Tags

Type your tag names separated by a space and hit enter

Comparison of the effects of repeated oral versus subcutaneous fenfluramine administration on rat brain monoamine neurons: pharmacokinetic and dose-response data.
Pharmacol Biochem Behav. 1991 Aug; 39(4):963-9.PB

Abstract

The importance of the route of drug administration (oral vs. subcutaneous) on the neurochemical effects and pharmacokinetics of repeated d,1-fenfluramine administration in rats (1-24 mg/kg b.i.d., i.e., 2-48 mg/kg/day for 4 days) was examined. Overall, comparable dose-dependent alterations in brain monoamine markers were observed following repeated oral (PO) and subcutaneous (SC) administration of fenfluramine. Doses of 1 and 2 mg/kg fenfluramine were without significant effects on the density of 3H-paroxetine-labeled serotonin (5-HT) uptake sites. Higher doses of fenfluramine (4, 12 and 24 mg/kg) produced dose-dependent decreases in 5-HT, 5-hydroxyindoleacetic acid and 5-HT uptake sites with maximal decreases (80-90%) occurring at the 12 mg/kg dose. Fenfluramine administration produced dose-dependent and biphasic effects on brain dopamine markers with increases in homovanillic acid (HVA) observed at 2 hours, whereas decreases in the levels of dopamine, HVA and dihydroxyphenylacetic acid were evident at 18 hours posttreatment. Norepinephrine levels were only decreased at the highest dose of fenfluramine. Significantly higher levels of brain fenfluramine were observed following SC than following PO administration of the drug. On the other hand, comparable levels of its active metabolite norfenfluramine were present in the brain following the two routes of fenfluramine administration. These data suggest the importance of norfenfluramine levels in the brain in determining the high-dose neurotoxic effects of fenfluramine on brain 5-HT neurons in rats.

Authors+Show Affiliations

Neurobiology Laboratory, National Institute on Drug Abuse, Baltimore, MD 21224.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Comparative Study
Journal Article
Research Support, U.S. Gov't, P.H.S.

Language

eng

PubMed ID

1763116

Citation

De Souza, E B., et al. "Comparison of the Effects of Repeated Oral Versus Subcutaneous Fenfluramine Administration On Rat Brain Monoamine Neurons: Pharmacokinetic and Dose-response Data." Pharmacology, Biochemistry, and Behavior, vol. 39, no. 4, 1991, pp. 963-9.
De Souza EB, Zaczek R, Culp S, et al. Comparison of the effects of repeated oral versus subcutaneous fenfluramine administration on rat brain monoamine neurons: pharmacokinetic and dose-response data. Pharmacol Biochem Behav. 1991;39(4):963-9.
De Souza, E. B., Zaczek, R., Culp, S., Appel, N. M., & Contrera, J. F. (1991). Comparison of the effects of repeated oral versus subcutaneous fenfluramine administration on rat brain monoamine neurons: pharmacokinetic and dose-response data. Pharmacology, Biochemistry, and Behavior, 39(4), 963-9.
De Souza EB, et al. Comparison of the Effects of Repeated Oral Versus Subcutaneous Fenfluramine Administration On Rat Brain Monoamine Neurons: Pharmacokinetic and Dose-response Data. Pharmacol Biochem Behav. 1991;39(4):963-9. PubMed PMID: 1763116.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Comparison of the effects of repeated oral versus subcutaneous fenfluramine administration on rat brain monoamine neurons: pharmacokinetic and dose-response data. AU - De Souza,E B, AU - Zaczek,R, AU - Culp,S, AU - Appel,N M, AU - Contrera,J F, PY - 1991/8/1/pubmed PY - 1991/8/1/medline PY - 1991/8/1/entrez SP - 963 EP - 9 JF - Pharmacology, biochemistry, and behavior JO - Pharmacol Biochem Behav VL - 39 IS - 4 N2 - The importance of the route of drug administration (oral vs. subcutaneous) on the neurochemical effects and pharmacokinetics of repeated d,1-fenfluramine administration in rats (1-24 mg/kg b.i.d., i.e., 2-48 mg/kg/day for 4 days) was examined. Overall, comparable dose-dependent alterations in brain monoamine markers were observed following repeated oral (PO) and subcutaneous (SC) administration of fenfluramine. Doses of 1 and 2 mg/kg fenfluramine were without significant effects on the density of 3H-paroxetine-labeled serotonin (5-HT) uptake sites. Higher doses of fenfluramine (4, 12 and 24 mg/kg) produced dose-dependent decreases in 5-HT, 5-hydroxyindoleacetic acid and 5-HT uptake sites with maximal decreases (80-90%) occurring at the 12 mg/kg dose. Fenfluramine administration produced dose-dependent and biphasic effects on brain dopamine markers with increases in homovanillic acid (HVA) observed at 2 hours, whereas decreases in the levels of dopamine, HVA and dihydroxyphenylacetic acid were evident at 18 hours posttreatment. Norepinephrine levels were only decreased at the highest dose of fenfluramine. Significantly higher levels of brain fenfluramine were observed following SC than following PO administration of the drug. On the other hand, comparable levels of its active metabolite norfenfluramine were present in the brain following the two routes of fenfluramine administration. These data suggest the importance of norfenfluramine levels in the brain in determining the high-dose neurotoxic effects of fenfluramine on brain 5-HT neurons in rats. SN - 0091-3057 UR - https://www.unboundmedicine.com/medline/citation/1763116/Comparison_of_the_effects_of_repeated_oral_versus_subcutaneous_fenfluramine_administration_on_rat_brain_monoamine_neurons:_pharmacokinetic_and_dose_response_data_ DB - PRIME DP - Unbound Medicine ER -