The Measurement ofD-Fenfluramine and Its Metabolite,D-Norfenfluramine in Plasma and Urine with an Application of the Method to Pharmacokinetic Studies

Abstract

1. A specific and sensitive gas chromatographic assay is described for the measurement of d-fenfluramine and its de-ethylated metabolite, d-norfenfluramine, in biological fluids, together with some data on its application to the oral pharmacokinetics of the drug. 2. The analytical method developed has advantages over the previously described methods since it uses nitrogen specific detection and, when applied routinely, enables smaller sample volumes to be used (typically 1 ml of plasma) with a shorter chromatography time and an improved sensitivity (minimum quantifiable level of 2.5 ng ml-1). 3. Peak plasma concentrations of 22 and 24 ng ml-1 of intact drug were reached at 4 h after an oral dose of 14C-d-fenfluramine hydrochloride (30 mg) given to two volunteers as part of a metabolism and disposition study. Subsequently, concentrations of intact drug declined monoexponentially with a half-life of approximately 13 h. Peak concentrations of 10 and 8 ng ml-1 of the metabolite, d-norfenfluramine, were reached after 4 and 6 h and were maintained as a plateau for a further 4-6 h. Assessment of the half-life of the metabolite could not be made because of lack of data on the terminal portion of the curves. 4. The urinary excretion of d-fenfluramine (6.0 and 10.6% of the dose) and d-norfenfluramine (5.8 and 8.8% of the dose) was low, indicating extensive metabolism of the parent drug.

Hair analysis for fenfluramine and norfenfluramine as biomarkers for N-nitrosofenfluramine ingestion

“…The detected amounts of Norf are lower than Fen, which could be related at least for two reasons. First, although the patients in this study are suspected to ingest N-Fen rather than Fen and the information concerning its metabolism in human are not available, the reported levels of Fen in human plasma following its oral administration compared to the metabolite, Norf, is much higher [24][25][26]. The second reason possibly related to the difference in the incorporation rates of Fen and Norf into hair where also no reports are available.…”

Lack of effect of hydrocortisone treatment on d -fenfluramine-mediated prolactin release

“…The inter-and intra-assay coe¦cients of variation over the ranges encompassed by the standard curve were 4.8 % and 2.4 % for prolactin and 4.1 % and 2.6 % for cortisol, respectively. d-Fenßuramine and its major metabolite, d-norfenßuramine, were assayed by a modiÞed gas liquid chromatographic technique with a nitrogen / phosphorus detector (Richards et al 1989). The inter-and intraassay coe¦cients of variation for d-fenßuramine were 6.9 % and 6.1 % and for d-norfenßuramine 16.6 % and 6.1 %.…”

Quantitation of dexfenflurainine/d‐norfenfluramine concentration in primate brain using 19F NMR spectroscopy

“…Methods of measuring the DF and dNF concentrations using GC and nitrogen specific detection have been described previously (23). GC was performed by the Poisons Unit at Guy's St. Thomas Hospital Trust (London, UK) on plasma and brain tissue samples taken from 10 widely distributed regions.…”