Vol. 27, Issue 2, 227-232, February 1999

High In Situ Rat Intestinal Permeability of Artemisinin Unaffected by Multiple Dosing and with No Evidence of P-glycoprotein Involvement

Ulrika S. H. Svensson, Rikard Sandström, Örjan Carlborg, Hans Lennernäs, and Michael Ashton

Department of Pharmacy, Division of Biopharmaceutics and Pharmacokinetics, Uppsala University, Uppsala, Sweden

The objective of this study was to investigate whether the decrease in artemisinin bioavailability after repeated oral dosing in humans can be a result of increased efflux of artemisinin by P-glycoprotein or decreased membrane transport at the intestinal barrier. The effective jejunal permeability (P_eff) of artemisinin was investigated using an in situ rat perfusion model. Fifty-four rats were randomized to one of three treatment arms: no pretreatment, pretreatment with artemisinin emulsion for 5 days (60 mg/kg/day, p.o.), or pretreatment with emulsion vehicle for 5 days. The rats within each treatment arm were randomized further to be jejunally perfused with either low (500 ng/ml) or high (5000 ng/ml) artemisinin concentration or low artemisinin concentration plus the P-glycoprotein inhibitor R,S-verapamil (400 µg/ml). Perfusate samples were assayed for content of artemisinin, R,S-verapamil, and perfusion viability markers. Artemisinin P_eff was 1.44 ± 0.38, 1.17 ± 0.32, and 1.71 ± 0.29 (·10⁴, cm/s) in rats receiving no pretreatment and perfused with low, high, or low artemisinin concentration plus verapamil, respectively. Multiple oral dosing of artemisinin did not affect the jejunal permeability of artemisinin. R,S-verapamil P_eff was similar in artemisinin-pretreated rats (1.09 ± 0.54 · 10⁴, cm/s) and rats pretreated with only vehicle (1.07 ± 0.37 · 10⁴, cm/s). The decrease in artemisinin bioavailability after multiple oral dosing in human is probably not a result of changes in P-glycoprotein expression or general intestinal transport. It seems more likely attributed to increased hepatocellular activity. Furthermore, artemisinin exhibits high jejunal permeability and is neither a substrate nor inducer of P-glycoprotein.