Pharmacokinetic studies of a novel tricyclic antidepressant, quinupramine in the old rats.

Abstract

In the present study, we examined the effects of aging on the pharmacokinetics of ¹⁴Cquinupramine in male rats, following the administration to the aged (2 and 1-year old) and young (8 weeks old) rats.
1. The concentration of radioactivity in blood of young rats reached the maximum 1hr after oral administration. In the older animals, T_max was more delayed. The blood concentration of radioactivity declined with the similar half-life times (T_α1/2=0.87-1.66hr., T_β1/2-19.2 -25.1hr ) in all groups of rats studied. C_max and the area under the blood concentration-time curve (AUC) in the aged rats were 2.8 and 2.7 times higer, respectively, than those in the young rats.
2. Two hours after oral administration of ¹⁴C-quinupramine, the tissue levels of radioactivity in the aged (2 years old) rats were 1.6-10.3 times higher than those in the young rats. The difference became more pronounced 24hr after administration. The distribution pattern of radioactivity in the aged rats was similar to that in the young rats. These findings were consistent with the results of whole body autoradiography.
3. The in vitro plasma protein binding assay of ¹⁴C-quinupramine showed that more than 80% was bound to the protein in every group of animals. In vivo plasma protein binding of radioactivity was 46.5% 2hr and 58.5% lhr after oral administration of ¹⁴C-quinupramine in the aged (2 years old) and young rats, respectivery.
4.The hepatic microsomal drug metabolizing activities (aminopyrine N-demethylation and aniline p-hydroxylation) and the content of cytochrome P-450 in rats decreased with aging. In vitro metabolic study of ¹⁴C-quinupramine with rat liver microsomes revealed that 48.2% and 8.4% of quinupramine remained unchanged in the aged (2 years old) and young rats, respectively.
After oral administration of ¹⁴C-quinupramine, the aged (2 years old) rats showed higher content of the unchanged form in the urine, faces, plasma, heart, liver and kidney than the young rats.
5. Within 24hr after oral administration, the recovery of radioactivity in excreta was 92.4 %, and 66.5% and 51.5% in the young and aged (1 and 2 years old) animals, respectively. The cumulative urinary excretion of radioactivity was 27.5%, 28.1% and 37.2% within 168hr after dosing in the young and aged (1 and 2 years old) rats, respectively.