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Liquid chromatographic methods in the determination of inosine monophosphate dehydrogenase enzyme activity: a review

    Shailesh Perdalkar

    Department of Gastroenterology & Hepatology, Kasturba Medical College, Manipal Academy of Higher Education, Manipal, 576104, India

    ,
    Dani Lakshman Yarlagadda

    Department of Pharmaceutical Quality Assurance, Manipal College of Pharmaceutical Sciences, Manipal Academy of Higher Education, Manipal, 576104, India

    ,
    Cannanore Ganesh Pai

    Department of Gastroenterology & Hepatology, Kasturba Medical College, Manipal Academy of Higher Education, Manipal, 576104, India

    ,
    Shiran Shetty

    Department of Gastroenterology & Hepatology, Kasturba Medical College, Manipal Academy of Higher Education, Manipal, 576104, India

    &
    Krishnamurthy Bhat

    *Author for correspondence:

    E-mail Address: km.bhat@manipal.edu

    Department of Pharmaceutical Quality Assurance, Manipal College of Pharmaceutical Sciences, Manipal Academy of Higher Education, Manipal, 576104, India

    Published Online:https://doi.org/10.4155/bio-2022-0212

    Inosine monophosphate dehydrogenase (IMPDH) is a crucial enzyme involved in the de novo synthesis of purine nucleotides. IMPDH activity is used to evaluate the pharmacodynamics/pharmacokinetics of immunosuppressant drugs such as mycophenolic acid and thiopurines. These drugs are often used to prevent organ transplant rejection and as steroid-sparing agents in autoinflammatory diseases such as inflammatory bowel disease and rheumatoid arthritis. Numerous analytical techniques have been employed to evaluate IMPDH activity in biological matrices. However, hyphenated LC techniques were most widely used in the literature. This review focuses on hyphenated LC methods used to measure IMPDH activity and provides detailed insight into the sample preparation techniques, chromatographic conditions, enzymatic assay conditions, detectors and normalization factors employed in those methods.

    Papers of special note have been highlighted as: • of interest; •• of considerable interest

