Development of an LC‐MS/MS method for determining the pharmacokinetics of clonidine following oral administration of Zhenju antihypertensive compound

Abstract

Zhenju antihypertensive compound (ZJAHC) is a combined Chinese-Western medicine formula including clonidine (CLO), hydrochlorothiazide (HCT), rutin, Chrysanthemum indicum extract and pearl powder. Compared with CLO preparations, ZJAHC shows improved activities and decreased adverse effects. It is believed that the side effects of CLO are caused by its high peak plasma concentration. Hence, study of the influence of ZJAHC on the pharmacokinetic behaviors of clonidine seems essential. In present study, the plasma concentrations of CLO were determined with a liquid chromatography-tandem mass spectrometry (LC-MS/MS) method. The MS/MS transitions monitored for clonidine and internal standard were 230.2 → 213.1 and 152.2 → 110.2, respectively. The analyte was quantified in a single run within 3 min. The pharmacokinetic study showed that the area under the plasma concentration-time curve of CLO in ZJAHC (60 µg/kg CLO) was similar to that of CLO-HCT-high (120 µg/kg CLO) but the peak concentration was much lower than that in CLO-HCT-high. ZJAHC could enhance the bioavailability without greatly increasing peak concentration of clonidine. This comprehensive effect of enhancing the bioavailability and avoiding the high peak plasma concentration for CLO might mainly result from the co-contribution of Western medicine and traditional Chinese medicine (TCM), while the effect of TCM was stronger than that of Western medicine.

Validation of a HPLC/MS method for simultaneous quantification of clonidine, morphine and its metabolites in human plasma

“…Solid-phase extraction was adopted for effective clean-up and enrichment and its simplicity over liquid-liquid extraction, which was adopted by most of the published assays for clonidine (Nirogi et al, 2008;Qin et al, 2015;Zhuang et al, 2015). Both morphine and clonidine are both weakly basic with similar pK a values (8.2 and 8.05, respectively) (Veigure et al, 2017).…”

“…A number of high-performance liquid chromatography-tandem mass spectrometry (HPLC-MS/MS) methods that quantified morphine, M3G and M6G and those that quantified clonidine in human plasma were reviewed. The lowest limits of quantification (LLOQ) were 0.25-3.5 ng/mL for morphine, 1-3.5 ng/mL for M3G/M6G (Clavijo et al, 2011;Eckart et al, 2015;Ghassabian et al, 2012) and 0.01-0.25 ng/mL for clonidine (Danafar & Hamidi, 2016;Muller et al, 2007;Nirogi, Kandikere, Mudigonda, & Komarneni, 2008;Parekh, Pudage, Joshi, Vaidya, & Gomes, 2008;Qin et al, 2015;Zhuang et al, 2015), and these methods required plasma volumes ranging from 100 μL up to 1 mL. There was one published HPLC-MS/MS method that simultaneously quantified clonidine, morphine and its two major metabolites that was highly sensitive and only required 100 μL of plasma (Veigure et al, 2017).…”

Analysis of the effects of Zhenju antihypertensive tablet on efficacy, safety and vascular endothelial function in patients with essential hypertension

“…It can contribute to improve the antihypertensive activity of HCT and reduce side effects. [13] Zhenju antihypertensive tablet combined with conventional antihypertensive drugs in the treatment of EH has been used in clinic for many years. In addition, a large number of clinical data have been accumulated.…”

“…It indicates that the drug composition of Zhenju antihypertensive tablet has a benign pharmacokinetic effect. It can contribute to improve the antihypertensive activity of HCT and reduce side effects [13] …”

Development and Validation of an HPLC-UV Detection Assay for the Determination of Clonidine in Mouse Plasma and Its Application to a Pharmacokinetic Study

“…Because of the reported variability in exposure to clonidine, the development of a sensitive and selective procedure for the determination of clonidine level in plasma is required. Various analytical techniques have been reported for clonidine determination by using spectrophotometry [ 6 , 7 , 8 ], potentiometry [ 9 , 10 ], capillary electrophoresis [ 11 ], liquid chromatography-mass spectrometry (LC-MS) [ 12 , 13 , 14 , 15 , 16 ], and gas chromatography-mass spectrometry (GC-MS) [ 17 , 18 ].…”