AIM: The aim of this study was to evaluate adherence to spironolactone in a group of unselected patients with arterial hypertension by analysis of measured serum spironolactone and canrenone concentrations according to a proposed two-step decision scheme based on pharmacokinetic considerations. MATERIALS AND METHODS: Simulation of serum concentration-time profiles of spironolactone and canrenone based on population pharmacokinetic parameters described in literature and a body weight-normalized spironolactone dose / canrenone level nomogram derived from a group of adherent patients with conservatively treated primary hyperaldosteronism, were used to create a two-step decision scheme. 71 outpatients treated with spironolactone for resistant hypertension with spironolactone and canrenone serum concentrations measured between 2018 and 2021 were analyzed according to the proposed scheme. We compared our proposed methodology to the standard approach for adherence testing. RESULTS: With the most sensitive traditional approach to adherence assessment through detectable serum concentrations of spironolactone and/or canrenone, 9 (12.7%) non-adherent patients were identified. With our two-step assessment of adherence, we were able to identify 18 (25.4%) non-adherent patients. CONCLUSION: Consideration of the pharmacokinetic properties of parental drug and its metabolite led to improved sensitivity in non-adherence detection in patients with arterial hypertension. This approach enables better interpretation of measured spironolactone and canrenone serum concentrations and should be used in clinical practice.

3rd Internal Department of Endocrinology and Metabolism 1st Faculty of Medicine Charles University and General University Hospital Prague Czech Republic

Department of Clinical Pharmacology and Pharmacy Institute of Pharmacology 1st Faculty of Medicine Charles University and General University Hospital Prague Czech Republic

Institute of Forensic Medicine and Toxicology Toxicology Laboratory 1st Faculty of Medicine Charles University and General University Hospital Prague Czech Republic

See more in PubMed

Hugtenburg JG, Timmers L, Elders PJ, Vervloet M, van Dijk L. Definitions, variants, and causes of nonadherence with medication: a challenge for tailored interventions. Patient Prefer Adherence 2013;7:675-82. DOI

Abegaz TM, Shehab A, Gebreyohannes EA, Bhagavathula AS, Elnour AA. Nonadherence to antihypertensive drugs: A systematic review and meta-analysis. Medicine (Baltimore) 2017;96(4):e5641. DOI

Burnier M, Egan BM. Adherence in Hypertension. Circ Res 2019;124(7):1124-40. DOI

Osman H, Alghamdi R, Gupta, P. Review of the methods to measure non-adherence with a focus on chemical adherence testing. Translational Metabolic Syndrome Res 2022;5:1-9. DOI

Strauch B, Petrák O, Zelinka T, Rosa J, Somlóová Z, Indra T, Chytil L, Marešová V, Kurcová I, Holaj R, Wichterle D, Widimský J Jr. Precise assessment of noncompliance with the antihypertensive therapy in patients with resistant hypertension using toxicological serum analysis. J Hypertens 2013;31(12):2455-61. DOI

Williams B, Mancia G, Spiering W, Agabiti Rosei E, Azizi M, Burnier M, Clement DL, Coca A, de Simone G, Dominiczak A, Kahan T, Mahfoud F, Redon J, Ruilope L, Zanchetti A, Kerins M, Kjeldsen SE, Kreutz R, Laurent S, Lip GYH, McManus R, Narkiewicz K, Ruschitzka F, Schmieder RE, Shlyakhto E, Tsioufis C, Aboyans V, Desormais I; ESC Scientific Document Group. 2018 ESC/ESH Guidelines for the management of arterial hypertension. Eur Heart J 2018;39(33):3021-104. DOI

Šíma M, Vodička M, Marešová V, Šálek T, Čabala R, Slanař O. Adherence with perindopril therapy: a pilot study using therapeutic drug monitoring of perindoprilat and an evaluation of the clearance estimation. Int J Clin Pharm 2017;39(5):1095-100. DOI

