Abstract
PurposeTo develop and validate a bio-analytical HPLC–MS/MS method for the determination of conivaptan (CVA) an arginine-vasopressin receptor blocker in human plasma and in rat liver microsomes (RLMs).MethodsAnalytes were separated on a reversed phase C18 column (50 mm × 2.1 mm, 1.8 μm). The mobile phase was a mixture of acetonitrile and 10 mM ammonium formate (40:60 v/v, pH 4.0) and was pumped isocratically for 4 min at a flow rate of 0.2 ml/min. Multiple reaction monitoring in positive ionization mode was used for the assay.ResultsThe method yielded a linear calibration plot (r2= 0.9977 and 0.9998) over 5–500 ng/ml with a limit of detection at 1.52 and 0.88 ng/ml for human plasma and RLMs, respectively. The reproducibility of detection of CVA in human plasma and RLMs was found to be in an acceptable range.ConclusionThe method developed in this study is applicable for accurately quantifying CVA in human plasma and rat liver microsomal samples. The optimized procedure was applied to study of metabolic stability of CVA. Conivaptan concentration rapidly decreased in the first 2 min of RLMs incubation and the conversion reached a plateau for the remainder of the incubation period. The in vitro half-life (t1/2) was estimated at 11.51 min and the intrinsic clearance (CLin) was 13.8 ± 0.48 ml/min/kg.
Highlights
Conivaptan (YM087, CVA) is a vasopressin receptor antagonist. It is approved for the treatment of hyponatremia [low blood levels of sodium caused by syndrome of inappropriate antidiuretic hormone secretion (SIADH)] [1, 2] under the brand name vaprisol
We have developed and validated an HPLC–MS/MS method for the detection and quantitation of CVA in human plasma and rat liver microsomes (RLMs)
Accuracy and prevision of CVA analysis was confirmed in both intra- and inter-day settings, with high levels of recovery from human plasma and RLMs
Summary
Conivaptan (YM087, CVA) is a vasopressin receptor antagonist (non-peptide inhibitor of antidiuretic hormone). It is approved for the treatment of hyponatremia [low blood levels of sodium caused by syndrome of inappropriate antidiuretic hormone secretion (SIADH)] [1, 2] under the brand name vaprisol. Vaptans such as CVA and tolvaptan represent a targeted approach to treatment of hyponatremia by inhibiting the interaction of arginine vasopressin with the V2 receptor [2, 3]. Conivaptan inhibits two subtypes of the vasopressin receptors (V1a and V2) and is utilized in the treatment of SIADH. It increases sodium concentration in the blood, and regulates diuresis to prevent water retention in the body [4–7].
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