THE PHARMACOKINETICS OF DEXFENFLURAMINE IN OBESE AND NONOBESE SUBJECTS

The pharmacokinetics of dexfenfluramine (d-F) and its metabolite dexno rfenfluramine (d-NF) were compared in 10 obese (145 +/- 13 s.d. % of i deal body weight (IBW)) and 10 non-obese healthy volunteers (93 +/- 8% IBW). Each group included five men and five women, aged 28 +/- 8 year s. Subjects were given single doses of d-F i.v. (15.5 mg base infused over 3 h) and orally (25.9 mg base in capsules) on separate occasions. After i.v. infusion in obese subjects, the volume of distribution (V- ss) of d-F was significantly higher (969.7 +/- 393.3 1; 95% CI 688.6-1 250 1) than in controls (668.7 +/- 139.6 1; 95% CI 568.9-768.5 1; P < 0.01). Clearance was not significantly different (43.9 +/- 21.0 1 h(-1 ) vs 37.3 +/- 10.6 1 h(-1)) and the terminal half-life tended to be lo nger (17.8 +/- 9.4 vs 13.5 +/- 3.9 h NS). Combined data from the two g roups indicated a positive correlation between V-ss and % IBW (r = 0.5 44; P < 0.02), The oral bioavailability of d-F was 0.61 +/- 0.15 in ob ese subjects and 0.69 +/- 0.11 in controls. There was no significant d ifference between obese subjects and controls in C-max, t(max) and t(1 /2,z) (C-max: 20.1 +/- 6.7 and 27.3) 6.2 mu g l(-1); t(max): 3.5 vs 3. 0; t(1/2,z): 16.5 +/- 7.1 vs 14.5 +/- 2.6 h respectively). The AUC rat io expressed in molar units for d-F/d-NF was 2.29 +/- 1.78 (i.v.) vs 1 .25 +/- 0.64 (oral) in obese subjects and 2.05 +/- 1.26 (i.v.) vs 1.40 +/- 0.87 (oral) in controls. Thus d-F has a high clearance with a lar ge tissue distribution in both excess lipid and lean tissues and V-ss varies directly and significantly with body weight. The clinical signi ficance of these data is not known.