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

Abstract

1. 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 μCi/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 N-glucuronides of CT and DDCT together with the O-acyl glucuronide of CT-acid.