Differential synergistic antimalarial effects of an A. annua extract on artemisinin via host pharmacokinetic modulation.

ETHNOPHARMACOLOGICAL RELEVANCE: The traditional antimalarial herb A. annua L. is not recommended for the treatment of malaria, due to the risk of subtherapeutic dose of artemisinin (ART). However, whole A. annua plant was reported to provide adequate ART exposure in healthy host.

AIM OF THE STUDY: To investigate whether and how A. annua L. enhanced ART potency based on the pharmacodynamic (PD)-pharmacokinetic (PK)-metabolic study of ART in both Plasmodium parasites and infected-host. The effect of infection severity on the synergistic effect was also evaluated.

METHODS

The synergistic potency of an A. annua extract (AAE) was evaluated using Pf3D7 incubated in vitro and P. yoelii inoculated in mice. The pharmacokinetic profiles of ART in both parasites and infected-host were studied after treatment with ART either alone or in AAE. The effect of AAE on drug metabolism-related genes (e.g., Cyps, transporters) was investigated. An LC-HRMS-based analytical strategy was employed to screen possible synergistic components in AAE, and the target component isolated from A. annua extract was then evaluated for its role in enhancing ART potency.

RESULTS

No synergistic antimalarial effect was found for ART against Pf3D7 when treated in AAE, which was correlated with the pharmacokinetics of ART (150 nM) in Pf3D7 parasites. However, AAE matrix showed a biphasic effect on ART antimalarial activity against P. yoelii, with a lower ED90 and a comparable ED50 for ART. Compared with pure ART, a higher exposure of ART was found in both parasites and infected mice (parasitemia of ∼10.0%) when treated with equivalent ART in AAE; however, as the infection progressed (parasitemia of ∼20%), comparable pharmacokinetic profiles of ART were revealed. AAE could inhibit the CAR/PXR-Cyp3a metabolic pathway. Chrysosplenetin was identified as a target synergistic component for ART.

CONCLUSION

Synergistic antimalarial effects of an A. annua extract on ART only occurred at the early stage of infection, possibly through modulation of ART absorption/metabolism in host. The flavonoid chrysosplenetin was identified as a synergistic component. The non-standardization of A. annua plant/extracts and different infection status indicated the careful use of A. annua for malaria treatment.