Arteether toxicokinetics and pharmacokinetics in rats after 25 mg/kg/day single and multiple doses

Abstract

Multiple doses of arteether (ARTE) at 25 mg/kg cause CNS and anorectic toxicities in rats. The same dose of ARTE was used to study the toxicokinetics (TK) after multiple injections and the pharmacokinetics (PK) following single administration. Animals were administered ARTE in sesame oil for 7 days, blood samples were collected using destructive sampling for up to 192 h after dosing and assayed by HPLC-ECD. Two other groups of rats were administered either a single 25 mg/kg i.v. or i.m. dose. In addition, the drug remaining in the i.m. injection site was measured. During the 7 day treatments, anorectic toxicity of ARTE was observed, and that caused significant reductions in food consumption and body weight after day 2. TK data on days 2-7 revealed marked changes compared to the PK parameters estimated on day 1. AUC (4367 ng x h/ml) on day 7 was 5-fold higher than AUC (905 ng x h/ml) on day 1. The volume of distribution at steady state (V(SS)) on day 7 (41.8 l) was 40% of the day 1 value of the V(SS) (104.3 l). Clearance (CL) was increased by 89% of the day 1 value, from 0.98 l/h to 1.85 l/h on day 7. The elimination t(1/2) of ARTE was also prolonged from 13.7 h (day 1) to 31.2 h (day 7). These data suggest that ARTE may have altered its distribution and elimination in rats as a result of the systemic toxicity. Analysis of the injection sites showed that 38% and 91% of the total amount of ARTE single dose remained in the muscles at 24 h (after first injection) and 168 h (at 24 h after 7 daily multiple doses), respectively. Fast and slow absorption phases from muscle were seen with t(1/2) of 0.97 h and 26.3 h, respectively. The apparent elimination t(1/2) of ARTE after i.m. injection (13.7 h) was much longer than that after i.v. dosing (0.67 h) due to the prolonged muscle absorption phase. Acute toxicity data of artemisinin drugs demonstrated that animals receiving a high single ARTE dose in sesame oil died between days 5-11, similar to artemether. When animals received dihydroartemisinin formulated in 50% DMAC/oil, or artesunic acid and artelinic acid in 0.9% saline vehicle, they died between days 1 and 2. This suggests that delayed onset toxicity and death in the ARTE rats may also be due to slow absorption and prolonged drug exposure. Therefore multiple i.m. administrations cause anorexia and drug accumulation, possibly affecting the toxicokinetics and efficacy of the drug.