Metabolism and excretion of citalopram in man: identification of O-acyl- and N-glucuronides

I. The antidepressant citalopram (CT), a selective serotonin uptake inhibitor, was given in its labelled form, [C-14]-CT, as a single oral dose in 50 ml aqueous solution (0.1 mmol/30 mu Ci/1.1 MBq) to four healthy male volunteers. 2. Concentrations of radioactivity in whole blood and plasma were similar. The respective pharmacokinetic parameters were: C-max = 214 +/- 41 and 246 +/- 69 nmol eq./litre, T-max = 3 and 2 h, AUC = 18289 +/- 2959 and 14537 +/- 2883 nmol eq. h/litre, and t(1/2) = 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 %). 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. 4. 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 W-glucuronides of CT and DDCT together with the O-acyl glucuronide of CT-acid.