Vet Hum Toxicol. 1993 Apr;35(2):134-6.
Red cell and plasma concentrations of fluoxetine and norfluoxetine.

Amitai Y, Kennedy E, DeSandre P, Fawcett J, Frischer H.

Department of Pharmacology (Genetics), Rush-Presbyterian St. Luke's Medical Center, Chicago, Illinois 60612.

To study the distribution of fluoxetine and norfluoxetine in blood compartments we determined their concentrations in red cells and plasma after the addition of 500 ng/ml of each compound to human blood in vitro. Red cell and plasma fluoxetine concentrations were 493 +/- 79 ng/ml and 454 +/- 53 ng/ml, respectively (P > 0.1). To assess the potential implications of this distribution on routine monitoring of these compounds in plasma, we determined fluoxetine and norfluoxetine concentrations in red cells and plasma in 6 patients receiving various doses of fluoxetine. While in 4 patients the concentrations of fluoxetine and norfluoxetine in red cells and plasma were comparable, 2 patients had higher concentrations of both compounds in red cells. Variations in the distribution of fluoxetine and norfluoxetine in blood compartments are relatively small. Plasma levels may reflect the drug concentration in whole blood more reliably for fluoxetine and norfluoxetine than for tricyclic antidepressants.

Source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=8470355&dopt=Abstract fluoxetine




JAMA. 1993 May 5;269(17):2246-8.
Pregnancy outcome following first-trimester exposure to fluoxetine (Prozac)

Pastuszak A, Schick-Boschetto B, Zuber C, Feldkamp M, Pinelli M, Sihn S, Donnenfeld A, McCormack M, Leen-Mitchell M, Woodland C, et al.

Motherisk Program, Hospital for Sick Children, Toronto, Ontario, Canada.

OBJECTIVE--To compare pregnancy outcome following first-trimester fluoxetine (Prozac) exposure with pregnancy outcome in two matched control groups. Fluoxetine is a new antidepressant used by many young women. Currently, no published data exist on its safety in pregnancy. DESIGN--We prospectively collected and followed up 128 pregnant women exposed to a mean daily dose of 25.8 mg (+/- 13 mg) of fluoxetine during the first trimester and compared pregnancy outcome with two matched groups of women exposed during the first trimester of pregnancy to either nonteratogens or tricyclic antidepressants. RESULTS--Rates of major malformations were comparable within the three groups and did not exceed those expected in the general population. Women treated with fluoxetine had a tendency for increased risk for miscarriage when compared with women exposed to nonteratogens (relative risk, 1.9; 95% confidence interval, 0.92 to 3.92). The rate of miscarriages in the fluoxetine group was comparable with the tricyclic group (13.5% and 12.2% vs 6.8% in the nonteratogens). CONCLUSIONS--Our study suggests that the use of fluoxetine during embryogenesis is not associated with an increased risk of major malformations. Women exposed to both fluoxetine and tricyclic antidepressants tended to report higher rates of miscarriage; further studies will be needed to confirm this observation and to separate the effects of the psychiatric condition from the associated drugs. Long-term studies will be warranted to rule out potential developmental teratology of fluoxetine, which affects a central nervous system neurotransmitter.

Source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=8474204&dopt=Abstract fluoxetine




J Chromatogr. 1993 Apr 21;614(1):175-9.
Determination of fluoxetine and norfluoxetine in human plasma by capillary gas chromatography with electron-capture detection.

Lantz RJ, Farid KZ, Koons J, Tenbarge JB, Bopp RJ.

Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, IN 46285.

A capillary gas chromatographic method with 63Ni electron-capture detection is reported for the determination of fluoxetine (Prozac) and its metabolite norfluoxetine in human plasma. A liquid-liquid extraction is used, followed by derivatization with heptafluorobutyric anhydride to increase the sensitivity of detection. A 30 m x 0.25 mm I.D. DB-17 capillary column resolves the compounds from endogenous matrix interferences. The limit of quantitation by this method is 5 ng/ml for each compound. Stability studies show that fluoxetine and norfluoxetine are stable in human plasma for up to 96 h at room temperature and up to one year at -20 degrees C.

