Fluoxetine Antidepressant

N-Methyl-g-[4-(trifluoromethyl)phenoxy]benzenepropanamineC17H18F3NO=309.3CAS—54910-89-3

Soluble in water (78.2mg/L at 258).

Fluoxetine HydrochlorideSynonym. LY-110140Proprietary names. Adofen; Docutrix; Erocap; Fluctin; Fluctine; Fluoxeren;Fontex; Foxetin; Lorien; Lovan; Mutan; Prozac; Prozyn; Reneuron; Sanzur;Zactin.C17H18F3NO.HCl=345.8CAS—59333-67-4A white to off-white crystalline solid. M.p. 1388. It is soluble in methanol,ethanol, acetonitrile, chloroform and acetone; slightly soluble in ethyl acetate,dichloromethane and water (maximum 14 g/L); insoluble in toluene, cyclohex-ane and hexane.

Fluoxetine OxalateC17H18F3NO.C2O4=397.4Crystals from ethylacetate–methanol. M.p. 1798 to 1828.

Partition Coefficient. Log P (octanol/water), 4.05; (octanol/pH 7.4),1.82.

Thin-layer Chromatography. System TAE—fluoxetine Rf 11; M(nor-)Rf 11; system TB—fluoxetine Rf 13;M(nor-) Rf 12; system TE—fluoxetineRf 47; M(nor-) Rf 47.

Plate: silica gel 60 F254. Mobile phase: methanol:concentrated ammoniumhydroxide (90:10). Fluoxetine hydrochloride Rf 0.58 [D. S. Risley and R. J.Bopp, in Analytical Profiles of Drug Substances and Excipients, Vol. 19, H.G. Brittain (ed), Academic Press, New York, 1990, p. 193–219].

Gas Chromatography. System GA—fluoxetine RI 1859; M(nor-) RI1851, fluoxetine-AC RI 2250, M(nor-)-AC RI 2190; system GB—fluox-etine RI 1903, M(nor-) RI 1888, acetylfluoxetine RI 2319, M(nor-) RI2278; system GM—fluoxetine RRT 0.304, M(nor-) RRT 0.284 (bothrelative to iprindole).

Column: DB-5 MS 5% phenylmethyl silicone (25m6 0.2mm i.d.,0.33mm film thickness). Column temperature: 1008 held 2min, 158/minto 2108, 2108 to 2808 at 208/min, held 5min. Carrier gas: helium, 0.7mL/min flow rate. MS detection (EI, SIM at m/z 117 and 294 for fluoxetine-pentafluoropropionic anhydride (PFPA), m/z 117, 176 and 280 for nor-fluoxetine-PFPA). Internal standard (IS): fluoxetine-d5-PFPA. Retentiontime: fluoxetine-PFPA, 13.4min; norfluoxetine-PFPA, 12.9min; IS,13.3min [J. A. Crifasi et al., J. Anal. Toxicol., 1997, 21, 415–419].

Column: HP-5 MS 5% PHME siloxane film (30mx0.25mm i.d., 0.25mmfilm thickness). Column temperature: 1508 for 0.5min then 108/min to2708, held 2.5min. Carrier gas: helium, 1.0mL/min flow rate. MS detection(EI, SIM at m/z 309.3 for fluoxetine and 295.3 for norfluoxetine). IS:clomipramine (m/z 314.3). Retention time: fluoxetine, 7.3min; norfluox-etine, 7min; IS, 12.3 [K. E. Ferslew et al., J. Forensic Sci., 1998, 43,1082–1085].

High Performance Liquid Chromatography. System HAA—reten-tion time 16.2min; system HAX—retention time 12.2min; system HAY—retention time 7.07min; system HY—RI 400; system HZ—fluoxetineretention time 7.6min; M(nor-) retention time 6.7min.

Ultraviolet Spectrum. Aqueous acid (methanol)—227, 264, 268,275 nm (fluoxetine); (0.025M sulfuric acid)—226.5 nm (fluoxetine);(0.2M NH2SO4)—226, 263, 275 nm (norfluoxetine); basic—264, 275 nm(norfluoxetine).

Infra-red Spectrum. Principal peaks at wavenumbers 2986, 2772, 1614,1329, 1257, 1122 cm71; norfluoxetine 1335, 1240, 1110 cm71 (KBr pellet).

Mass Spectrum. Principal ions atm/z 44, 309, 183, 104, 251, 91, 197, 242;norfluoxetine m/z 134, 104, 191, 143, 162, 77.

QuantificationGas chromatography. In plasma: fluoxetine and norfluoxetine, limit ofdetection 0.3 mg/L, nitrogen–phosphorus detection—P. Fontanille et al.,J. Chromatogr. B Biomed. Sci. Appl., 1997, 692, 337–343. In plasma:fluoxetine and norfluoxetine, limit of detection 5mg/L, ECD—R. J.Lantz et al., J. Chromatogr., 1993, 614, Biomed. Appl., 125, 175–179.

