Fluoxetine

Fluoxetine

Antidepressant

N-Methyl-g-[4-(trifluoromethyl)phenoxy]benzenepropanamine C17H18F3NO=309.3 CAS54910-89-3

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

Fluoxetine Hydrochloride
Synonym. LY-110140 Proprietary names. Adofen; Docutrix; Erocap; Fluctin; Fluctine; Fluoxeren;
Fontex; Foxetin; Lorien; Lovan; Mutan; Prozac; Prozyn; Reneuron; Sanzur; Zactin. C17H18F3NO.HCl=345.8 CAS59333-67-4 A 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, cyclohexane and hexane.

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

Fluoxetine Oxalate
C17H18F3NO.C2O4=397.4 Crystals from ethylacetatemethanol. M.p. 1798 to 1828.

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

1.82.

Thin-layer Chromatography. System TAEfluoxetine Rf 11; M(nor-) Rf 11; system TBfluoxetine Rf 13; M(nor-) Rf 12; system TEfluoxetine Rf 47; M(nor-) Rf 47.
Plate: silica gel 60 F254. Mobile phase: methanol:concentrated ammonium hydroxide (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. 193219].

Gas Chromatography. System GAfluoxetine RI 1859; M(nor-) RI 1851, fluoxetine-AC RI 2250, M(nor-)-AC RI 2190; system GBfluoxetine RI 1903, M(nor-) RI 1888, acetylfluoxetine RI 2319, M(nor-) RI 2278; system GMfluoxetine RRT 0.304, M(nor-) RRT 0.284 (both relative to iprindole).
Column: DB-5 MS 5% phenylmethyl silicone (25 m 6 0.2 mm i.d., 0.33 mm film thickness). Column temperature: 1008 held 2 min, 158/min to 2108, 2108 to 2808 at 208/min, held 5 min. Carrier gas: helium, 0.7 mL/ min flow rate. MS detection (EI, SIM at m/z 117 and 294 for fluoxetinepentafluoropropionic anhydride (PFPA), m/z 117, 176 and 280 for norfluoxetine-PFPA). Internal standard (IS): fluoxetine-d5-PFPA. Retention time: fluoxetine-PFPA, 13.4 min; norfluoxetine-PFPA, 12.9 min; IS, 13.3 min [J. A. Crifasi et al., J. Anal. Toxicol., 1997, 21, 415419]. Column: HP-5 MS 5% PH ME siloxane film (30 m x 0.25 mm i.d., 0.25 mm film thickness). Column temperature: 1508 for 0.5 min then 108/min to 2708, held 2.5 min. Carrier gas: helium, 1.0 mL/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, 7.3 min; norfluoxetine, 7 min; IS, 12.3 [K. E. Ferslew et al., J. Forensic Sci., 1998, 43, 10821085].

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

High Performance Liquid Chromatography. System HAAretention time 16.2 min; system HAXretention time 12.2 min; system HAY retention time 7.07 min; system HYRI 400; system HZfluoxetine retention time 7.6 min; M(nor-) retention time 6.7 min. Ultraviolet Spectrum. Aqueous acid (methanol)227, 264, 268, 275 nm (fluoxetine); (0.025 M sulfuric acid)226.5 nm (fluoxetine); (0.2 M NH2SO4)226, 263, 275 nm (norfluoxetine); basic264, 275 nm (norfluoxetine).

Quantification
Gas chromatography. In plasma: fluoxetine and norfluoxetine, limit of detection 0.3 mg/L, nitrogenphosphorus detectionP. Fontanille et al., J. Chromatogr. B Biomed. Sci. Appl., 1997, 692, 337343. In plasma: fluoxetine and norfluoxetine, limit of detection 5 mg/L, ECDR. J. Lantz et al., J. Chromatogr., 1993, 614, Biomed. Appl., 125, 175179. Gas chromatographymass spectrometry. In blood, urine, vitreous and other tissue samples: limit of quantification 25.0 mg/L and limit of

