Metabolism and Disposition of the Antihypertensive Agent Moxonidine in Humans

Abstract

ABSTRACT:The metabolism and pharmacokinetics of moxonidine, a potent central-acting antihypertensive agent, were studied in four healthy subjects after a single oral administration of approximately 1 mg (ϳ60 Ci) of [ 14 C 3 ]moxonidine. Moxonidine was rapidly absorbed, with peak plasma concentration achieved between 0.5 to 2 h postdose. The maximal plasma concentration and the area under the curve of unchanged moxonidine are lower than those determined for radioactivity, indicating presence of circulating metabolite(s). The total recovery of radiocarbon over 120 h ranged from 99.6 to 105.2%, with 92.3 to 103.3% of the radioactivity excreted in the urine and only 1.9 to 7.3% of the dose excreted in the feces. Thus, renal elimination represented the principal route of excretion of radioactivity. Metabolites of moxonidine were identified in urine and plasma samples by high performance liquid chromatography and liquid chromatography-tandem mass spectrometry. Oxidation of moxonidine on the methyl group or on the imidazoline ring resulted in the formation of hydroxymethyl moxonidine, hydroxy moxonidine, dihydroxy moxonidine, and dehydrogenated moxonidine. Metabolite profiling results indicated that parent moxonidine was the most abundant component in the urine. The dehydrogenated moxonidine was the major urinary metabolite as well as the major circulating metabolite. Moxonidine also underwent phase II metabolism, generating a cysteine conjugate. In summary, moxonidine is well absorbed after oral administration. The major clearance pathway for moxonidine in humans is via renal elimination. Furthermore, seven metabolites were identified with three metabolites unique to humans.Moxonidine is a new antihypertensive agent that acts on central nervous system imidazoline receptors to decrease sympathetic nervous system tone (Ernsberger et al., 1992;Prichard and Graham, 1996). It has been marketed throughout Europe for the treatment of hypertension. The safety and efficacy of moxonidine in hypertension patients has been established (Ollivier et al., 1992;Sides et al., 1998). In comparison to clonidine and rilmenidine, moxonidine has fewer adverse effects such as dry mouth and sedation because it is considerably more selective for the I 1 receptor than the ␣ 2 receptor that is associated with these indicated side effects (Yu and Frishman, 1996). In elderly patients, the clearance of moxonidine is reduced, and the area under the curve of unchanged drug is greater in comparison with younger patients suggesting the existence of an age-related decrease in metabolism (Theodor et al., 1996). Moxonidine has a relatively short half-life (about 2-3 h). However, it has long duration of effect and is given only once daily clinically. There is no clear correlation between the pharmacokinetics and pharmacodynamic effect of moxonidine.To determine whether the long duration of moxonidine is attributed to the production of active metabolite(s), efforts were undertaken to identify and synthesize major metabolites of moxonidine and test their ph...

Characterization of benzimidazole and other oxidative and conjugative metabolites of brimonidinein vitroand in ratsin vivousing on-line H/D exchange LC-MS/MS and stable-isotope tracer techniques

“…The metabolism of imidazoline containing compounds, such as clonidine (Baillie et al 1979), lofexidine (Midgley et al 1983), imidazolidine (Schulz-Jander and Casida 2002) and moxonidine (He et al 2000;2003) have been extensively studied. The common metabolic pathways on the imidazoline ring involved hydroxylation, dehydrogenation and ring opening, which are typically mediated by cytochrome P450 enzymes.…”