of familial adenomatous polyposis. Clin Cancer Res. 2004;10:8357–62.

    Article  CAS  Google Scholar 

  38. Kang JH, Chung WG, Lee KH, Park CS, Kang JS, Shin IC, et al. Phenotypes of flavin-containing monooxygenase activity determined by ranitidine N-oxidation are positively correlated with genotypes of linked FM03 gene mutations in a Korean population. Pharmacogenetics. 2000;10:67–78.

    Article  CAS  Google Scholar 

  39. Catucci G, Bortolussi S, Rampolla G, Cusumano D, Gilardi G, Sadeghi S. Flavin-containing monooxygenase 3 polymorphic variants significantly affect clearance of tamoxifen and clomiphene.

  40. Fields PA, Houseman DE. Decreases in activation energy and substrate affinity in cold-adapted A4-lactate dehydrogenase: evidence from the Antarctic notothenioid fish Chaenocephalus aceratus. Mol Biol Evol. 2004;21:2246–55.

    Article  CAS  Google Scholar 

  41. Garattini E, Terao M. The role of aldehyde oxidase in drug metabolism. Expert Opin Drug Metab Toxicol. 2012;8:487–503.

    Article  CAS  Google Scholar 

  42. Barr JT, Choughule K, Jones JP. Enzyme kinetics, inhibition, and regioselectivity of aldehyde oxidase. Methods Mol Biol. 2014;1113:167–86.

    Article  CAS  Google Scholar 

Download references

Acknowledgments

This work was supported by the National Research Foundation of Korea (NRF) funded by the Korean government (MEST) (grant number: NRF-2010-0022544) and the research fund of Hanyang University (grant number: HY-2018-N).

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Author notes

  1. Jin Won Sung and Hwi-yeol Yun contributed equally to this work.

Authors and Affiliations

  1. College of Pharmacy & Division of Life and Pharmaceutical Sciences, Ewha Womans University, Ewhayeodae-gil Seodaemun-Gu, Seoul, 03760, Republic of Korea

    Jin Won Sung, Sunny Park, Jeong Yee & Hye Sun Gwak

  2. College of Pharmacy, Chungnam National University, Daejeon, 34134, South Korea

    Hwi-yeol Yun & Byungjeong Song

  3. Department of Obstetrics and Gynecology, Ewha Womans University School of Medicine, Seoul, 07985, South Korea

    Young Ju Kim

  4. College of Pharmacy, Chungbuk National University, Cheongju, 28644, South Korea

    Kyung Eun Lee

  5. College of Pharmacy and Institute of Pharmaceutical Science and Technology, Hanyang University, 55 Hanyangdeahak-ro, Sangnok-gu, Ansan, Gyeonggido, 15588, South Korea

    Jee Eun Chung

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  1. Jin Won Sung
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Sung, J.W., Yun, Hy., Park, S. et al. Population Pharmacokinetics of Sulindac and Genetic Polymorphisms of FMO3 and AOX1 in Women with Preterm Labor. Pharm Res 37, 44 (2020). https://doi.org/10.1007/s11095-020-2765-6

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