Source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=8496280&dopt=Abstract fluoxetine




Arterioscler Thromb. 1993 Jun;13(6):907-14.
Potentiation of the vasospastic response to angioplasty by pretreatment with fluoxetine. A study in the atherosclerotic rabbit.

Sigal SL, Gellman J, Anderson GM, True LD, Chen Q, Tselentakis MJ, Ling FS, Ezekowitz MD.

Yale University School of Medicine/West Haven VA Department of Medicine, Conn.

There is evidence that angioplasty-induced vasospasm is mediated by serotonin (5-hydroxytryptamine [5-HT]) release from platelets. We tested the hypothesis that pretreatment of the atherosclerotic rabbit with fluoxetine, a platelet-uptake inhibitor of 5-HT, would reduce vasospasm after balloon angioplasty. Short-term administration of fluoxetine reduced platelet 5-HT uptake to 4% of baseline. Daily administration of fluoxetine for 7 days reduced whole-blood 5-HT levels to 28% of baseline. Thus, fluoxetine inhibited platelet 5-HT uptake in this model as predicted. Contrary to our expectations and despite the substantial reduction in whole-blood 5-HT levels, pretreatment with fluoxetine for 1 week resulted in augmentation of angioplasty-induced vasospasm in atherosclerotic rabbits. Intraperitoneal administration of fluoxetine produced vasoconstriction in normal rabbits that was augmented by 5-HT and not reversed with LY53857, a specific serotonin receptor antagonist. We postulate that this new observation is probably a result of the inhibition of the clearance mechanism for serotonin, with resultant enhancement of the effect of serotonin released by the activated platelets that are deposited on the vessel wall surface at the time of angioplasty. A direct effect of fluoxetine on serotonergic receptors is a second possible mechanism for the observed effect.

Source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=8499412&dopt=Abstract fluoxetine




Neuropsychopharmacology. 1993 Jun;8(4):337-44.
Norfluoxetine enantiomers as inhibitors of serotonin uptake in rat brain.

Wong DT, Bymaster FP, Reid LR, Mayle DA, Krushinski JH, Robertson DW.

Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, Indiana 46285.

Like fluoxetine, the N-demethylated metabolite norfluoxetine exists in R- and S-enantiomeric forms. S-Norfluoxetine inhibited serotonin (5-HT) uptake and [3H]paroxetine binding to 5-HT uptake sites with a pKi of 7.86 and 8.88 or 14 and 1.3 nM, respectively, whereas R-norfluoxetine was 22 and 20 times, respectively, less potent. R- and S-Norfluoxetine were less potent than the corresponding enantiomers of fluoxetine as inhibitors of norepinephrine uptake and [3H]tomoxetine binding to norepinephrine uptake sites. Ex vivo studies showed that S-norfluoxetine inhibited 5-HT uptake with an ED50 of 3 mg/kg intraperitoneally, 4.7 mg/kg subcutaneously, and 9 mg/kg orally (7.3, 11.4 and 21.9 mumol/kg, respectively), while the ED50 for R-norfluoxetine exceeded 20 mg/kg intraperitoneally (48.6 mumol/kg). Inhibition of 5-HT uptake in cerebral cortex ex vivo and decrease in 5-HIAA levels in hypothalamus persisted for 24 hours after administration of S-norfluoxetine as demonstrated with the administration of fluoxetine. Thus, S-norfluoxetine is the active N-demethylated metabolite responsible for the persistently potent and selective inhibition of 5-HT uptake in vivo.

Source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=8512621&dopt=Abstract fluoxetine




Biochem Pharmacol. 1993 Jun 9;45(11):2355-8.
Drug concentrations in mouse brain at pharmacologically active doses of fluoxetine enantiomers.

Fuller RW, Snoddy HD.

Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, IN 46285.