Gas chromatography–mass spectrometry. In blood, urine, vitreousand other tissue samples: limit of quantification 25.0mg/L and limit of

Fluoxetine 1

2 Fluoxetine

detection 12.5mg/L—J. A. Crifasi et al., J. Anal. Toxicol., 1997, 21,415–419. In plasma: fluoxetine and norfluoxetine, limit of detection 1 mg/L—C. B. Eap et al., J. Chromatogr., 1996, 682, Biomed. Appl., 265–272.

High performance liquid chromatography. In serum: limit of detection25 mg/L. UV detection (l=226nm)—P. J. Orsulak et al., Clin. Chem.,1988, 34(9), 1875–1878. In plasma or brain tissue: limit of detection0.7 mg/L in plasma, fluorescence detection (lex=345 nm,lem=470 nm)—P. Clausing et al., J. Chromatogr. B Biomed. Sci. Appl.,1997, 692, 419–426. In plasma: fluoxetine and norfluoxetine, limit ofdetection 6 mg/L, UV detection (l=214nm)—S. H. Wong et al., J.Chromatogr., 1990, 499, 601–608. In plasma: fluoxetine and norfluoxe-tine, limit of detection 2mg/L, UV detection (l=226nm)—P. Thomare etal., J. Chromatogr., 1992, 583; Biomed. Appl., 121, 217–221. In plasma:fluoxetine and norfluoxetine, limit of detection 5 mg/L, UV detection(l=226, 254 nm)—G. Aymard et al., J. Chromatogr. B Biomed. Sci.Appl., 1997, 700, 183–189. In plasma: fluoxetine and norfluoxetine, limitof detection 3mg/L, fluorescence detection (lex=235 nm,lem=470 nm)—R. F. Suckow et al., Clin. Chem., 1992, 38, 1756–1761.

Disposition in the Body. Fluoxetine is readily absorbed after oraladministration and is extensively metabolised in the liver by demethyla-tion. The primary active metabolite is norfluoxetine, which is excreted viathe kidneys. Further metabolism can occur byO-dealkylation producing p-trifluoromethylphenol and hippuric acid. 80% of a drug dose is excreted inurine with less than 10% as the unchanged parent drug and 15% excretedin faeces. Fluoxetine is widely distributed throughout the body and secretedinto breast milk.

Therapeutic concentrationTherapeutic serum concentrations are 0.15 to 0.5mg/L for fluoxetine andfor norfluoxetine 0.1 to 0.5mg/L.

Following a single dose of 40mg to 6 subjects, peak plasma concentrationsof 0.030 to 0.055mg/L were attained after 4 to 8 h; peak norfluoxetineplasma concentrations were 0.006 to 0.036mg/L after 48 to 96 hours. [G.R. Aronoff et al., Clin. Pharmacol. Ther., 1984, 36, 138–144].

Toxicity. Blood concentrations of 1.3 to 6.8mg/L fluoxetine and 0.9 to5.0mg/L norfluoxetine have been associated with fatalities. Serum levels of1.96mg/L fluoxetine (0.42mg/L norfluoxetine) have been associated withseizures.

A 46-year-old man with a history of drug abuse was found dead in a chairand toxicological analysis revealed blood levels of 1.3mg/L fluoxetine and1.2mg/L norfluoxetine [A. D. Fraser et al., TIAFT Bulletin Case Notes,1991, 21(3)].

A 44-year-old man was found dead and medication at the scene includedclozapine (Clorazil) and fluoxetine (Prozac). Toxicological analysisrevealed blood levels of 0.7mg/L for fluoxetine and 0.6mg/L fornorfluoxetine; clozapine (4.9mg/L) and ethanol (350mg/L) were alsodetected. Death was due to an overdose of fluoxetine and clozapine, whichresulted in a fatal drug interaction [K. E. Ferslew et al., J. Forensic Sci.,1998, 43, 1082–1085].

A 13-year-old boy who claimed to have taken 1880mg of fluoxetinesuffered abdominal pain and nausea, and, about 3.5 h after ingestion, ageneralised tonic-clonic seizure. The serum fluoxetine concentration about90min after ingestion was 0.428mg/L; serum norfluoxetine concentrationwas 0.211mg/L [M. A. Riddle et al., J. Am. Acad. Child Adolesc.Psychiatry, 1989, 28, 587–588].

Bioavailability. Approx. 60%.

Half-life. 4 to 6 days (fluoxetine); 4 to16 days (norfluoxetine).

Volume of distribution. 27L/kg (between 20 and 42L/kg for both fluoxetineand norfluoxetine).

Clearance. Renal clearance, 0.6L/kg/h; also reported as 20.8L/h forfluoxetine and 8.7L/h for norfluoxetine.

Protein binding. About 94.5%.

Dose. A usual dose of 20mg daily is administered for depression and60mg daily for bulimia nervosa. A maximum dose of 80mg may be givendaily. Dose is reduced for patients with renal and hepatic impairment. Notrecommended for children.