    References

    • 1. Beringer A, Citterio-Quentin A, Otero RO et al. Determination of inosine 5′-monophosphate dehydrogenase activity in red blood cells of thiopurine-treated patients using HPLC. J. Chromatogr. B Analyt. Technol. Biomed. Life Sci. 1044–1045, 194–199 (2017). •• The only study that evaluates inosine monophosphate dehydrogenase activity in thiopurine-treated patients to study the potential relationship between inosine monophosphate dehydrogenase activity in red blood cells, drug response and adverse events
    • 2. Laverdière I, Caron P, Couture F, Guillemette C, Lévesque É. Liquid chromatography-coupled tandem mass spectrometry based assay to evaluate inosine-5′-monophosphate dehydrogenase activity in peripheral blood mononuclear cells from stem cell transplant recipients. Anal. Chem. 84(1), 216–223 (2012). • The first study to use tandem mass spectrometric detection techniques for the assessment of inosine monophosphate dehydrogenase activity to improve the sensitivity of the assay
    • 3. Sintchak MD, Fleming MA, Futer O. Structure and mechanism of inosine monophosphate dehydrogenase in complex with the immunosuppressant mycophenolic acid Cell 85(6), 921–930 (1996).
    • 4. Weißbarth G, Wiesen MHJ, Fietz C et al. Pharmacodynamic monitoring of mycophenolic acid therapy: improved liquid chromatography–tandem mass spectrometry method for measuring inosin-5′-monophosphate dehydrogenase activity. Ther. Drug Monit. 42(2), 282–288 (2020).
    • 5. Weimert NA, DeRotte M, Alloway RR, Woodle ES, Vinks AA. Monitoring of inosine monophosphate dehydrogenase activity as a biomarker for mycophenolic acid effect: p otential clinical implications. Ther. Drug Monit. 29(2), 141–149 (2007).
    • 6. Citterio-Quentin A, el Mahmoudi A, Perret T et al. Red blood cell IMPDH activity in adults and children with or without azathioprine: r elationship between thiopurine metabolites, ITPA and TPMT activities. Basic Clin. Pharmacol. Toxicol. 124(5), 600–606 (2019).
    • 7. Bayoumy AB, Simsek M, Seinen ML et al. The continuous rediscovery and the benefit–risk ratio of thioguanine, a comprehensive review. Expert Opin. Drug Metab. Toxicol. 16(2), 111–123 (2020).
    • 8. Haglund S, Taipalensuu J, Peterson C, Almer S. IMPDH activity in thiopurine-treated patients with inflammatory bowel disease – relation to TPMT activity and metabolite concentrations. Br. J. Clin. Pharmacol. 65(1), 69–77 (2008).
    • 9. Montero C, Duley JA, Fairbanks LD et al. Demonstration of induction of erythrocyte inosine monophosphate dehydrogenase activity in ribavirin-treated patients using a high performance liquid chromatography linked method. Clin. Chim. Acta 238(2), 169–178 (1995).
    • 10. Langman LJ, LeGatt DF, Yatscoff RW. Pharmacodynamic assessment of mycophenolic acid-induced immunosuppression by measuring IMP dehydrogenase activity. Clin. Chem. 41(2), 295–299 (1995).
    • 11. Blanchet B, Taieb F, Conti F et al. Comparison of a new enzymatic assay with a high-performance liquid chromatography/ultraviolet detection method for therapeutic drug monitoring of mycophenolic acid in adult liver transplant recipients. Liver Transpl. 14(12), 1745–1751 (2008).
    • 12. van Gelder T, Domke I, Engelmayer J et al. Clinical utility of a new enzymatic assay for determination of mycophenolic acid in comparison with an optimized LC–MS/MS method. Ther. Drug Monit. 31(2), 218–223 (2009).
    • 13. Fleming MA, Chambers SP, Connelly PR et al. Inhibition of IMPDH by mycophenolic acid: dissection of forward and reverse pathways using capillary electrophoresis. Biochemistry 35(22), 6990–6997 (1996).
    • 14. Vannozzi F, Filipponi F, di Paolo A et al. An exploratory study on pharmacogenetics of inosine-monophosphate dehydrogenase II in peripheral mononuclear cells from liver-transplant recipients. Transplant. Proc. 36(9), 2787–2790 (2004).
    • 15. Storck M, Abendroth D, Albrecht W, Sollinger HW. Evaluation of IMPDH-activity in whole blood and isolated blood cell fractions for monitoring of Cell-Cept®-mediated immunosuppression. Transplantation 65(12), S29 (1998).
