Abstract
TJ0711∙HCl, which is a novel α1/β1 adrenoceptor blocking agent with a ratio of 1:1 for α1/β1, is designed to treat and prevent perioperative hypertension. M1 and M3 were identified as important metabolites in vitro for either antihypertension activity or the major metabolite production. In order to obtain a pharmacokinetic profile of both TJ0711 and its metabolites, a rapid, selective, and reliable LC-MS/MS method was developed and validated for simultaneous determination of TJ0711 and two metabolites in beagle dog plasma via efficiently separating two interferential metabolites M16 and M4 from M1 and M3, respectively. Chromatographic separation was achieved on a Waters CORTECS C18+ column (2.1 × 100 mm, 2.7 μm). The mass spectrometric detection was carried out in positive ion MRM mode with ESI+ source. Protein precipitation was used in sample preparation and provided good recovery without a matrix effect. Good linearity was observed at the ranges of 0.5–100 ng/mL for TJ0711 and M3, 0.1–20 ng/mL for M1. Additional validation results were within the acceptance limits followed U.S. FDA guidelines for bioanalytical method validation. This method was successfully applied to an intravenous infusion pharmacokinetic study of TJ0711 at dosing rates of 3, 6, and 12 µg/kg/min in anesthetized beagle dogs for the first time. TJ0711 and its two metabolites exhibited effective proportionality in the dosage of 3 to 12 µg/kg/min. Neither TJ0711 nor its metabolites showed significant differences in pharmacokinetic parameters such as t1/2, CL, and Vss among three dose groups.
Highlights
Hypertension has become an important risk factor for cardiovascular disease and the leading causes of death [1,2,3,4]
Perioperative hypertension is treated with four categories of hypotensive drugs including β blockers, angiotensin-converting enzymes (ACE) inhibitors, calcium channel blockers (CCB), and vasodilators [5,7,8]
Chromatographic conditions including organic chromatographic separation and improved peak shape compared to methanol
Summary
Hypertension has become an important risk factor for cardiovascular disease and the leading causes of death [1,2,3,4]. Due to its augmentation of coronary blood flow and increasing cardiac output nicardipine can reduce cardiac and cerebral ischemia, balance myocardial oxygen demand, and (CO), nicardipine can reduce cardiac and cerebral ischemia, balance myocardial oxygen supply after intravenous administration [13]. The idealare agent treatment of perioperative hypertension shouldeach be rapid advantages and disadvantages [5,8]. The ideal agent for treatment of perioperative hypertension acting, predictably and titrated, safe, and inexpensive [6]. It is of great clinical should be rapid acting, predictably and titrated, and inexpensive [6].minimal. Clinical significance to develop a novel, safe hypotensive drug with high efficacy and minimal toxicity.
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