Neuropharmacological study of aged MAM-treated rats.

After evaluation of activity in an open field, norepinephrine (NE), serotonin (5HT), 5-hydroxyindolacetic acid (5HIAA), homovanillic acid (HVA), and choline acetyltransferase (CAT) were investigated in cortex of 26-month-old rats poisoned with methylazoxymethanol (MAM) as compared to control rats of the same age. NE and 5HT concentrations showed a marked increase, but levels were normal when expressed as total content, just as in MAM-exposed young adults. Concentrations of 5HIAA were also increased but to a lesser extent than 5 HT. Aged MAM rats did not show any modification of spontaneous activity although hyperactivity is characteristic of young adults exposed to MAM. Together with this behavioral observation, a significant decrease in total HVA content was measured. Because HVA levels seem correlated with activity in MAM-exposed rats, we speculate that the behavioral abnormality recovers in old age. Total CAT activity was also reduced. These results indicate that the neurochemical pattern of young adult MAM-poisoned rats is conserved in aged rats except for some changes in the dopaminergic and cholinergic systems.

Evaluation of first pass effect and biliary excretion of diperdipine in the dog.

Intravenous, oral and intraportal doses of diperdipine were given to bile duct cannulated dogs in order to assess the impact of first pass effect on the pharmacokinetics of this compound. After intravenous and oral doses, absolute bioavailability was calculated to be 18.7%. Biliary excretion accounted for about 0.1% of the total clearance of diperdipine and did not contribute to the overall elimination of the drug. After intraportal administration, the bioavailable fraction of diperdipine was increasing up to 44.3% suggesting a prehepatic site of loss of the drug. This was also substantiated by the fact that after oral administration a lesser fraction was excreted in the bile, than after the intraportal dose. The drug was highly bound to plasma proteins (greater than 96%) and was largely distributed in the blood cells for which a concentration dependent process was observed.

Pharmacokinetics of (-)-folinic acid after oral and intravenous administration of the racemate.

1. A pharmacokinetic study of the natural (-)-isomer of folinic acid ((-)-5 CHOTHF) and of total (-)-folates was performed in 12 healthy subjects after i.v. and oral administration of the racemic form of folinic acid. 2. After a 25 mg i.v. injection, (-)-5 CHOTHF kinetics were described by a biexponential function. The mean steady state volume of distribution (Vss) was 161; systemic and renal clearances averaged 335 and 53 ml min-1, respectively. After the same oral dose, (-)-5 CHOTHF was rapidly absorbed. Plasma concentrations of unchanged drug were much lower than those achieved after i.v. administration but in nine subjects, the disposition kinetics were also biexponential. Absolute bioavailability was only 4% as a consequence of a significant intestinal first pass effect. 3. AUC and t1/2Z values for total (-)-folates were similar after both routes of administration, indicating that the drug was fully absorbed. However the AUC of the active metabolite after i.v. dosage was only half that after oral dosage. 4. The amounts of total (-)-folates excreted in urine after both routes of administration were not significantly different and averaged one third of the dose after 24 h, whereas excretion of (-)-5 CHOTHF was three times less after oral treatment than after parenteral treatment. 5. Oral administration is a more suitable route for folinic acid therapy because more of the active metabolite is produced than after parenteral injection.

High performance liquid chromatography of a new 1,4-dihydropyridine: applications to pharmacokinetic study in dogs.

A new nitrendipine derivative [ethyl-2-(1-piperidino)ethyl-1,4-dihydro-2,6-dimethyl-4-(3-nitrophenyl)- 3,5-pyridine dicarboxylate hydrochloride;1] was assayed in plasma by high-performance liquid chromatography. After deproteinization and extraction, 1 and nitrendipine, as the external standard, were separated by ion-pair chromatography and measured by UV detection (254 nm). The method is rapid and specific: the limit of sensitivity of the assay was 5 ng/mL and the concentration range was linear between 5 and 2000 ng/mL. In vitro studies showed that, in contrast to nifedipine and nicardipine, 1 and nitrendipine were stable when exposed to light for at least 4 h. Pharmacokinetic parameters obtained in three beagle dogs after oral and intravenous administration are reported. Comparison with a nicardipine pharmacokinetic study showed similar results for the distribution and elimination characteristics of these two drugs.