PHARMACOLOGY AND TOXICOLOGY OF ARTELINIC ACID - PRECLINICAL INVESTIGATIONS ON PHARMACOKINETICS, METABOLISM, PROTEIN AND RED-BLOOD-CELL BINDING, AND ACUTE AND ANORECTIC TOXICITIES

The pharmacokinetics, metabolism, protein binding, red blood cell (RBC ) binding, stability in vitro, and acute and anorectic toxicity of art elinic acid (ARTL) were investigated in various animal species and hum an blood samples. Absorption and distribution following IO mg/kg intra muscular or oral administration in dogs and rats were very rapid with t(1/2) 0.12-0.54; there were also a high AUC (11262 ng/h/ml) and V-SS (9.5 L/kg), low CL (15 mL/min/kg) and long elimination time (t(1/2 )= 2.6 h), compared with rat data. Oral bioavailability of ARTL was 79.7% in dogs and 30.1% in rats. The conversion of ARTL to dihydroartemisin in (DART) in dogs (0.1-0.5% of total dose) after 3 routes of administr ation (intravenous, intramuscular and oral) was 10-fold lower than tha t in rats. In rats dosed with [C-14]ARTL, unchanged ARTL accounted for less than 13% of the total radioactivity after all ? administration r outes, suggesting that ARTL was extensively biotransformed. The half-l ives of total radioactivity (21-49 h) in urine were much longer than t hat of unchanged ARTL in plasma (1.4-3.7 h), indicating that some long -lasting metabolites of ARTL were formed in rats. The mass balance dat a showed that 77-83% of total radioactivity was recovered in urine and faeces. High binding capacity (79-95%) and low binding affinity (1.1- 9.3x 10(-7) M) of ARTL were measured in rat, rabbit, dog, monkey and h uman plasma. The RBC/plasma ratios of [C-14]ARTL were 0.35 and 0.44 fo r dog and human plasma, respectively ARTL was much more stable than ar tesunic acid (ARTS) in rat and dog plasma, and both ARTL and ARTS were more stable in dog plasma than in rat plasma tit vitro. The 50% letha l dose (LD50) of ARTL in rats was about 535 mg/kg. Multiple intramuscu lar dosing for 7 d of 50 mg/kg/d of ARTL caused mild anorectic toxicit y compared to ARTS in rats. In contrast to 4 other artemisinin derivat ives, ARTL seems to be a good antimalarial candidate as it has the hig hest plasma concentration, the highest binding capacities in RBC, the highest oral bioavailability, the longest elimination half-life, the l owest metabolism rate and the lowest toxicity at equivalent dose level s.