Clinical pharmacology of homoharringtonine

Clinical pharmacology of homoharringtonine (HHT) were studied in eight patients who received uniformly labeled HHT at 3-4 mg/m² (150 μCi) by continuous 6-hour infusion. The drug and metabolites were quantified by radiochemical and high-performance liquid chromatographic techniques. Computerized nonlinear least-square regression and curve stripping were used to characterize HHT and total [³H]HHT equivalent pharmacokinetics. Unchanged HHT in the plasma declined biphasically, with an α-half-life of 0.5 ± 0.1 hours and a β-half-life of 9.3 ± 1.4 hours. The total clearance of HHT was 177.4 ± 27.7 ml·hour^-1·kg^-1, and the apparent volume of distribution, estimated from the area under the drug concentration versus time curve, was 2.4 ± 0.4 L·kg^-1. Correspondingly, the total [³H]HHT equivalent disappeared from the plasma in a triphasic manner. Compared with the pharmacokinetic parameters of unchanged HHT, the terminal half-life of total ³H was 67.5 ± 7.5 hours, 7.4 times longer; the total clearance was 30.9 ± 3.1 ml·hour^-1·kg^-1, 5.5 times slower; but the volume of distribution by area was 2.7 ± 0.1 L·kg^-1, nearly the same. The 72-hour cumulative urinary excretion of total tritium was 28.2% of the administered dose and only 38.3% of this resided in unchanged HHT. Thus, urinary excretion was not a major route of elimination of HHT. Moreover, HHT underwent extensive metabolism; one major and two minor unidentified products were detected in both plasma and urine.