The i.p. injection of R-fluoxetine into mice at doses of 1-10 mg/kg led to higher concentrations of the desmethyl metabolite, R-norfluoxetine, in whole brain than was true for S-fluoxetine. R-Norfluoxetine, but not S-norfluoxetine, concentrations predominated over those of the parent drug at 7-24 hr after injection of the corresponding fluoxetine enantiomer. The more rapid N-demethylation of R-fluoxetine, and the relative inactivity of R-norfluoxetine as a serotonin uptake inhibitor compared with S-norfluoxetine, may explain the earlier report that R-fluoxetine is less potent than S-fluoxetine in antagonizing p-chloroamphetamine depletion of brain serotonin in mice. In the present study, a 10 mg/kg, i.p., dose of S-fluoxetine completely prevented p-chloroamphetamine given 24 hr later from depleting brain serotonin, whereas R-fluoxetine offered no protection at this time.

Source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=8517878&dopt=Abstract fluoxetine




J Pharmacol Exp Ther. 1993 Jun;265(3):1319-24.
Acute uptake inhibition increases extracellular serotonin in the rat forebrain.

Rutter JJ, Auerbach SB.

Department of Biological Sciences, Rutgers University, Piscataway, New Jersey.

The effect of acute uptake inhibition on serotonin (5-HT) in the rat central nervous system was monitored by using in vivo dialysis. Peripheral administration of the selective 5-HT uptake blocker, fluoxetine, caused a dose-dependent increase in extracellular 5-HT in both the diencephalon and the striatum. Administration of fluoxetine or sertraline, another selective 5-HT uptake inhibitor, caused a prolonged (24 hr) increase in 5-HT and decrease in 5-hydroxyindoleacetic acid. In addition, fluoxetine and sertraline attenuated the 5-HT releasing effect of fenfluramine administered 24 hr later. Local infusion of fluoxetine into the diencephalon caused an increase in 5-HT that was twice as large as the effect of peripheral injection. Peripheral fluoxetine, by enhancing extracellular 5-HT in the raphe, probably resulted in activation of somatodendritic autoreceptors and inhibition of 5-HT neuronal discharge. Thus, the increase in 5-HT in the diencephalon after peripheral fluoxetine presumably reflected a balance between decreased release and inhibition of reuptake. In support of this, after first infusing fluoxetine into the diencephalon to maximally block reuptake, peripheral injection of the uptake inhibitor caused a decrease in 5-HT.

Source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=7685386&dopt=Abstract fluoxetine




J Neural Transm Gen Sect. 1994;96(3):165-77.
Fluoxetine at anorectic doses does not have properties of a dopamine uptake inhibitor.

Fuller RW, Hemrick-Luecke SK, Snoddy HD.

Eli Lilly and Company, Lilly Corporate Center, Indianapolis, IN.

Although fluoxetine is a highly selective inhibitor of serotonin uptake in vitro and in vivo, some investigators have suggested that dopamine uptake inhibition may contribute to anorectic actions of fluoxetine. The present experiments were done to determine fluoxetine's effects in some animal protocols in which dopamine uptake inhibitors have characteristic actions. Mazindol prevented the depletion of striatal dopamine and its metabolites by amphetamine in iprindole-pretreated rats, but fluoxetine had no effect. Mazindol prevented the depletion of striatal dopamine and its metabolites by 6-hydroxydopamine injected intracerebroventricularly into rats, but fluoxetine had no effect. Mazindol enhanced the elevation of 3,4-dihydroxyphenylacetic acid concentration in rat brain after spiperone injection, but fluoxetine did not cause that effect. Fluoxetine did not mimic amfonelic acid in antagonizing the retention of alpha-methyl-m-tyramine invant striatum after the injection of alpha-methyl-m-tyrosine. These results show that fluoxetine, at doses that are effective in blocking the serotonin uptake carrier and causing anorexia, does not block the dopamine uptake carrier.

Source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=7826568&dopt=Abstract fluoxetine