THE PHARMACOKINETIC BEHAVIOR OF HYPOXOSIDE TAKEN ORALLY BY PATIENTS WITH LUNG-CANCER IN A PHASE-I TRIAL

Objective. To study the pharmacokinetic behaviour of hypoxoside taken orally by 24 patients with lung cancer. Design. Randomised open study with three single doses of 1 600, 2 400 and 3 200 mg standardised Hypo xis plant extract (200 mg capsules) and a multiple-dose study on the f irst 6 patients taking 4 capsules 3 times daily for 11 days, Participa nts and setting. Patients with histologically proven squamous, large-c ell or adenocarcinoma were hospitalised at the Radiation Oncology Ward , Karl Bremer Hospital, Bellville, W. Cape. Methods. Blood was drawn a t regular intervals up to 75 hours after single doses and the concentr ations of metabolites of the aglucone of hypoxoside, rooperol, were me asured with a high-performance liquid chromatography method, For the m ultiple-dose study blood was drawn before the first dose each day, Con centration-time relationships were analysed according to a conventiona l single open-compartment model and also by using the NONMEM digital c omputer programme, Results. Neither hypoxoside nor rooperol appear in circulation, This is due to complete phase II biotransformation to dig lucuronide, disulphate and mixed glucuronide-sulphate metabolites, of which the latter is the major component, Considerable interpatient var iation in concentration-time relationships was found in the single-dos e studies, It was due to an active enterohepatic recirculation in some patients and a distinct lag phase in others together with zero-order rate of formation of rooperol in the colon, Computer modelling indicat ed a single open-compartment model in which the mass of the patient di d not influence volume of distribution and clearance because formation of the metabolites is dependent on the metabolising capacity of the p atient, However, the elimination of the metabolites follows first-orde r kinetics with half-lives ranging from 50 hours for the major metabol ite to 20 hours for-the two minor metabolites, Multiple-dose studies a lso showed large interpatient variation. Conclusion. In order to reach metabolite levels near 100 mu g/ml, which have been shown to be tumou ricidal after enzymatic deconjugation to rooperol, maintenance doses n eed to be individualised for each patient, For most patients, however, a daily dose of 2 400 mg was sufficient.