    • 16. Albrecht W, Storck M, Pfetsch E, Martin W, Abendroth D. Development and application of a high-performance liquid chromatography-based assay for determination of the activity of inosine 5′-monophosphate dehydrogenase in whole blood and isolated mononuclear cells. Ther. Drug Monit. 22(3), 283–294 (2000).
    • 17. Kalsi K, Marinaki AM, Yacoub MH, Smolenski RT. HPLC/tandem ion trap mass detector methods for determination of inosine monophosphate dehydrogenase (IMPDH) and thiopurine methyltransferase (TPMT). Nucleosides Nucleotides Nucleic Acids 25(9–11), 1241–1244 (2006).
    • 18. Daxecker H, Raab M, Müller MM. Influence of mycophenolic acid on inosine 5′-monophosphate dehydrogenase activity in human peripheral blood mononuclear cells. Clin. Chim. Acta 318(1–2), 71–77 (2002).
    • 19. Glander P, Patrick Braun K, Hambach P et al. Non-radioactive determination of inosine 5′-monophosphate dehydro-genase (IMPDH) in peripheral mononuclear cells. Clin. Biochem. 34(7), 543–549 (2001).
    • 20. Liu F, Xu L, Sheng C, Qiu X, Zhang M, Jiao Z. Optimization and application of an HPLC method for quantification of inosine-5′-monophosphate dehydrogenase activity as a pharmacodynamic biomarker of mycophenolic acid in Chinese renal transplant patients. Clin. Chim. Acta 485, 333–339 (2018).
    • 21. Sobiak J, Jóźwiak A, Wziętek H, Zachwieja J, Ostalska-Nowicka D. The application of inosine 5′-monophosphate dehydrogenase activity determination in peripheral blood mononuclear cells for monitoring mycophenolate mofetil therapy in children with nephrotic syndrome. Pharmaceuticals 13(8), 1–14 (2020).
    • 22. Bemer MJ, Risler LJ, Phillips BR et al. Recipient pretransplant inosine monophosphate dehydrogenase activity in nonmyeloablative hematopoietic cell transplantation. Biol. Blood Marrow Transplant. 20(10), 1544–1552 (2014).
    • 23. Glander P, Sombogaard F, Budde K et al. Improved assay for the nonradioactive determination of inosine 5′-monophosphate dehydrogenase activity in peripheral blood mononuclear cells. Ther. Drug Monit. 31(3), 351–359 (2009). •• This study utilizes intracellular adenosine-5′-monophosphate to normalize the inosine monophosphate dehydrogenase activity in the view of improving the reproducibility and robustness of the existing inosine monophosphate dehydrogenase activity assay.
    • 24. Kawanishi M, Yano I, Yoshimura K et al. Sensitive and validated LC–MS/MS methods to evaluate mycophenolic acid pharmacokinetics and pharmacodynamics in hematopoietic stem cell transplant patients. Biomed. Chromatogr. 29(9), 1309–1316 (2015).
    • 25. Nguyen MT, Tran NT, Vincent M, Capron A, Mourad M, Wallemacq P. Determination of inosine 5′-monophosphate dehydrogenase activity by high performance liquid chromatography in comparison with normalization methods Mahidol University Journal of Pharmaceutical Sciences 42(4), 162–168 (2015).
    • 26. Nguyen Thi MT, Mourad M, Capron A, Musuamba Tshinanu F, Vincent MF, Wallemacq P. Plasma and intracellular pharmacokinetic-pharmacodynamic analysis of mycophenolic acid in de novo kidney transplant patients. Clin. Biochem. 48(6), 401–405 (2015).
    • 27. Mino Y, Naito T, Otsuka A, Ozono S, Kagawa Y, Kawakami J. Inosine monophosphate dehydrogenase activity depends on plasma concentrations of mycophenolic acid and its glucuronides in kidney transplant recipients. Clin. Chim. Acta 409(1–2), 56–61 (2009).
    • 28. Vethe NT, Ali AM, Reine PA et al. Simultaneous quantification of IMPDH activity and purine bases in lymphocytes using LC–MS/MS. Ther. Drug Monit. 36(1), 108–118 (2014).
    • 29. Vethe NT, Bergan S. Determination of inosine monophosphate dehydrogenase activity in human CD4+ cells isolated from whole blood during mycophenolic acid therapy. Ther. Drug Monit. 28(5), 608–613 (2006).
