Determination of GLG-V-13, a Novel Antiarrhythmic Agent, in Plasma and Urine by High-Performance Liquid Chromatography

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Abstract
A sensitive reversed-phase HPLC technique with UV detection has been developed to determine the concentration of GLG-V-13 (3-[4-(1H-imidazol-1-yl)benzoyl]-7-isopropyl-3,7-diazabicyclo[3.3.1]nonane dihydroperchlorate) (I), a novel combined class I and class III antiarrhythmic agent, in dog plasma and urine. Alkalinized plasma and urine samples were extracted with chloroform, and the extracts were reconstituted in methanol. An aliquot was injected on to a Waters HPLC system with a 250 × 4.6 mm Ultramex 5 C6 analytical column (5 μm) and 30 × 4.6 mm Ultramex 5 C6 guard column (5 μm). The elute was detected by a UV detector at 256 nm. Acetonitrile-methanol-37.5 mM phosphate buffer. pH6.8 (27:27:46 v/v) containing 3.6 mM triethylamine was used as the mobile phase. The average extraction recovery was 89% from plasma and 93% from urine. Good lineary (r > 0.999) was observed throughout the range of 8–8000 ng/ml in plasma and in urine with the quantitation limit of 8 ng/ml. Intra- and inter-assay variabilities were less than 4%. HPLC analysis of plasma and urine samples from a dog treated with I has demonstrated that the method was accurate and reproducible. Preliminary pharmacokinetic results showed that the plasma concentration-time curves fitted a two compartment open model with slow elimination (t1/2ß 3.0827 h−1); wide distribution (Vc 2.389 L/kg and Vd(ss) 3.6808 L/h.kg); and longer mean residual time (MRT 4.7632 h), respectively. It seems that there is a difference in disposition of this compound in pathological dogs compared to normal one.

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