Quantitative in vivo and in vitro sex differences in artemisinin metabolism in rat

Abstract

1. The pharmacokinetics of the antimalarial compound artemisinin were compared in the male and female Sprague-Dawley rat after single dose i.v. (20 mg x kg(-1)) or i.p. (50 mg x kg(-1)) administration of an emulsion formulation. 2. Plasma clearance of artemisinin was 12.0 (95% confidence interval: 10.4, 13.0) 1 x h(-1) x kg(-1) in the male rat and 10.6 (95% CI: 7.5, 15.0) 1 x h(-1) x kg(-1) in the female rat suggesting high hepatic extraction in combination with erythrocyte uptake or clearance. Artemisinin half-life was approximately 0.5 h after both routes of administration in both sexes. Values for plasma clearance and half-lives did not statistically differ between the sexes. 3. After i.p. administration artemisinin AUCs were 2-fold higher in the female compared with male rat (p < 0.001). Artemisinin disappearance was 3.9-fold greater in microsomes from male compared with female livers and it was inhibited in male microsomes by goat or rabbit serum containing antibodies against CYP2C11 and CYP3A2 but not CYP2B1 or CYP2E1. 4. The unbound fraction of artemisinin in plasma was lower (p < 0.001) in plasma obtained from the male (8.8 +/- 2.0%) compared with the female rat (11.7 +/- 2.2%). 5. The possibility of a marked sex difference, dependent on the route of administration, has to be taken into account in the design and interpretation of toxicological studies of artemisinin in this species.

Antimalarial Artemisinin Drugs Induce Cytochrome P450 and MDR1 Expression by Activation of Xenosensors Pregnane X Receptor and Constitutive Androstane Receptor

“…Activation of human CAR requires the same range of concentration as PXR; however, EC 50 could not be calculated accurately because of the small effect on CAR activity in vitro. Because animal and human studies have indicated that artemisinin is eliminated mainly by extensive hepatic extraction (Dien et al, 1997;Ashton et al, 1998;Ashton et al, 1999), it can be assumed that the concentration of artemisinin is considerably higher in the intestinal epithelium and in the liver, which also are the relevant sites of PXR and CAR expression, than in the systemic circulation. In conclusion, activation of PXR and CAR most probably represents the molecular mechanism of induction by artemisinin.…”

Characterisation of the human liver in vitro metabolic pattern of artemisinin and auto‐induction in the rat by use of nonlinear mixed effects modelling

“…It is not known which enzymes that are important in the metabolism of artemisinin in the rat. The involvement of CYP2C11 and CYP3A2 has been tentatively suggested [16]. Artemisinin intrinsic clearance in rat microsomes pre-treated with the same artemisinin regimen as in this study, was estimated to be 8-fold higher compared with controls [17], corresponding to a 8-fold decrease in bioavailability assuming a high extraction ratio over the liver, constant hepatic blood flow and protein binding.…”

Establishment of anIn Vitro screening model for neurodegeneration induced by antimalarial drugs of the artemisinin-type

“…Half-lives were 2 h in humans, 1-2 h in dogs and 30 min in rats (Ashton et al, 1999;Dien et al, 1997. One plausible explanation for the species sensitivity were given by Ashton et al, 1999 which described a marked sex difference in rats based on a different liver P 450 enzyme pattern in male and in female rats. These variations very also obvious between species.…”