THE PHARMACOKINETICS AND BIOAVAILABILITY OF DIHYDROARTEMISININ, ARTEETHER, ARTEMETHER, ARTESUNIC ACID AND ARTELINIC ACID IN RATS

The pharmacokinetics and bioavailability of dihydroartemisinin (DQHS), artemether (AM), arteether (AE), artesunic acid (AS) and artelinic ac id (AL) have been investigated in rats after single intravenous, intra muscular and intragastric doses of 10 mg kg(-1) Plasma was separated f rom blood samples collected at different times after dosing and analys ed for parent drug. Plasma samples from rats dosed with AM, AE, AS and At were also analysed for DQHS which is known to be an active metabol ite of these compounds. Plasma levels of all parent compounds decrease d biexponentially and were a reasonable fit to a two-compartment open model. The resulting pharmacokinetic parameter estimates were substant ially different not only between drugs but also between routes of admi nistration for the same drug. After intravenous injection the highest plasma level was obtained with AL, followed by DQHS, AM, AE and AS. Th is resulted in the lowest steady-state volume of distribution (0.39 L) for AL, increasing thereafter for DQHS (0.50 L), AM (0.67 L), AE (0.7 2 L) and AS (0.87 L). Clearance of AL (21-41 mL min(-1) kg(-1)) was sl ower than that of the other drugs for all three routes of administrati on (DQHS, 55-64 mL min(-1) kg(-1); AM, 91-92 mL min(-1) kg(-1); AS, 19 1-240 mL min kg(-1); AE, 200-323 mL min(-1) kg(-1)). In addition the t erminal half-life after intravenous dosing was longest for AL (1.35 h) , followed by DQHS (0.95 h), AM (0.53 h), AE (0.45 h) and AS (0.35 h). Bioavailability after intramuscular injection was highest for AS (105 %), followed by AL (95%) and DQHS (85%). The low bioavailability of AM (54%) and AE (34%) is probably the result of slow, prolonged absorpti on of the sesame-oil formulation from the injection site. After oral a dministration, low bioavailability (19-35%) was observed for all five drugs. In-vivo AM, AE, AS and AL were converted to DQHS to different e xtents; the ranking order of percentage of total dose converted to DQH S was AS (25.3-72.7), then AE (3.4-15.9), AM (3.7-12.4) and AL (1.0-4. 3). The same ranking order was obtained for all formulations and route s of administration. The drug with the highest percentage conversion t o DQHS was artesunic acid. Because DQHS has significant antimalarial a ctivity, relatively low DQHS production could still contribute signifi cantly to the antimalarial efficacy of these drugs. This is the first time the pharmacokinetics, bioavailability and conversion to DQHS of t hese drugs have been directly compared after different routes of admin istration. The results show that of all the artemisinin drugs studied the plasma level was highest for artelinic acid; this reflects its low est extent of conversion to DQHS and its slowest rate of elimination.