High-performance liquid chromatography combined with a UV absorbance detector and electrospray ionization mass spectrometer is used for the simultaneous analysis of moexipril and moexiprilat in biological samples. Moexipril and moexiprilat

Moexipril hydrochloride [(3S)-2-[(2S)-2-{[(1S)-1-(ethoxycarbonyl)-3-phenylpropyl]amino}-1-oxopropyl]-6,7-dimethoxy1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid hydrochloride] (Figure 1A) is a long-acting, non-sulfhydryl angiotensin-converting enzyme inhibitor (ACEI) used in the treatment of hypertension (1). Moexipril can be preferentially used to lower blood pressure without a significant change in cardiac output and heart rate. Moexipril is one of the non-sulfhydryl ACEIs. Further ACEIs are benazepril, captopril, cilazapril, enalapril, fosinopril, imidapril, lisinopril, perindopril, quinapril, ramipril, spirapril, trandolapril, and zofenopril as indicated by the suffix “pril”. These drugs differ in their chemical structure and pharmacokinetics; in clinical use, they are probably interchangeable. The overwhelming majority of ACEIs are prodrugs, so the active compound is generated by metabolic hydrolysis of the ethyl ester group. The alteration takes place mainly in the liver. These active metabolites are identifiable by the suffix “prilat”. As such, the metabolic hydrolysis of moexipril yields moexiprilat (Figure 1B). Pharmacokinetic studies generally require determination of both the parent compound and of its active metabolites. This is the main reason why there is an effort to determine the ACEIs together with their respective “prilat”. Prieto et al. (2) analyzed cilazapril and cilazaprilat, and Gu et al. (3) simultaneously measured the level of enalapril and enalaprilat. The mass spectra of enalapril and enalaprilat differ by 28 amu. This difference corresponds to the loss of the ethyl ester during metabolic alteration. Moexipril can be determined using both gas chromatography (GC) (4) and high-performance liquid chromatography (HPLC) (5). The GC analysis (4) consists of several steps, such as: (a) clean-up using Bond Elute C18, (b) methylation, (c) acid-base partition, and (d) converting both moexipril and moexiprilat to the corresponding trifluoroacetamides. GC separation can be monitored using negative-ion chemical ionization (NICI) mass spectrometry (MS) for the fragment ions of m/z 302 and 288 for moexipril and moexiprilat, respectively. The use of GC has been limited by the requirement of two-steps derivatization, that is, methylation and trifluoroacetylation. J. Kóti1, V. Háda1, G. Petroianu2, M.Y. Hasan2, K. Tekes3, Z. Szücs4, and H. Kalász2,5,* 1Spectroscopic Research Division, Gedeon Richter Ltd., Budapest, Hungary; 2Department of Pharmacology and Therapeutics, Faculty of Medicine & Health Sciences, United Arab Emirates University, Al Ain, United Arab Emirates; 3Department of Pharmacodynamics, Semmelweis University, Budapest, Hungary; 4Research Institute of Medicinal Plants Ltd., Budakalász, Hungary; and 5Department of Pharmacology and Pharmacotherapy, Semmelweis University, Budapest, Hungary