Pharmacokinetics Of Piperaquine After Oral Administrations In Beagle Dogs

Piperaquine phosphate (PQP),an potent antimalarial drug,possess a 4-aminoquinolinestructure,recording in the Pharmacopeia of China.PQP in combination withdihydroartemisinin(DHA)is strongly recommended to use in the first-line antimalarial drugby the WHO.Although some data about preclinical toxicity in animal have beenpublished,there were not information of the pharmacokinetics of piperaquine in dogs.The purpose of this study is to develope and validate a bioanalytic method for thedetermination of piperaquine in dog plasma by HPLC with solid-phase extraction;andalso to study the pharmacokinetics of piperaquine in the Beagle dogs after oral multi-doseadministration of a combination of PQP with DHA.1.The development of a SPE-HPLC method for determination of piperaquinein dog plasma.Piperaquine was analysed by liquid chromatography with UV detection on aphenomenex-Kromasil C18 (150 mm×4.6 mm)column with a mobile phase containingmethanol-water-triethylamine(83:17:0.01,v/v/v)at a flow rate of 1.0 mL·min^-1,and UV detection at 324 nm.The samples were extracted on a solid phase extraction (SPE)beforeinjection into chromatography.There was no endogenous interference from plasma or in all the procedure in thechromatogram.The linear range of piperaquine phosphate plasma concentration was0.044～3.30μg·mL^-1(r=0.9984).The intra-day precisions and inter-day precisions RSD for piperaquine were less than 10%.The method recovery of piperaquine phosphate was92.7%～97.1% and the extraction recovery was 89.3%～94.9%.The limit ofquantification (LOQ)and the limit of detection (LOD)were 44 and 20 ng·mL^-1,respectively.The SPE-HPLC method was proved simple,rapid,specific and sensitive.2.Pharmacokinetics of piperaquine after oral administrations in Beagle dogs.The disposition of piperaquine was studied in 6 male Beagle dogs after received tablets of piperaquine phosphate-dihydroartemisinin by oral administration.All dogswere given tablets orally at 0,8,24 and 32 h with a total piperaquine phosphate dose of80.85 mg·kg^-1.Blood samples were frequently drawn on days 1 and 3 and sparsely drawn until day 35.Piperaquine in plasma was quantified by high performance liquidchromatography.Compartmental pharmacokinetic analysis of plasma PQ concentration vs.time data was carried out using PKsolution2 (USA)to estimate the absorption rateconstant,apparent volume of distribution,oral clearance,elimination half-life and otherpharmacokinetic parameters.The curve of plasma PQ concentration-time was described with a opentwo-compartment models after oral administration in dogs.The pharmacokineticparameters of PQ were as follows:C_max was 1.79±0.62μg·mL^-1,T_max was 39.67±4.08 h,AUC_0-t was 83.80±9.53μg·h·mL^-1,Vd was 241.5±83.54L,C1 was 0.98±0.11L·h^-1,t_1/2(β)was 186.49±80.34 h.Piperaquine pharmacokinetics after repeated oral doses werecharacterized by multiple concentration peaks and multiphasic disposition,resulting in along terminal half-life,and significant inter-individual difference.This stuy is a supplementof PQ on nonrodents.