The Absorption, Excretion and Plasma Protein Binding of Lofepramine in the Rat, Dog and Man

Abstract

1. Lofepramine labelled with ³H in the dihydrodibenzazepine moiety and ¹⁴C in the chlorobenzene moiety was given orally to rats (20 mg/kg), dogs (3 mg/kg) and man (2 mg/kg).

2. In dogs and man blood isotope levels were determined by combustion. In both species the ¹⁴C-levels were higher than the ³H-lcvels during the first 6 h after dosing. Later more ³H was found.

3. In all three species most of the ¹⁴C activity was rapidly excreted in the urine as the glycine conjugate of p-chlorobenzoic acid.

4. No significant species difference in the urinary excretion of ³H-labelled metabolites was found and the major metabolites were 2-hydroxydesmethylimi-pramine, 2-hydroxyiminodibenzyl and desmethylimipramine.

5. Considerable amounts of desmethylimipramine were found in faeces of dog and man but not rat. This difference is discussed.

6. By the ultrafiltration technique, lofepramine was found to be bound to plasma proteins of the rat, dog and man to an extent of 99%.