Ro 42-1611 (
arteflene) is a new synthetic structural analogue of
yingzhaosu, a Chinese traditional herbal
drug, now under development for treatment of
malaria. The in vivo activity of
arteflene in a mouse animal model was 4-5 fold higher after parenteral than after
oral administration. Pharmacokinetics of the
drug were investigated in mice, rats, dogs, marmosets and cynomolgus monkeys. Plasma concentrations of
arteflene were determined using a specific HPLC-UV method; the limit of quantification was 45 ng/ml using 0.5 ml plasma. The oral bioavailability was very low and variable (0.6% in mice, 4-5% in rats, 2.5 +/- 1% in dogs, < or = 0.5% in marmosets and < 0.5% in cynomolgus) as expected from the high metabolic clearance and the relative short apparent half-life (1.4-4.7 h). However, a metabolite (MA) was observed in plasma of all species indicating that
drug was absorbed but underwent extensive first-pass metabolism. MA was also detected in samples of human plasma, collected during an oral tolerability study in healthy volunteers. After incubation of 14C-arteflene with liver microsomes of mice, rats, dogs and humans, the same major metabolite was detected and both samples were identical to Ro 47-6936 which was chemically synthesized as a reference compound. The in vitro activity of Ro 47-6936 was tested against Plasmodium falciparum and found to be about 1/4 that of the parent
drug. Therefore, this metabolite makes a significant contribution to the
biological activity in vivo, partially explaining the high activity of
arteflene after
oral administration in spite of its low bioavailability. Moreover, comparison of the metabolic patterns from human, rat and dog microsomes indicated that the dog is an appropriate species for toxicological evaluations.