    • 30. Pérez-Milicua MB, Zenteno-Savín T, Crocker DE, Gallo-Reynoso JP. Hypoxanthine-guanine phosphoribosyltransferase and inosine 5′-monophosphate dehydrogenase activities in three mammalian species: a quatic (Mirounga angustirostris), semi-aquatic (Lontra longicaudis annectens) and terrestrial (Sus scrofa). Front. Physiol. 6(JUL), 212 (2015).
    • 31. Molinaro M, Chiarelli LR, Biancone L et al. Monitoring of inosine monophosphate dehydrogenase activity and expression during the early period of mycophenolate mofetil therapy in de novo renal transplant patients. Drug Metab. Pharmacokinet. 28(2), 109–117 (2013).
    • 32. Tang JT, de Winter BC, Hesselink DA, Sombogaard F, Wang LL, van Gelder T. The pharmacokinetics and pharmacodynamics of mycophenolate mofetil in younger and elderly renal transplant recipients. Br. J. Clin. Pharmacol. 83(4), 812–822 (2017).
    • 33. Li H, Mager DE, Sandmaier BM et al. Pharmacokinetic and pharmacodynamic analysis of inosine monophosphate dehydrogenase activity in hematopoietic cell transplantation recipients treated with mycophenolate mofetil. Biol. Blood Marrow Transpl. 20(8), 1121–1129 (2014).
    • 34. Maiguma T, Yosida T, Otsubo K et al. Evaluation of inosin-5′-monophosphate dehydrogenase activity during maintenance therapy with tacrolimus. J. Clin. Pharm. Ther. 35(1), 79–85 (2010).
    • 35. Rother A, Glander P, Vitt E et al. Inosine monophosphate dehydrogenase activity in paediatrics: a ge-related regulation and response to mycophenolic acid. Eur. J. Clin. Pharmacol. 68(6), 913–922 (2012).
    • 36. Chiarelli LR, Molinaro M, Libetta C et al. Inosine monophosphate dehydrogenase variability in renal transplant patients on long-term mycophenolate mofetil therapy. Br. J. Clin. Pharmacol. 69(1), 38–50 (2010).
    • 37. Patel CG, Richman K, Yang D, Yan B, Gohh RY, Akhlaghi F. Effect of diabetes mellitus on mycophenolate sodium pharmacokinetics and inosine monophosphate dehydrogenase activity in stable kidney transplant recipients. Ther. Drug Monit. 29(6), 735–742 (2007).
    • 38. Rath T, Küpper M. Comparison of inosine-monophosphate-dehydrogenase activity in patients with enteric-coated mycophenolate sodium or mycophenolate mofetil after renal transplantation. Transpl. Proc. 41(6), 2524–2528 (2009).
    • 39. Raggi MC, Siebert SB, Steimer W, Schuster T, Stangl MJ, Abendroth DK. Customized mycophenolate dosing based on measuring inosine-monophosphate dehydrogenase activity significantly improves patients' outcomes after renal transplantation. Transplantation 90(12), 1536–1541 (2010).
    • 40. Fukuda T, Goebel J, Thøgersen H et al. Inosine monophosphate dehydrogenase (IMPDH) activity as a pharmacodynamic biomarker of mycophenolic acid effects in pediatric kidney transplant recipients. J. Clin. Pharmacol. 51(3), 309–320 (2011).
    • 41. Haglund S, Vikingsson S, Söderman J et al. The role of inosine-5′-monophosphate dehydrogenase in thiopurine metabolism in patients with inflammatory bowel disease. Ther. Drug Monit. 33(2), 200–208 (2011).
    • 42. Gonçalves D, Alves G, Soares-da-Silva P, Falcão A. Bioanalytical chromatographic methods for the determination of catechol-O-methyltransferase inhibitors in rodents and human samples: a review . Anal. Chim. Acta 710, 17–32 (2012).
    • 43. Caro YS, Cámara MS, de Zan MM. A review of bioanalytical methods for the therapeutic drug monitoring of β-lactam antibiotics in critically ill patients: e valuation of the approaches used to develop and validate quality attributes. Talanta 210, 120619 (2020).
    • 44. Cristina MMA. Overview of sample preparation and chromatographic methods to analysis pharmaceutical active compounds in waters matrices. Separations 8(2), 16 (2021).
    • 45. Hyötyläinen T. Critical evaluation of sample pretreatment techniques. Anal. Bioanal. Chem. 394(3), 743–758 (2009).
    • 46. Sharma MK, Dhakne P, Nn S, Ajitha Reddy P, Sengupta P. Paradigm shift in the arena of sample preparation and bioanalytical approaches involving liquid chromatography mass spectroscopic technique. Anal. Sci. 35(10), 1069–1082 (2019).
