The influence of the sparteine/debrisoquine genetic polymorphism on the disposition of dexfenfluramine

1 To determine whether dexfenfluramine is a substrate of cytochrome P450 2D6 (CYP2D6), its disposition has been studied in nine extensive (EM) and eight poor metabolizers (PM) of debrisoquine. 2 Following a 30 mg dose of dexfenfluramine hydrochloride, urine was collected in all subjects for 96 h post-dose and plasma samples were collected in 11 subjects (six EMs and five PMs). Dexfenfluramine and nordexfenfluramine were measured in urine by h.p.l.c. and in plasma by g.c. 3 Urinary recovery of dexfenfluramine was greater in PMs than EMs (4136+/-1509 mu g vs 1986+/-792 mu g; 95% CI of difference 926-3374; P<0.05) whereas that of nordexfenfluramine was similar in both phenotypes (PM: 1753+/-411 mu g vs 1626+/-444 mu g), 4 Dexfenfluramine AUC was higher in PMs (677+/-348 mu g l(-1) h) than EMs (359+/-250 mu g l(-1) h). The apparent oral clearance of dexfenfluramine was greater in EMs than PMs (93.6+/-42.4 l h(-1) vs 45.6+/-19.5 l h(-1); 95% CI of difference 1.2-94.7; P<0.05). The renal clearance was similar in both phenotypes (EMs: 5.88+/-2.83 l h(-1); PMs 6.60+/-2.01 l h(-1)), indicating that the higher urinary recovery of dexfenfluramine in PMs reflects higher plasma concentrations, rather than phenotype differences in the renal handling, of dexfenfluramine. 5 The apparent nonrenal clearance of dexfenfluramine was substantially lower (P<0.05; 95% CI of difference 3.0-94.1) in PMs (39.0+/-19.5 l h(-1)) than EMs (87.6/-41.2 l h(-1)). 6 There was a significant inverse correlation (r(s)=-0.776 95% CI -0.31--0.94; n=11; P=0.005) between the debrisoquine metabolic ratio and the apparent nonrenal clearance of dexfenfluramine. 7 PMs had a higher incidence of adverse effects (nausea and vomiting) than EMs. 8 In conclusion, the metabolism of dexfenfluramine is impaired in PMs. Thus CYP2D6, the isoenzyme deficient in poor metabolizers of debrisoquine, must catalyse at least one pathway of dexfenfluramine biotransformation.