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

Multiple doses of arteether (ARTE) at 25 mg/kg cause CNS and anorectic toxi cities in rats. The same dose of ARTE was used to study the toxicokinetics (TK) after multiple injections and the pharmacokinetics (PK) following sing le administration. Animals were administered ARTE in sesame oil for 7 days, blood samples were collected using destructive sampling for up to 192 h af ter dosing and assayed by HPLC-ECD. Two other groups of rats were administe red either a single 25 mg/kg i.v. or i.m. dose. In addition, the drug remai ning in the i.m. injection site was measured. During the 7 day treatments, anorectic toxicity of ARTE was observed, and that caused significant reduct ions in food consumption and body weight after day 2. TK data on days 2-7 r evealed marked changes compared to the PK parameters estimated on day 1. AU C (4367 ng.h/ml) on day 7 was 5-fold higher than AUC (905 ng.h/ml) on day 1 . The volume of distribution at steady state (V-ss) on day 7 (41.81) was 40 % of the day 1 value of the V-ss (104.31). 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). T hese data suggest that ARTE may have altered its distribution and eliminati on 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 remai ned 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 fro m muscle were seen with t(1/2) Of 0.97 h and 26.3 h, respectively. The appa rent elimination t(1/2) Of ARTE after i.m. injection (13.7 h) was much long er than that after i.v, dosing (0.67 h) due to the prolonged muscle absorpt ion phase. Acute toxicity data of artemisinin drugs demonstrated that anima ls 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 vehicl e, they died between days 1 and 2. This suggests that delayed onset toxicit y and death in the ARTE rats may also be due to slow absorption and prolong ed drug exposure. Therefore multiple i.m. administrations cause anorexia an d drug accumulation, possibly affecting the toxicokinetics and efficacy of the drug.