    • 47. Cohen S, Jordheim LP, Megherbi M, Dumontet C, Guitton J. Liquid chromatographic methods for the determination of endogenous nucleotides and nucleotide analogs used in cancer therapy: a review. J. Chromatogr. B Analyt. Technol. Biomed. Life Sci. 878(22), 1912–1928 (2010).
    • 48. Javorska L, Krcmova LK, Solichova D, Solich P, Kaska M. Modern methods for vancomycin determination in biological fluids by methods based on high-performance liquid chromatography – a review. J. Sep. Sci. 39(1), 6–20 (2016).
    • 49. Huang Y, Shi R, Gee W, Bonderud R. Matrix effect and recovery terminology issues in regulated drug bioanalysis. Bioanalysis 4(3), 271–279 (2012).
    • 50. Alvarez-Segura T, Torres-Lapasió JR, Ortiz-Bolsico C, García-Alvarez-Coque MC. Stationary phase modulation in liquid chromatography through the serial coupling of columns: a review. Anal. Chim. Acta 923, 1–23 (2016).
    • 51. Esteve-Romero J, Albiol-Chiva J, Peris-Vicente J. A review on development of analytical methods to determine monitorable drugs in serum and urine by micellar liquid chromatography using direct injection. Anal. Chim. Acta 926, 1–16 (2016).
    • 52. Subirats X, Rosés M, Bosch E. On the effect of organic solvent composition on the pH of buffered HPLC mobile phases and the pKa of analytes – a Review. Separation & Purification Reviews 36 (3), 231–255 (2007).
    • 53. Elizabeth DC, Alison ON, Dafydd et al. Nucleic acid separations using superficially porous silica particles Journal of Chromatography A 1440, 135–144 (2016).
    • 54. Kaczmarkiewicz A, Nuckowski Ł, Studzińska S, Buszewski B. Analysis of antisense oligonucleotides and their metabolites with the use of ion pair reversed-phase liquid chromatography coupled with mass spectrometry. Crit. Rev. Anal. Chem. 49(3), 256–270 (2019).
    • 55. Hendrickx S, Adams E, Cabooter D. Recent advances in the application of hydrophilic interaction chromatography for the analysis of biological matrices. Bioanalysis 7(22), 2927–2945 (2015).
    • 56. Teunissen SF, Rosing H, Schinkel AH, Schellens JHM, Beijnen JH. Bioanalytical methods for determination of tamoxifen and its phase I metabolites: a review. Anal. Chim. Acta 683(1), 21–37 (2010).
    • 57. Gouveia F, Bicker J, Gonçalves J, Alves G, Falcão A, Fortuna A. Liquid chromatographic methods for the determination of direct oral anticoagulant drugs in biological samples: a critical review. Anal. Chim. Acta 1076, 18–31 (2019).
    • 58. Oliveira E, Muller E, Abad F, Dallarosa J. Internal standard versus external standard calibration: an uncertainty case study of a liquid chromatography analysis. Quim. Nova 33(4), 984–987 (2004).
    • 59. Fu Y, Barkley D, Li W, Picard F, Flarakos J. Evaluation, identification and impact assessment of abnormal internal standard response variability in regulated LC-MS bioanalysis. Bioanalysis 12(8), 545–559 (2020).
    • 60. O'Rourke MB, Town SEL, Dalla PV et al. What is normalization? The strategies employed in top-down and bottom-up proteome analysis workflows. Proteomes 7(3), 1–19 (2019).
    • 61. Dudzinska W, Lubkowska A. Changes in the concentration of purine and pyridine as a response to single whole-body cryostimulation. Front. Physiol. 12, 33 (2021).
    • 62. Gardani CFF, Cappellari AR, de Souza JB et al. Hydrolysis of ATP, ADP, and AMP is increased in blood plasma of prostate cancer patients. Purinergic Signal. 15(1), 95–105 (2019).
    • 63. Rodziewicz E, Król-Zielińska M, Zieliński J, Kusy K, Ziemann E. Plasma concentration of irisin and brain-derived-neurotrophic factor and their association with the level of erythrocyte adenine nucleotides in response to long-term endurance training at rest and after a single bout of exercise. Front. Physiol. 11, 923 (2020).
    • 64. Dudzinska W, Suska M, Lubkowska A et al. Comparison of human erythrocyte purine nucleotide metabolism and blood purine and pyrimidine degradation product concentrations before and after acute exercise in trained and sedentary subjects. J. Physiol. Sci. 68(3), 293–305 (2018).