Fluoxetine

detection 12.5 mg/LJ. A. Crifasi et al., J. Anal. Toxicol., 1997, 21, 415419. In plasma: fluoxetine and norfluoxetine, limit of detection 1 mg/ LC. B. Eap et al., J. Chromatogr., 1996, 682, Biomed. Appl., 265272. High performance liquid chromatography. In serum: limit of detection 25 mg/L. UV detection (l=226 nm)P. J. Orsulak et al., Clin. Chem., 1988, 34(9), 18751878. In plasma or brain tissue: limit of detection 0.7 mg/L in plasma, fluorescence detection (lex=345 nm, lem=470 nm)P. Clausing et al., J. Chromatogr. B Biomed. Sci. Appl., 1997, 692, 419426. In plasma: fluoxetine and norfluoxetine, limit of detection 6 mg/L, UV detection (l=214 nm)S. H. Wong et al., J. Chromatogr., 1990, 499, 601608. In plasma: fluoxetine and norfluoxetine, limit of detection 2 mg/L, UV detection (l=226 nm)P. Thomare et al., J. Chromatogr., 1992, 583; Biomed. Appl., 121, 217221. 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, 183189. In plasma: fluoxetine and norfluoxetine, limit of detection 3 mg/L, fluorescence detection (lex=235 nm, lem=470 nm)R. F. Suckow et al., Clin. Chem., 1992, 38, 17561761.

Disposition in the Body. Fluoxetine is readily absorbed after oral administration and is extensively metabolised in the liver by demethylation. The primary active metabolite is norfluoxetine, which is excreted via the kidneys. Further metabolism can occur by O-dealkylation producing ptrifluoromethylphenol and hippuric acid. 80% of a drug dose is excreted in urine with less than 10% as the unchanged parent drug and 15% excreted in faeces. Fluoxetine is widely distributed throughout the body and secreted into breast milk.
Therapeutic concentration
Therapeutic serum concentrations are 0.15 to 0.5 mg/L for fluoxetine and for norfluoxetine 0.1 to 0.5 mg/L. Following a single dose of 40 mg to 6 subjects, peak plasma concentrations of 0.030 to 0.055 mg/L were attained after 4 to 8 h; peak norfluoxetine plasma concentrations were 0.006 to 0.036 mg/L after 48 to 96 hours. [G. R. Aronoff et al., Clin. Pharmacol. Ther., 1984, 36, 138144].

Toxicity. Blood concentrations of 1.3 to 6.8 mg/L fluoxetine and 0.9 to 5.0 mg/L norfluoxetine have been associated with fatalities. Serum levels of 1.96 mg/L fluoxetine (0.42 mg/L norfluoxetine) have been associated with seizures.
A 46-year-old man with a history of drug abuse was found dead in a chair and toxicological analysis revealed blood levels of 1.3 mg/L fluoxetine and 1.2 mg/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 included clozapine (Clorazil) and fluoxetine (Prozac). Toxicological analysis revealed blood levels of 0.7 mg/L for fluoxetine and 0.6 mg/L for norfluoxetine; clozapine (4.9 mg/L) and ethanol (350 mg/L) were also detected. Death was due to an overdose of fluoxetine and clozapine, which resulted in a fatal drug interaction [K. E. Ferslew et al., J. Forensic Sci., 1998, 43, 10821085]. A 13-year-old boy who claimed to have taken 1880 mg of fluoxetine suffered abdominal pain and nausea, and, about 3.5 h after ingestion, a generalised tonic-clonic seizure. The serum fluoxetine concentration about 90 min after ingestion was 0.428 mg/L; serum norfluoxetine concentration was 0.211 mg/L [M. A. Riddle et al., J. Am. Acad. Child Adolesc. Psychiatry, 1989, 28, 587588].

Bioavailability. Approx. 60%. Half-life. 4 to 6 days (fluoxetine); 4 to16 days (norfluoxetine). Volume of distribution. 27 L/kg (between 20 and 42 L/kg for both fluoxetine and norfluoxetine). Clearance. Renal clearance, 0.6 L/kg/h; also reported as 20.8 L/h for fluoxetine and 8.7 L/h for norfluoxetine. Protein binding. About 94.5%.

Dose. A usual dose of 20 mg daily is administered for depression and

60 mg daily for bulimia nervosa. A maximum dose of 80 mg may be given daily. Dose is reduced for patients with renal and hepatic impairment. Not recommended for children.