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The influence of the sparteine/debrisoquine genetic polymorphism on the disposition of dexfenfluramine
Author(s) -
GROSS A. S.,
PHILLIPS A. C.,
RIEUTORD A.,
SHENFIELD G. M.
Publication year - 1996
Publication title -
british journal of clinical pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.216
H-Index - 146
eISSN - 1365-2125
pISSN - 0306-5251
DOI - 10.1046/j.1365-2125.1996.03178.x
Subject(s) - dexfenfluramine , debrisoquine , fenfluramine , cyp2d6 , medicine , endocrinology , urine , pharmacokinetics , anorectic , pharmacology , chemistry , cytochrome p450 , serotonin , metabolism , body weight , receptor
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 μg vs 1986±792 μg; 95% CI of difference 926–3374; P <0.05) whereas that of nordexfenfluramine was similar in both phenotypes (PM: 1753±411 μg vs 1626±444 μg). 4 Dexfenfluramine AUC was higher in PMs (677±348 μg l −1 h) than EMs (359±250 μg 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.