DISPOSITION OF AMODIAQUINE IN EXPERIMENTAL ANIMALS

Abstract

The pharmacokinetics of amodiaquine have been examined in experimental animals (rats and rabbits) using an improved non-selective fluorimetric and more selective high performance liquid chromatographic (HPLC) methods with detection limits of 20 ng/ml and 5 ng/ml respectively. There was about 60% increase in sensitivity (20 ng/ml) when phosphate buffer pH10.9 was used. The mean percentage recoveries after the extraction of 0.5 ug/ml of amodiaquine from plasma in phosphate and borate buffers at similar pH value (9.5) were between 98-100% and 80-100% respectively. Generally higher concentrations of amodiaquine (ng/ml) were measured with the fluorimetric method than in HPLC method. However, the latter method selectively separated the metabolites from amodiaquine while total quinoline concentrations were measured with fluorimetric method. The pharmacokinetic property of amodiaquine followed dose-independent kinetics in albino rabbits and rat after a mingle oral dose of 10 mg/kg and intravenous dose of 5 mg/kg amodiaquine. In rabbits, the mean ± S.D. of the terminal half-life (t½), area under the plasma concentration time curve (AUCo-00) and total compartment apparent volume of distribution (vd) for AQ were 34.7±0.19 h, 14.7±0.17 ug.h ml -1 and 69.28±9.24 1 kg-1; 8.66± 0.84 h,4.94 ± 1.15 ug.h ml -1 and 13.03±2.32 1kg-1 for the oral and intravenous routes of administration respectively. In rats, the half-life, elimination rate constant and apparent volume of distribution for the normal, protein-energy malnutrition (P.E.M) and re-fed P.E.M rats after an intraperitonial dose of 10 mg/kg were 28.7±6.0 h, 0.0251±0.0053h-1 and 84.2±8.6 kg-1, 43.9±4.4h, 0.0158±0.0053h-1 and 66.1±6.6 kg-1 ;30.2±.2.0h, 0.0223±0.0016h-1 and 74.0±9.4 kg-1 respectively. These data showed that the pharmacokinetic parameters were altered in rats with protein deficiency (P.E.M rats). The concentration (ug/g ) of amodiaquine levels in the tissues of rabbits followed the same pattern for the oral and intravenous routes after eighth hour of analysis (kidney> liver>spleen>lungs>ear>eye>brain). In rats the mean tissue to plasma amodiaquine concentration ratios after 24h in the liver of normal, P .E .M and re-fed P.E.M rats were 10.7, 15 and 6.6 respectively.

After a successful thin-layer chromatographic separation of amodiaquine from its metabolites (AQm and 2-0H AQm) the Rf values were calculated for AQ(0.71), AQm (0.42) and 2-0H AQm(0.31). By RP-HPLC method, amodiaquine and desethylamodiaquine were measurable. At 72h, the meant ± S.D of AQm concentration of 106± 4.22 and 94±3.20 ng/ml) were detected for the oral and I.V routes respectively. Amodiaquine could not be detected at this hour. This suggests a higher clearance for the parent drug than for the metabolite. Moreover amodiaquine has been shown to be about 70% bound to plasma protein by equilibrium dialysis experiment. The percentage bound of amodiaquine to human plasma protein was found between 63 and 76% while that of 4% bovine serum Albumin was between 55 and 69%. These bindings were not affected by the presence of paracetamol trimethoprim ± sulphamethoxazole, and promethazine. However the presence of quinine and acetylsalicylic acid appeared to have 9% and 31% reductions in protein binding of amodiaquine respectively. Care should be taken therefore, when prescribing amodiaquine combination with acetylsalicylic acid or quinine in order to achieve the correct therapeutic value of this drug.