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Fenfluramine and norfenfluramine levels in brain microdialysate, brain tissue and plasma of rats administered doses of d-fenfluramine known to deplete 5-hydroxytryptamine levels in brain.
J Pharmacol Exp Ther. 1998 Feb; 284(2):618-24.JP

Abstract

The relationship between dose, frontal cortex (brain) microdialysate and brain tissue levels of fenfluramine (FEN) and norfenfluramine (NF), as well as the effect that these levels have on body temperature, was determined after systemic d-FEN. FEN and NF levels were monitored continuously in the microdialysate of adult male Sprague-Dawley rats dosed with 3 x 5 mg/kg s.c. (spaced 2 hr apart), 1 x 2 mg/kg s.c. or 1 x 10 mg/kg i.p. d-FEN (at ambient temperatures of either 23 degrees C or 27 degrees C). Drug concentrations in plasma and brain regions were also determined 1 hr after one or three doses of 5 mg/kg of d-FEN and 1 and 8 hr after 10 mg/kg d-FEN, and the levels of 5-hydroxytryptamine and 5-hydroxyindole acetic acid in the frontal cortex of FEN and controls were determined 4 days after dosing. Peak microdialysate FEN levels, occurring between 40 and 60 min after the first dose, were 0.24 +/- 0.07 microM after 2 mg/kg, 0.33 +/- 0.04 microM after 5 mg/kg and 1.65 microM after 10 mg/kg. After multiple doses of 5 mg/kg FEN the time-to-peak level was greater than 80 min with peaks of 0.68 +/- 0.04 microM after the second dose and 1.20 +/- 0.07 microM after the third dose. There was a positive correlation between combined (FEN + NF) peak levels in microdialysate and the increase in body temperature after 10 mg/kg d-FEN at 27 degrees C; however, the group mean and peak levels of FEN and NF in microdialysate were statistically the same at either 23 degrees C or 27 degrees C. The indole-depleting effect of d-FEN at 4 days after dosing was exacerbated at 27 degrees C when hyperthermia occurred. Thus, hyperthermia does not affect the pharmacokinetics of d-FEN but pharmacokinetics can influence the degree of hyperthermia in a 27 degrees C environment. Plasma levels, brain extracellular and brain levels of approximately 1 microM, 2.5 microM and 50 microM FEN (respectively), or greater, result from 5-hydroxytryptamine-depleting doses of 5 mg/kg s.c. FEN.

Authors+Show Affiliations

Division of Neurotoxicology, National Center for Toxicological Research, Jefferson, Arkansas 72079-9502, USA.No affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

9454806

Citation

Clausing, P, et al. "Fenfluramine and Norfenfluramine Levels in Brain Microdialysate, Brain Tissue and Plasma of Rats Administered Doses of D-fenfluramine Known to Deplete 5-hydroxytryptamine Levels in Brain." The Journal of Pharmacology and Experimental Therapeutics, vol. 284, no. 2, 1998, pp. 618-24.
Clausing P, Newport GD, Bowyer JF. Fenfluramine and norfenfluramine levels in brain microdialysate, brain tissue and plasma of rats administered doses of d-fenfluramine known to deplete 5-hydroxytryptamine levels in brain. J Pharmacol Exp Ther. 1998;284(2):618-24.
Clausing, P., Newport, G. D., & Bowyer, J. F. (1998). Fenfluramine and norfenfluramine levels in brain microdialysate, brain tissue and plasma of rats administered doses of d-fenfluramine known to deplete 5-hydroxytryptamine levels in brain. The Journal of Pharmacology and Experimental Therapeutics, 284(2), 618-24.
Clausing P, Newport GD, Bowyer JF. Fenfluramine and Norfenfluramine Levels in Brain Microdialysate, Brain Tissue and Plasma of Rats Administered Doses of D-fenfluramine Known to Deplete 5-hydroxytryptamine Levels in Brain. J Pharmacol Exp Ther. 1998;284(2):618-24. PubMed PMID: 9454806.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Fenfluramine and norfenfluramine levels in brain microdialysate, brain tissue and plasma of rats administered doses of d-fenfluramine known to deplete 5-hydroxytryptamine levels in brain. AU - Clausing,P, AU - Newport,G D, AU - Bowyer,J F, PY - 1998/3/7/pubmed PY - 1998/3/7/medline PY - 1998/3/7/entrez SP - 618 EP - 24 JF - The Journal of pharmacology and experimental therapeutics JO - J Pharmacol Exp Ther VL - 284 IS - 2 N2 - The relationship between dose, frontal cortex (brain) microdialysate and brain tissue levels of fenfluramine (FEN) and norfenfluramine (NF), as well as the effect that these levels have on body temperature, was determined after systemic d-FEN. FEN and NF levels were monitored continuously in the microdialysate of adult male Sprague-Dawley rats dosed with 3 x 5 mg/kg s.c. (spaced 2 hr apart), 1 x 2 mg/kg s.c. or 1 x 10 mg/kg i.p. d-FEN (at ambient temperatures of either 23 degrees C or 27 degrees C). Drug concentrations in plasma and brain regions were also determined 1 hr after one or three doses of 5 mg/kg of d-FEN and 1 and 8 hr after 10 mg/kg d-FEN, and the levels of 5-hydroxytryptamine and 5-hydroxyindole acetic acid in the frontal cortex of FEN and controls were determined 4 days after dosing. Peak microdialysate FEN levels, occurring between 40 and 60 min after the first dose, were 0.24 +/- 0.07 microM after 2 mg/kg, 0.33 +/- 0.04 microM after 5 mg/kg and 1.65 microM after 10 mg/kg. After multiple doses of 5 mg/kg FEN the time-to-peak level was greater than 80 min with peaks of 0.68 +/- 0.04 microM after the second dose and 1.20 +/- 0.07 microM after the third dose. There was a positive correlation between combined (FEN + NF) peak levels in microdialysate and the increase in body temperature after 10 mg/kg d-FEN at 27 degrees C; however, the group mean and peak levels of FEN and NF in microdialysate were statistically the same at either 23 degrees C or 27 degrees C. The indole-depleting effect of d-FEN at 4 days after dosing was exacerbated at 27 degrees C when hyperthermia occurred. Thus, hyperthermia does not affect the pharmacokinetics of d-FEN but pharmacokinetics can influence the degree of hyperthermia in a 27 degrees C environment. Plasma levels, brain extracellular and brain levels of approximately 1 microM, 2.5 microM and 50 microM FEN (respectively), or greater, result from 5-hydroxytryptamine-depleting doses of 5 mg/kg s.c. FEN. SN - 0022-3565 UR - https://www.unboundmedicine.com/medline/citation/9454806/Fenfluramine_and_norfenfluramine_levels_in_brain_microdialysate_brain_tissue_and_plasma_of_rats_administered_doses_of_d_fenfluramine_known_to_deplete_5_hydroxytryptamine_levels_in_brain_ L2 - https://jpet.aspetjournals.org/cgi/pmidlookup?view=long&pmid=9454806 DB - PRIME DP - Unbound Medicine ER -