Abstract
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 (Peff) 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 inhibitorR,S-verapamil (400 μg/ml). Perfusate samples were assayed for content of artemisinin,R,S-verapamil, and perfusion viability markers. Artemisinin Peff was 1.44 ± 0.38, 1.17 ± 0.32, and 1.71 ± 0.29 (·10−4, 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 Peff was similar in artemisinin-pretreated rats (1.09 ± 0.54 · 10−4, cm/s) and rats pretreated with only vehicle (1.07 ± 0.37 · 10−4, 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.
Footnotes
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Send reprint requests to: Dr. Ulrika S. H. Svensson, Department of Pharmacy, Division of Biopharmaceutics and Pharmacokinetics, Uppsala University, BMC, Box 580, S-751 23 Uppsala, Sweden. E-mail: Ulrika.Svensson{at}biof.uu.se
- Abbreviations used are::
- Peff, rat
- effective permeability in rat
- Peff, man
- effective permeability in humans
- MDR
- multidrug resistant
- CYP
- cytochrome P-450
- Qin
- perfusion flow rate
- NWF
- net water flux
- Received May 27, 1998.
- Accepted October 6, 1998.
- The American Society for Pharmacology and Experimental Therapeutics
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