Metabolism and excretion of citalopram in man: identification of O-acyl- and N-glucuronides.
The antidepressant citalopram (CT), a selective serotonin uptake inhibitor, was given in its labelled form, [14C]-CT, as a single oral dose in 50 ml aqueous solution (0.1 mmol/30 microCi/1.1 MBq) to four healthy male volunteers. Concentrations of radioactivity in whole blood and plasma were similar. The respective pharmacokinetic parameters were: Cmax = 214+/-41 and 246+/-69 nmol eq./litre, Tmax = 3 and 2 h, AUC = 18289+/-2959 and 14537+/-2883 nmol eq. h/litre, and t1/2 = 90.2+/-22.5 and 79.5 +/- 14.9 h respectively. A mean of 85.2 +/- 10.4% of the radioactive dose was recovered after 17 days of collection of excreta. The majority of radioactivity was excreted in urine (74.7+/-8.9%) and the remaining part in faeces (10.5+/-2.3%). The HPLC profile of urinary components showed that besides the known metabolites of citalopram, three glucuronides were present. The relative amounts of CT and its metabolites in urine collected for 7 days were: CT (26 %), N-demethyl-CT (DCT, 19%), N,N-didemethyl-CT (DDCT,9%), the N-oxide (7%), the quaternary ammonium glucuronide of CT (CT-GLN, 14%), the N-glucuronide of DDCT (DDCT-GLN, 6%), and the glucuronide of the acid metabolite (CT-acid-GLN, 12%) formed by N,N-dimethyl deamination of CT. CT-GLN was isolated using preparative chromatography and identified by LC-MS-MS and NMR. DDCT-GLN and CT-acid-GLN were identified by LC-MS. This study shows that protracted renal excretion represents the major route of elimination, with a small fraction voided with faeces. A considerable portion of the urinary excreted dose consists of N-glucuronides of CT and DDCT together with the O-acyl glucuronide of CT-acid.
Dalgaard
L
L
R & D, H. LUNDBECK A/S, Copenhagen, Denmark. LDA@Lundbeck.com
Larsen
C
C
D000215:Acylation; D000328:Adult; D002851:Chromatography, High Pressure Liquid; D002853:Chromatography, Liquid; D015283:Citalopram / Q000378:metabolism*; D020719:Glucuronides / Q000032:analysis* / Q000378:metabolism; D006801:Humans; D008297:Male; D013058:Mass Spectrometry; D017367:Selective Serotonin Reuptake Inhibitors / Q000097:blood / Q000493:pharmacokinetics* / Q000652:urine*
D015283:Citalopram; D020719:Glucuronides; D017367:Selective Serotonin Reuptake Inhibitors