Overdiek HW, Merkus FW. The metabolism and biopharmaceutics of spironolactone in man. Rev Drug Metab Drug Interact 1987;5(4):273-302. DOI

Overdiek HW, Merkus FW. Influence of food on the bioavailability of spironolactone. Clin Pharmacol Ther 1986;40(5):531-6. DOI

Gardiner P, Schrode K, Quinlan D, Martin BK, Boreham DR, Rogers MS, Stubbs K, Smith M, Karim A. Spironolactone metabolism: steady-state serum levels of the sulfur-containing metabolites. J Clin Pharmacol 1989;29(4):342-7. DOI

Abshagen U, von Grodzicki U, Hirschberger U, Rennekamp H. Effect of entekohepatic circulation on the pharmacokinetics of spironolactone in man. Naunyn Schmiedebergs Arch Pharmacol 1977;300(3):281-7. DOI

Verospiron SmPC. Databáze léků [drug database on the Internet] [cited 2022 Nov 6]. Available from https://www.sukl.cz/modules/medication/search.php

Peeters LEJ, Tjong LK, Rietdijk WJR, van Gelder T, Koch BCP, Versmissen J. Sex Differences in Spironolactone and the Active Metabolite Canrenone Concentrations and Adherence. Biomedicines 2022;10(1):137. DOI

Nikrýnová Nguyen TMP, Štrauch B, Petrák O, Krátká Z, Holaj R, Kurcová I, Marešová V, Pilková A, Hartinger J, Waldauf P, Zelinka T, Widimský J. Adherence and blood pressure control in patients with primary aldosteronism. Blood Press 2022;31(1):58-63. DOI

Dong H, Xu F, Zhang Z, Tian Y, Chen Y. Simultaneous determination of spironolactone and its active metabolite canrenone in human plasma by HPLC-APCI-MS. J Mass Spectrom 2006;41(4):477-86. DOI

Vlase L, Imre S, Muntean D, Achim M, Muntean D. Determination of Spironolactone and Canrenone in Human Plasma by High-performance Liquid Chromatography with Mass Spectrometry Detection. Croatica Chemica Acta 2011;84:361-6. DOI

Sora DI, Udrescu S, Albu F, David V, Medvedovici A. Analytical issues in HPLC/MS/MS simultaneous assay of furosemide, spironolactone and canrenone in human plasma samples. J Pharm Biomed Anal 2010;52(5):734-40. DOI

Takkis K, Aro R, Kõrgvee LT, Varendi H, Lass J, Herodes K, Kipper K. Signal Enhancement in the HPLC-ESI-MS/MS analysis of spironolactone and its metabolites using HFIP and NH4F as eluent additives. Anal Bioanal Chem 2017;409(12):3145-51. DOI

Krause W, Karras J, Seifert W. Pharmacokinetics of canrenone after oral administration of spironolactone and intravenous injection of canrenoate-K in healthy man. Eur J Clin Pharmacol 1983;25(4):449-53. DOI

Lee EKP, Poon P, Yip BHK, Bo Y, Zhu MT, Yu CP, Ngai ACH, Wong MCS, Wong SYS. Global Burden, Regional Differences, Trends, and Health Consequences of Medication Nonadherence for Hypertension During 2010 to 2020: A Meta-Analysis Involving 27 Million Patients. J Am Heart Assoc 2022;11(17):e026582. DOI

Lins RL, Matthys KE, Verpooten GA, Peeters PC, Dratwa M, Stolear JC, Lameire NH. Pharmacokinetics of atorvastatin and its metabolites after single and multiple dosing in hypercholesterolaemic haemodialysis patients. Nephrol Dial Transplant 2003;18(5):967-76. DOI

Kosoglou T, Statkevich P, Johnson-Levonas AO, Paolini JF, Bergman AJ, Alton KB. Ezetimibe: a review of its metabolism, pharmacokinetics and drug interactions. Clin Pharmacokinet 2005;44(5):467-94. DOI