The Pharmacokinetics and Bioavailability of Dihydroartemisinin, meether, Artemether, Artesunic Acid and Artelinic Acid in Rats

Abstract

The pharmacokinetics and bioavailability of dihydroartemisinin (DQHS), artemether (AM), arteether (AE), artesunic acid (AS) and artelinic acid (AL) have been investigated in rats after single intravenous, intramuscular and intragastric doses of 10 mg kg(-1). Plasma was separated from blood samples collected at different times after dosing and analysed for parent drug. Plasma samples from rats dosed with AM, AE, AS and AL were also analysed for DQHS which is known to be an active metabolite of these compounds. Plasma levels of all parent compounds decreased biexponentially and were a reasonable fit to a two-compartment open model. The resulting pharmacokinetic parameter estimates were substantially different not only between drugs but also between routes of administration for the same drug. After intravenous injection the highest plasma level was obtained with AL, followed by DQHS, AM, AE and AS. This 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 (0.72 L) and AS (0.87 L). Clearance of AL (21-41 mL min(-1) kg(-1)) was slower than that of the other drugs for all three routes of administration (DQHS, 55-64 mL min(-1) kg(-1); AM, 91-92 mL min(-1) kg(-1); AS, 191-240 mL min(-1) kg(-1); AE, 200-323 mL min(-1) kg(-1)). In addition the terminal 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 absorption of the sesame-oil formulation from the injection site. After oral administration, low bioavailability (19-35%) was observed for all five drugs. In-vivo AM, AE, AS and AL were converted to DQHS to different extents; the ranking order of percentage of total dose converted to DQHS 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 routes of administration. The drug with the highest percentage conversion to DQHS was artesunic acid. Because DQHS has significant antimalarial activity, relatively low DQHS production could still contribute significantly to the antimalarial efficacy of these drugs. This is the first time the pharmacokinetics, bioavailability and conversion to DQHS of these drugs have been directly compared after different routes of administration. The results show that of all the artemisinin drugs studied the plasma level was highest for artelinic acid; this reflects its lowest extent of conversion to DQHS and its slowest rate of elimination.

Pharmacokinetic (PK) and Pharmacodynamic Profiles of Artemisinin Derivatives Influence Drug Neurotoxicity in Animals

“…The slow elimination of AE was recently demonstrated in a rat study, which also found significant accumulation of AE in the plasma from injection sites (Li et al, 1999b). The results of a rat study conducted by daily intramuscular injections of AE at 25 mg/kg in sesame oil for 7 days confirmed and extended the results of earlier studies (Li et al, 1998b) by demonstrating that the absorption of AE from the injection site of the muscle was incomplete. This study also indicated that up to 38% of the total single dose of AE remained in the injection site for 24 hr after dosing, and 22% of the total single dose still remained in the muscle 48 hr after dosing.…”

Comparative study of the effects of artemether and artesunate on juvenile and adult Schistosoma mansoni in experimentally infected mice

“…The similarities in susceptibility of different developmental stages of S. mansoni to artemether and artesunate might be explained by the fact that the 2 compounds are remarkably related in terms of chemical structures and also pharmacodynamic properties (ZIFFER et al, 1997;LI et al, 1998;VROMAN et al, 1999). In this connection, it could be speculated that other artemisinin derivatives should exhibit similar antischistosomal properties, which has indeed been confirmed in viva for arteether (XIAO et aZ., 1992) and also dihydroartemisinin (ABDEL AZIZ & EL-BADAWY, 2000).…”

Pharmacokinetic Profiles of Artesunate After Single Intravenous Doses at 0.5, 1, 2, 4, and 8 mg/kg in Healthy Volunteers: A Phase I Study

“…It is known that DHA has a longer half-life of 1.15-2.37 hours, which is 7.12-to 12.68-fold longer than AS, which has a short half-life of 0.12-0.24 hours. Therefore, the effectiveness of AS has been attributed to its rapid and extensive hydrolysis to DHA 5,7,32 and also to AS itself with a high initial C max . 23,24 In this study, the pharmacokinetics and possible side effects of an intravenous infusion of AS were studied in healthy volunteers.…”

“…4 The effectiveness of AS has been mostly attributed to its rapid and extensive hydrolysis to DHA. [5][6][7][8] Artemisinins have been used in malaria treatments with monotherapy regimen since 1983. However, the monotherapy with the artemisinin derivatives was significantly discouraged after 2001 to prevent the emergence of resistance.…”