Abstract
Detection of antihypertensive drugs in biological samples is an important tool to assess the adherence of hypertensive patients. Urine and serum/plasma screenings based on qualitative results may lead to misinterpretations regarding drugs with a prolonged detectability. The aim of the present study was to develop a method that can be used for therapeutic drug monitoring (TDM) of antihypertensive drugs with focus on adherence assessment. Therefore, a method for quantification of four diuretics and four β-blockers using high-performance liquid chromatography-mass spectrometric analysis (LC-MS/MS) of combined acidic and basic serum extracts was developed and validated. The method was applied to 40 serum samples from 20 patients in a supervised medication setting (trough and peak serum samples). Literature data on therapeutic concentration ranges, as well as dose-related drug concentrations (calculated from data of pharmacokinetic studies) were used to evaluate adherence assessment criteria. Concentrations were measured for bisoprolol (n = 9 patients), metoprolol (n = 7), nebivolol (n = 1), canrenone (n = 2, metabolite of spironolactone), hydrochlorothiazide (n = 10) and torasemide (n = 8). The measured concentrations were within the therapeutic reference ranges, except for 24% of the samples (mainly β-blockers). In contrast, all measured concentrations were above the lower dose-related concentration (DRC), which appears superior in evaluating adherence. In conclusion, the quantitative analysis of antihypertensive drugs in serum samples and its evaluation on the basis of the individually calculated lower DRC is a promising tool to differentially assess adherence. This method could possibly detect a lack of adherence or other causes of insufficient therapy more reliably than qualitative methods.
Highlights
Detection of antihypertensive drugs in biological samples is an important tool to assess the adherence of hypertensive patients
This method based on a two-step liquid liquid-extraction at acidic and basic pH was validated for quantification of four β-blockers and four diuretics
Blank and zero serum samples showed no significant interference in terms of endogenous substances at retention times of analytes or internal standards except that a signal at the retention time of HCT was detected (c.f. chromatogram of a blank sample in Fig. 1) which obviously resulted from non-deuterated HCT present in the HCT-d2
Summary
Detection of antihypertensive drugs in biological samples is an important tool to assess the adherence of hypertensive patients. The quantitative analysis of antihypertensive drugs in serum samples and its evaluation on the basis of the individually calculated lower DRC is a promising tool to differentially assess adherence. This method could possibly detect a lack of adherence or other causes of insufficient therapy more reliably than qualitative methods. A diagnostic advancement was achieved by implementing a quantitative method for 21 antihypertensive drugs in serum that was recently published by Gundersen et al.[10] They set up a therapeutic drug monitoring (TDM) system and used pharmacokinetic data to establish calibration ranges to classify measured serum concentrations with respect to adherence. The concentrations were evaluated with respect to the diagnosis of non-adherence according to two concepts: published reference ranges and the calculated lower dose-related concentration as established for psychiatric TDM11
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