Biomedical subjects

A Bergami

Publications and source records attributed to A Bergami.

21 records · Page 2Linked to original sources

PubMed1995

Effect of d-fenfluramine on the indole contents of the rat brain after treatment with different inducers of cytochrome P450 isoenzymes.

The effects of pretreatment with inducers of hepatic cytochrome P450 isoenzymes (phenobarbital, dexamethasone and beta-naphthoflavone) on the metabolism of d-fenfluramine (d-F) and its acute and long-lasting indole-depleting effects were studied in rats, in an effort to obtain further information on the importance of hepatic drug metabolism in relation to its neurochemical actions. Twenty-four hours after the last dose of each inducer, rats were injected with d-F hydrochloride (5 mg/kg, IP) and killed at various times thereafter for parallel determination of indoles and drug concentrations in plasma and brain. Additional rats were treated as above and killed 1 week after d-F hydrochloride (5 and 10 mg/kg) to study the recovery of indole in the cortex, a particularly sensitive brain area. Phenobarbital and beta-naphthoflavone and, to a lesser degree, dexamethasone, stimulated the metabolism of d-F, as evidenced by a decrease in plasma and brain areas under the curve (AUC) compared to vehicle-treated rats. This indicated that multiple isoenzymes are capable of mediating the drug's metabolism, primarily by N-dealkylation to d-norfenfluramine (d-NF). None of the inducers raised plasma and brain AUC of the nor-derivative, and in fact phenobarbital and particularly beta-naphthoflavone reduced it. These different effects were even apparent in rats given d-NF (2.5 mg/kg), indicating that both phenobarbital and beta-naphthoflavone also stimulate the sequential metabolism of the nor-metabolite (by N-deamintaion) which, however, is apparently enhanced most actively by beta-naphthoflavone-inducible forms of P-450.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

PubMed1995

Depletion and time-course of recovery of brain serotonin after repeated subcutaneous dexfenfluramine in the mouse. A comparison with the rat.

The indole-depleting effects of repeated subcutaneous doses of dexfenfluramine (D-F) (2.5, 5, 10, 20 and 40 mg/kg/day, for four days) in mice were examined with regard to the initial response and time-course of recovery and related to the pharmacokinetics of D-F and its active metabolite dexnorfenfluramine (D-NF). Steady-state plasma and brain concentrations of D-F rose dose-dependently with a metabolite-to-drug ratio averaging 0.4 in brain. This confirmed that in mice D-NF contributes less than in other species to the effects of D-F. Regional serotonin (5-HT) and 5-hydroxyindoleacetic acid (5-HIAA) contents were decreased dose-dependently 4 hr after the last injection of D-F. However, two weeks after D-F (2.5-10 mg/kg/day) brain indoles had almost totally recovered, and the long-term effects of the 20 mg/kg/day dose were completely reversed by six weeks, when significant effects are still observable in rats. Although substantial recovery was evident even at 40 mg/kg/day, 5-HT but not 5-HIAA was still slightly reduced nine weeks later. Comparative studies in rats given 2.5-20 mg/kg/day D-F indicated much more severe initial indole depletions than in mice. Brain levels of D-F and D-NF were much higher in rats than in mice. The total active drug brain concentration (D-F + D-NF) was significantly correlated with 5-HT content in both species, with approx 20 nmol/g of total drug causing 50% reduction. These findings point to species differences in D-F kinetics as a main reason for differences in the neurochemical response, supporting the view that the recovery of indoles over time is related to the extent of initial depletion, which in turn depends on critical drug brain concentrations. In view of the qualitative and quantitative species differences in the pharmacodynamics and pharmacokinetics of D-F neither of these rodent species is a suitable model for predicting potential drug toxicity in humans.

Animals↗

PubMed1995

Oral kinetics of dexfenfluramine and dexnorfenfluramine in non-human primates.

1. Large doses of dexfenfluramine in animals cause a decrease of serotoninergic markers but none of the species so far investigated shows sufficient kinetic and metabolic similarity with man to be a valid model for safety studies. The plasma kinetics of dexfenfluramine and its active metabolite dexnorfenfluramine were therefore studied in baboon, rhesus and cynomolgus monkeys given dexfenfluramine hydrochloride orally (2 mg/kg) in order to investigate whether any of these primates have a biodisposition particularly similar to man. 2. The drug was rapidly N-deethylated to dexnorfenfluramine achieving comparatively low mean maximum plasma levels (Cmax) of 12-14 ng/ml in all primates, and rapidly disappeared thereafter with half-lives (t1/2) ranging from 2 to 3 h in the baboon and rhesus monkey to 6 h in the cynomolgus monkey. Its normetabolite reached higher mean Cmax (52-97 ng/ml) and the t1/2's were longer, varying from about 11 h in the rhesus monkey to 22 h in the cynomolgus monkey. The metabolite-to-parent drug ratio (14-37), in terms of plasma area under curve (AUC), greatly exceeded that in man (< 1), being higher than in all species investigated so far. 3. Comparative repeat dose simulation in monkey and man indicated that the dosage in primates would need to be increased 10-fold to achieve comparable dexfenfluramine steady-state plasma Cmax, producing nor-metabolite levels several times those in man, whilst for comparable metabolite Cmax, those of the parent drug would be correspondingly too low. 4. In view of the different mechanism of action of dexfenfluramine and dexnorfenfluramine within the serotoninergic system none of these primates is therefore a suitable model for safety assessment in terms of exposure of the active moieties in comparison with man.

Animals↗