The Distribution and Excretion of [3H,14C]Lofepramine* in the Rat

Abstract

1. Lofepramine hydrochloride (N-methyl-N-[4-chlorobenzoylmethyl-3-(10, 11-dihydro-5H-dibenz(b,f)azepin-5-yl)]-propylamine hydrochloride) labelled with ³H in the dihydrobenzazepine moiety and ¹⁴C in the chlorobenzene moiety was synthesized and its distribution, urinary and biliary excretion were studied in female rats after oral administration. 2. For both isotopes, high ratios were established between tissues and blood. 3. Extensive N-dealkylation of lofepramine occurred in the rat. One of the metabolites, desmethylimipramine, was found in high concentrations in most tissues, especially the lungs and brain. 4. Desmethylimipramine was further metabolized to 2-hydroxydesmethyl-imipramine and 2-hydroxy-iminodibenzyl, and the corresponding glucuronides. These metabolites were mainly excreted via the bile. 5. p-Chlorobenzoic acid was found in the liver and lungs but not in the urine where most of the excreted ¹⁴C-activity was found. The identity of the major urinary metabolite is discussed.