tolerance Granisetron (BRL 43694) is a potent 5-HT~ receptor antagonist which, at doses of 40 ggkg 1, is effective for the treatment of emesis induced by cytotoxic chemotherapeutic agents [1][2][3][4]. Preliminary examination of its pharmacokinetics in healthy young volunteers over the intravenous dose range 30-300 gg-kghas shown that granisetron is extensively distributed (Vz-~ 3 1. kg 1) and rapidly eliminated in most subjects, with a mean total plasma clearance (predominantly non-renal) of 30-50 1. h-1 and terminal phase half-life of about 5 h [5,6]. The present study was conducted to evaluate any difference in the pharmacokinetics of granisetron between young and elderly volunteers. Patients and methodsTwenty young adults [mean (range) age 29.5 (18 to 45) years, mean (range) weight 63.5 (49 to 82) kg] and twenty elderly adults aged above 65 years [where 50% were older than 70 years; mean age 71.1 years, mean (range) weight 63.8 (43 to 82) kg at two centres, balanced between the centres for both gender and age were included in the study. Granisetron (40 ug/kg as a solution in 0.9% saline) was administered to all subjects by intravenous infusion into a forearm vein, after an overnight fast. Plasma samples were obtained by centrifugation from blood samples taken predose, at the end of infusion (3 min), 10, 20, 30, 45 min and 1, 1.5, 2, 3, 4, 6, 8, 12, 16, 24, 30 and 48 h after the start of the infusion for plasma drug assay. Urine samples were taken predose, and at 0 2, 2-4, 4-8, 8 12, 1~24 and 24-48 h after the start of the infusion. All samples were stored at approximately -20 °C until analysed.All plasma and urine samples were analysed for granisetron using a specific reversed phase HPLC method with fluorimetric detection [7]; sensitivity 0.1 ng-ml -~ (plasma) and 0.5ng.ml -~ (urine), and coefficient of variation and accuracy generally within 10%. Pharmacokinetic parameters (C .... AUG, CL, Vz, t~j2, MRT, Ae48 and CLR) for granisetron were calculated by model-independent methods [8] and compared between young and elderly subjects by analysis of variance, before and after logarithmic transformation. Results and conclusionsIn the elderly, volume of distribution (4.0 (1.4) l'kg -1) was significantly higher than in the young (3.0 (1,1) 1 kg 1; Table 1), In addition, there was, in the elderly, an approximately 45% reduction in mean (S.D.) systemic clearance compared to values in younger subjects, though this difference was only statistically significant when data were not log-transformed. Consequently values of terminal phase half-life and mean residence time (MRT) were overall about 57% and 46%, respectively, longer in the elderly than in the young subjects. The lower clearance in the elderly was associated with a somewhat higher mean area under the plasma concentration-time curve, AUC, (115 (52.2) ng h m1-1) than in the young (89.7 (58.8) ng h ml 1), though this difference was not statistically significant. C .... extent of urinary excretion and renal clearance were unaffected by age. Despite the observed diff...