Twenty-nine overweight schizophrenic patients maintained on depot neuroleptic injections who wished to lose weight took part in a double-blind, placebo-controlled trial of 30 mg D-fenfluramine. All subjects received dietary advice. Sixteen patients completed the 12-week trial. Rate of weight loss was significantly greater in those taking D-fenfluramine. Side-effects were reported, but no deterioration in mental state was noted.
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.
The pharmacokinetics of high-dose fotemustine followed by autologous bone-marrow transplantation during a phase I-II clinical trial in 24 patients with glioblastoma or astrocytoma (grade III-IV) was investigated. Plasma levels of fotemustine were determined by high-performance liquid chromatography (HPLC) and UV detection. The metabolite, 2-chloroethanol, was simultaneously followed in six patients by gag liquid chromatography and electron capture detection (GLC-ECD) assay. The drug was given as a 1-h infusion on 2 consecutive days. In all, 40 pharmacokinetic determinations of fotemustine were made at dose levels ranging from 2 x 300 to 2 x 500 mg/m2. Plasma drug elimination was best described by a bi-exponential model, with short distribution and elimination half-lives of 4.15 +/- 2.57 and 28.8 +/- 12.1 min being observed, respectively. No significant difference in half-lives or clearance was seen between the first and the second administration. During dose escalation, the mean area under the concentrationtime curve (AUC) increased from 5.96 +/- 2.89 to 12.22 +/- 3.95 mg l-1 h. Drug clearance was independent of the dose given and equal to 109 +/- 65 l/h, indicating no possible saturation of metabolism and elimination mechanisms at these high-dose levels. The metabolite 2-chloroethanol appeared very early in plasma samples. Its elimination was rapid and rate-limited by the kinetics of the parent compound, giving the same apparent terminal half-life. A close relationship between AUC and C45 values was evidenced (r = 0.890). Associated with the stability of fotemustine kinetic parameters, this could be used in future studies for individual dose adjustment, particularly for high-dose fractionated regimens.
1. An analytical method for a novel nitrosourea, fotemustine, has been developed using solid-phase extraction and h.p.l.c. with u.v. detection. As part of the development, different methods for stabilising fotemustine after sample collection have been investigated. The method has been successfully applied to pharmacokinetic studies in monkeys and man. 2. Providing plasma was separated immediately from blood and frozen within 3 min of collection, negligible degradation of fotemustine occurred. The samples could then be stored at -20 degrees C in the dark for up to six days particularly if thawing prior to analysis was accelerated using a 50 degrees C water-bath so that it was complete within 3 min. Equivalent results were also obtained with samples stabilised with 0.1 M citric acid immediately after the preparation of plasma. 3. The analytical method showed good precision with a within-day variation ranging between +/- 10.7% at the lowest concentration investigated (0.1 micrograms ml-1) to 2.0% at 50.0 micrograms ml-1. The accuracy of measurement was from 108.9% to 97.6% at 0.1 and 50.0 micrograms ml-1 respectively and the response was linear up to 50 micrograms ml-1. The minimum level of quantitation was 20 ng ml-1. 4. After a single intravenous bolus dose of [14C]fotemustine (100 mg m-2) to Cynomolgus monkeys, intact drug levels rapidly declined (t1/2 12.6 +/- 0.5 min) although the half-life of radioactivity (approx 100 h) was much longer. The plasma clearance of fotemustine was 225 +/- 63 ml min-1 with a volume of distribution based on area of 4.1 +/- 1.2 litres. 5. As with monkey, plasma levels of intact fotemustine in a patient given [14C]-drug as a 1 h constant rate intravenous infusion (approx. 100 mg m-2), declined rapidly but with a half-life of 23.2 min. Again, the half-life for total radioactivity was considerably longer (30.8 h). The plasma clearance was 1426 ml min-1 and the volume of distribution based on area was 47.71.
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