Studies on biological fate of 14C-trazodone hydrochloride in rats.

Abstract

Absorption, distribution and excretion of trazodone hydrochloride, a new antidepressant, after single and repeated oral administration in rats were studied using 14C-labelled drug (14C-trazodone hydrochloride). After single dose (4 mg/kg), the concentration of radioactivity in blood increased rapidly in male and female rats, suggesting rapid absorption of this drug. Similarly, tissue levels of radioactivity were immediately increased after the administration and declined thereafter without delay, which was consistent with the results of wholebody autoradiography. Urinary and fecal excretion during 96 hours was 38.6 and 60.1 % of total ingested radioactivity, respectively. At least 72.9 % of radioactivity excreted in bile was shown to be reabsorbed, which suggested significant contribution of enterohepatic circulation to time course of blood concentration. Concentration of radioactivity in the milk of lactating rats was slightly higher than that in the blood. Plasma protein binding of 14C-tradozone was shown to be constant within the concentration range studied in both in vitro and in vivo, although a large difference in fraction bound (88.7-89.9 % and 33.1-41.5 % for in vitro and in vivo, respectively) was found. After repeated oral dose (4 mg/kg/day), values of Cmax, AUC and T1/2 in blood concentration and tissue levels of radioactivity tended to increase with increasing administration period. However, values of tissue-to-plasma concentration ratio and the minimum blood concentration after each administration had reached the steady-state after 14 th administration. Ratio of radioactivities excreted into urine and feces was not so much changed by multiple dosing.