Secondary Topic: Basic Science
Tertiary Topic: Research Methodology
ADME and Anti-Inflammatory Activity of the Antimalarial Drug Artemisinin Delivered Orally as Dried Leaves of Artemisia annua
Matthew Desrosiers, BS; Pamela Weathers, PhD, Worcester Polytechnic Institute, Worcester, MA, United States
Late Breaker: No
Artemisia annua offers a new treatment for malaria. The plant produces the antimalarial drug artemisinin (AN) whose derivatives make up the major component of artemisinin combination therapies, the frontline global treatment for malaria. Previously we showed that AN delivered as powdered, dried leaves of A. annua (DLA) is >40 fold more bioavailable in mice, about 4 times more soluble in intestinal fluid, and 37% more permeable to the intestinal membrane than pure AN. Furthermore, AN and several phytochemicals native to A. annua have known anti-inflammatory activity making DLA a potential anti-inflammatory therapeutic.
We performed tissue distribution and elimination studies in rats orally dosed with pure AN or a slurry of DLA containing an equal amount of AN. Rats were euthanized 1 or 8 hours after dosing, tissues harvested, and analyzed for AN content. Blood, urine and feces were collected at regular intervals for analysis. To study inflammation, rats were given an intraperitoneal injection of lipopolysaccharide from E. coli or vehicle (saline) and immediately treated with pure AN, DLA, or vehicle (water) via oral gavage. Serum samples were taken at regular intervals and analyzed by ELISA for TNF-α, IL-6, and IL-10.
DLA-delivered AN was distributed in significantly higher quantities, up to 6 fold greater than from pure AN throughout all tested tissues. Serum TNF-α was significantly reduced at 1-hour post-gavage in DLA-treated rats. Similarly, serum IL-6 was significantly reduced at 2 and 4-hours post-gavage in DLA-treated rats.
In agreement with in vitro solubility and intestinal permeability data, AN delivered as DLA is more bioavailable and more readily distributed than pure AN in vivo. The effects of DLA phytochemicals on the liver need investigating to determine their role in these bioavailability differences. DLA, but not AN, given orally decreases inflammatory cytokine secretion and requires further investigation in specific inflammatory disease models.