Universität zu Köln

Johannsen, Jan-Ole, Reuter, Hannes, Hoffmann, Fabian ORCID: 0000-0002-3199-9924, Blaich, Cornelia, Wiesen, Martin H. J., Streichert, Thomas and Mueller, Carsten (2019). Reliable and easy-to-use LC-MS/MS-method for simultaneous determination of the antihypertensives metoprolol, amlodipine, canrenone and hydrochlorothiazide in patients with therapy-refractory arterial hypertension. J. Pharm. Biomed. Anal., 164. S. 373 - 382. AMSTERDAM: ELSEVIER SCIENCE BV. ISSN 1873-264X

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Abstract

Background: Therapy-refractory arterial hypertension is defined as a blood pressure (BP) in a subset of patients who fail to achieve BP control despite a three-drug regimen (including a diuretic). Various factors have impact on loss of therapy response. Drug-drug-interactions (DDIs) may cause altered pharmacokinetics (PK) of antihypertensive drugs. Upregulation of activity and expression of cytochrome P450 (CYP) enzymes can result in decreased plasma drug levels. Besides these PK considerations a significant problem could be nonadherence to drug therapy. In this regard Therapeutic Drug Monitoring (TDM) is a useful tool for detecting nonadherence. Therefore a LC-MS/MS-method for determination of Metoprolol (MET), Amlodipine (AML), Canrenone (CAN) and Hydrochlorothiazide (HCT) was developed. Methods: An UHPLC-MS/MS method was developed and validated for simultaneous determination of MET, AML, CAN and HO' in plasma matrix. Extraction of serum samples consisted of simple protein precipitation using acetonitrile. Stable isotope labeled analogues for each antihypertensive were obtained for internal standardization and quantitative analysis ([H-2(7)]-MET, ([C-13(6)]-AML, [H-2(4)]-CAN, [C-13(6)]-HCT). Calibrators and quality controls were prepared in plasma matrix of normal individuals. Sample preparation: protein precipitation with acetonitrile and addition of internal standard-mix. Results: All analytes were eluted within a runtime of 2.5 min. Linearity experiments were demonstrated in plasma over following concentration ranges: MET: 5-750 mu g/l, AML: 1-50 mu g/l, CAN: 10-500 mu g/l, 5-500 mu g/l (R-2 > 0.993). Chromatographic separation was achieved using a C18 column (50 x 2.1 mm, 1.9 mu m particle size) and an isocratic elution. LC-MS/MS analyses were performed on a triple quadrupole mass spectrometer using positive and negative electrospray ionization in selected reaction monitoring (SRM) mode. Ion transitions monitored for quantitation were m/z 268.2 -> 74.1 for MET, m/z 409.1 -> 238.0 for AML, m/z 341.2 -> 91.0 for CAN and m/z 296.0 -> 205.1 for HCT. For all analytes, inter- and intra-day precision (CV, %) varied between 1.7 and 14.0 and inter- and intra-day accuracy values ranged from -2.5 to 7.1%. The lower limits of detection and quantification were: 0.08 and 0.23; 0.05 and 0.15; 2.82 and 8.54; and 0.02 and 0.0514/1 for MET, AML, CAN and HCT, respectively. Results of stability experiments were within the required range of +/- 15%. Conclusions: Although the level of recommendation of TDM of antihypertensive drugs in patients with refractory hypertension is not yet established, the present LC-MS/MS-method can serve as an effective tool for detection of PK-alterations/nonadherence and may help to monitor antihypertensive pharmacotherapy. (C) 2018 Elsevier B.V. All rights reserved.

Item Type:	Journal Article
Creators:	Creators Email ORCID ORCID Put Code Johannsen, Jan-Ole UNSPECIFIED UNSPECIFIED UNSPECIFIED Reuter, Hannes UNSPECIFIED UNSPECIFIED UNSPECIFIED Hoffmann, Fabian UNSPECIFIED orcid.org/0000-0002-3199-9924 UNSPECIFIED Blaich, Cornelia UNSPECIFIED UNSPECIFIED UNSPECIFIED Wiesen, Martin H. J. UNSPECIFIED UNSPECIFIED UNSPECIFIED Streichert, Thomas UNSPECIFIED UNSPECIFIED UNSPECIFIED Mueller, Carsten UNSPECIFIED UNSPECIFIED UNSPECIFIED
URN:	urn:nbn:de:hbz:38-156954
DOI:	10.1016/j.jpba.2018.11.002
Journal or Publication Title:	J. Pharm. Biomed. Anal.
Volume:	164
Page Range:	S. 373 - 382
Date:	2019
Publisher:	ELSEVIER SCIENCE BV
Place of Publication:	AMSTERDAM
ISSN:	1873-264X
Language:	English
Faculty:	Unspecified
Divisions:	Unspecified
Subjects:	no entry
Uncontrolled Keywords:	Keywords Language RAT PLASMA APPLICATION; SIMULTANEOUS QUANTIFICATION; METABOLITES; VALIDATION; URINE; PRECIPITATION; OLMESARTAN; DRUGS Multiple languages Chemistry, Analytical; Pharmacology & Pharmacy Multiple languages
Refereed:	Yes
URI:	http://kups.ub.uni-koeln.de/id/eprint/15695