Metabolism of homoharringtonine, a cytotoxic component of the evergreen plant Cephalotaxus harringtonia

Homoharringtonine (HHT), first isolated from the Chinese evergreen Cephalotaxus harringtonia , has been demonstrated to have a broad antitumor activity in rodents and antileukemic effects in humans. We found that HHT was metabolized to an acid product [HHT‐acid; 2′‐hydroxy‐2′‐(α‐acetic acid)‐6′‐hydroxy‐6′‐methylheptanoyl cephalotaxine] when incubated with either human plasma or mouse plasma in vitro. The conversion was faster, however, in mouse plasma, and was both time‐ and temperature‐dependent. Boiled plasma prevented the conversion of HHT to HHT‐acid, suggesting that the conversion was enzymatically mediated. When mice were given an intravenous (i.v.) injection of HHT (4 mg/kg), the HHT‐acid metabolite was found in both plasma and urine. In mice, HHT‐acid was detected in the plasma within 5 min of the i.v. injection of HHT and declined rapidly thereafter. The initial half‐lives ( t ½α) of HHT and HHT‐acid were 9 and 17 min, respectively. Twenty‐four hours after HHT dosing in mice, approximately 29% of the dose was excreted in the urine as HHT and 20% as HHT‐acid. High‐pressure liquid chromatography and mass spectrometry were used to confirm the identity and quantify HHT and its metabolite, HHT‐acid. The HHT concentration inhibiting 50% of the growth of human leukemic HL‐60 cells was 20 ng/ml, while for HHT‐acid it was 14,500 ng/ml, indicating that the acid form was more than 700 times less cytotoxic than HHT. The lethal dose of HHT affecting 50%(LD 50 ) of mice was 6.7 mg/kg, but HHT‐acid produced no apparent toxic effects at doses up to 280 mg/kg.