Effects of L-fenfluramine on rat liver drug-metabolizing enzymes.

The kinetics of l-fenfluramine (l-F) are dose-dependent in man and rats, suggesting self-inhibition of metabolism and saturation of microsomal enzymes. Possible alterations in the oxidative metabolism of model drug substrates were therefore evaluated in rats given l-F orally (12.5 mg/kg). The compound slightly impaired the clearance of antipyrine but had no effect on the kinetics of highly extracted compounds such as lidocaine. l-F did not alter the hepatic content of the main components of the cytochrome P-450 system and did not affect the in vitro metabolism of enzyme activity markers, even after daily doses of 12.5 mg/kg. It was concluded that at doses with dose-dependent behaviour l-F may impair clearance of drugs such as antipyrine and that this interaction most probably occurs through inhibition of specific isoenzymes involved in the metabolism of the test substrate.

Effect of chronic oral delorazepam on in vitro and in vivo hepatic drug-metabolizing enzyme activities in the rat.

In vivo (delorazepam clearance) and in vitro (monooxygenase activity markers) alterations in drug metabolism and the extent of enzyme induction of the hepatic cytochrome P-450 system were evaluated after oral administration of delorazepam (2.5, 25 and 150 mg/kg) for two weeks to male Sprague-Dawley rats. This benzodiazepine had no significant effect on drug metabolizing enzymes, except for slight enhancement of in vitro aniline p-hydroxylase activity which occurred at doses approximately 100 times those used clinically (0.5-2 mg). Under the likely conditions of exposure to delorazepam in human therapy therefore, such alteration in liver enzymes would be unlikely to have clinical relevance.

Kinetics of MK-801 and its effect on quinolinic acid-induced seizures and neurotoxicity in rats.

MK-801 [(+)-5-methyl-10,11-dihydro-5H-dibenzo(a,d)cyclo-hepten-5,10-imine maleate], a noncompetitive antagonist of the N-methyl-D-aspartate-type of excitatory aminoacid receptors, was measured in plasma and brain tissues after i.p. administration to rats by using a novel high-performance liquid chromatography assay. The drug reached maximal concentrations in plasma and brain within 10 to 30 min of injection (2 mg/kg) with an elimination half-life of 1.9 and 2.05 hr, respectively. Mean ratio of brain area concentration-time curve to plasma area concentration time curve was 12.5, referring to total plasma concentrations. MK-801 distributed almost equally between plasma and red cells (mean blood-to-plasma ratio averaged 1.2 +/- 0.2 when calculated 30 and 180 min from drug administration). Plasma and brain concentrations of MK-801 rose almost linearly from 0.5 to 4 mg/kg 30 min after injection and the brain-to-plasma ratio (12.9 +/- 2.8) was constant in the dose range studied. The distribution of the drug in various brain regions 30 and 180 min after 2 mg/kg i.p. showed no preferential concentration or retention in any of the areas studied. The anticonvulsant effect of MK-801 was evaluated against limbic seizures (measured by EEG) induced by intrahippocampal injection of 120 nmol of quinolinic acid, an agonist of the N-methyl-D-aspartate-type receptors, in freely moving rats. At 0.25 and 0.5 mg/kg, MK-801 significantly lowered by 71 to 77% the number of seizures and by 80% the total time spent in seizures (P less than .01).(ABSTRACT TRUNCATED AT 250 WORDS)