Metabolism of 6-fluoro-DL-tryptophan and its specific effects on the rat brain serotoninergic pathway.

We administered 6-fluoro-DL-tryptophan (6F-Trp) to rats (50-200 mg/kg i.p.) and evaluated its neurochemical effects on central catechole and indole compounds; we also determined the time course of its action, together with its metabolism and kinetics in four rat brain areas. Neither norepinephrine nor dopamine and its major metabolites were affected by 6F-Trp. With regard to serotonin (5-HT), 6F-Trp induced a transient depletion in all the brain areas studied, with a maximum of about 60-65% obtained between 1 and 3 hr depending on the dose administered. After 6 hr, 5-HT levels generally returned to control values. 5-Hydroxyindolacetic acid (5-HIAA) levels were also reduced 3 hr after administration (-40 to -60%). A large dose-dependent increase in tryptophan (Trp) was observed in the four brain areas, possibly because of an inhibition of Trp incorporation into protein, as suggested by experiments with mouse neuroblastoma cells. The brain elimination half-life of 6F-Trp was estimated at 0.5-1 hr. Regarding 6F-Trp metabolism, three new compounds were detected in all four brain areas after 6F-Trp administration. They were identified by means of liquid chromatography with electrochemical detection and/or radioenzymology, in comparison with fluorinated standards, or after NSD 1015 or pargyline coadministration with 6F-Trp. The first two 6F-Trp metabolites detected were probably 6-fluoro-5-hydroxytryptophan and 6-fluoro-5-HIAA. The third, identified and quantified by means of the two analytical methods, was 6-fluoro-5-HT (6F-5-HT). These findings suggest that 6F-Trp could be used as the in vivo precursor of 6F-5-HT with a view to tracing neuronal serotoninergic pools, as has already been done with platelets.

Pharmacokinetic studies of N-butyric acid mono- and polyesters derived from monosaccharides.

The pharmacokinetics of seven butyric esters derived from monosaccharides were studied after iv administration of a bolus dose to rabbits. Results obtained showed that a constant plasma level of butyric acid is maintained due to the slow disappearance of butyric acid esters from the plasma in contrast to the case of salts, such as arginine butyrate, which are rapidly cleared. The maintenance of these covalent compounds in the body can increase concentrations of n-butyric acid in the tumor area for more efficient chemotherapy. These results seem to be directly related to the in vitro anticellular activity of butyric esters and the prolonged therapeutic protection in tumor-bearing animals.

Extrahepatic metabolism of propofol in man during the anhepatic phase of orthotopic liver transplantation.

We have investigated extrahepatic metabolism of propofol in 10 patients undergoing orthotopic liver transplantation (group 1) (mean age 38 yr, mean weight 60 (SD 7) kg) and compared it with that in 10 patients without liver dysfunction undergoing extrahepatic abdominal surgery (group 2) (mean age 56 yr, mean weight 68 (11) kg). A single i.v. bolus dose of propofol 0.5 mg kg-1 was injected into a peripheral vein 5 min after the beginning of the anhepatic phase in group 1 and 60 min after the induction of anaesthesia in group 2. Arterial blood samples were obtained at 5, 10, 15, 20, 30, 40, 50 and 60 min after injection and urine samples were collected every 15 min. Propofol concentrations in whole blood and urine were measured by high performance liquid chromatography with fluorescence detection. Propofol glucuronide was measured in urine by incubation with a specific beta-glucuronidase. The area under the time-blood concentration curve from 0 to 60 min was found to be significantly greater in group 1 (13743 (2830) micrograms litre-1 h-1) than in group 2 (7992 (4895) micrograms litre-1 h-1) (P less than 0.05). Unchanged propofol was not detected in the urine of either group. No significant difference was found in the amount of propofol glucuronide excreted by patients in group 1 (457 (269) micrograms) and in group 2 (921 (672) micrograms). The presence of a propofol metabolite in urine when the liver was excluded from the circulation suggests that extrahepatic metabolism occurred.

Biogenic amines in newly-ecdysed cockroaches.

1. Simultaneous quantification (HPLC and electrochemical detection) of biological extracts have shown dopamine, N-acetyl dopamine, tryptophan, 5-hydroxytryptamine, a 5-hydroxyindolacetic acid-like substance in nervous tissue and hemolymph of Blaberus craniifer and Periplaneta americana. 2. 5-Hydroxytryptophan was only detected in head and thoraco-abdominal nerve cord. 3. Octopamine, but not N-acetyl-5-HT was quantified in the hemolymph.

Acebutolol and diacetolol plasma levels in patients undergoing myocardial revascularization with hypothermic cardiopulmonary bypass.

Cardiopulmonary bypass (CPB) has been reported to alter the disposition of numerous drugs and consequently to modify their plasma levels. The present study was designed to delineate the time course of acebutolol (a cardioselective beta-blocker) and diacetolol (its main metabolite) plasma levels in seven patients undergoing myocardial revascularization with hypothermic CPB. All patients were given oral acebutolol twice daily until 3 hours before surgery. Initiation of CPB produced an immediate and significant, but transient, decrease in acebutolol and diacetolol plasma concentrations. Cessation of CPB was not associated with an increase in plasma beta-blocker levels. It is concluded that CPB does not induce major alterations in the time course of acebutolol and diacetolol plasma concentrations.