Dihydroartemisinin photoirradiation: reduced antiplasmodic activity and toxicological implications

Abstract

Many antimalarial drugs are photoreactive inducing varied phototoxic reactions. Dihydroartemisinin, the active metabolite of all artemisinins possesses sesquiterpene ring with an endoperoxide bridge which is essential for the antiplasmodial activity, and is strong site for photochemical reaction. This accelerated photochemical stability study evaluated the physicochemical and biological implications of photo irradiation of dihydroartemisinin. Dihydroartemisin (0.04%w/v) in aqueous methanol solution (50%v/v) was irradiated for 1 hour using ICH Photostability testing guidelines at 365nm. Photoirradiated samples were analysed using thin layer chromatography (TLC), ultraviolet spectrophotometry (UV) and high performance liquid chromatography (HPLC). Antiplasmodial activity, packed cell volume (PCV), liver enzyme assay and histopathology were also determined. Photo irradiation of the dihydroartemisinin solution gave golden brown colour with formation of needle like crystals and two additional TLC spots. The UV spectra showed a broad band at 229 – 302nm and the presence of four new photodegradation products in the HPLC chromatogram. Significant reduction in body weights (p=0.0001), PCV (p=0.0002 and antiplasmodial properties was observed with the irradiated dihydroartemisinin samples (p=0.0002). Aspartate aminotransferase and alanine aminotransferase levels of the mice were significantly increased. Photo irradiated samples showed various stages of hepatotoxicity; massive hepatic degeneration and necrosis of the liver with hyperplaxia and hemosiderin laden kupffer cells as well as multifocal lymphocytic infiltration of liver with the parasite not cleared. This study confirms that dihydroartemisinin has the potential of undergoing photodegradation with reduction in antiplasmodial activity and possible hepatotoxicity.

Keywords: Dihydroartemisinin, Photodegradation, Antiplasmodial activity, Hepatotoxicity