Pharmacokinetics and disposition of the novel dopamine agonist Z-7760 in rat after intravenous and oral administration

Abstract

1. Z-7760 (S(−)-N-[N-2-phenylethyl)-6-hexylamino]-N-propyl-5,6-dihydroxy- 1,2,3,4-tetrahydro-2-naphthylamine dihydrobromide) is a potent dopamine D-1 and D-2 agonist synthesized during a search for agents to treat heart failure. Reported is the fate of the drug in rat. 2. ³H-Z-7760 was administered p.o. and i.v. to male Sprague-Dawley rats (0.4 mg and 400 μCi/kg in 0.1% ascorbic acid) and venous blood samples collected at intervals up to 48 h. Comparison of the AUC for total ³H showed that 37% of an oral dose of Z-7760 was absorbed. The percentage plasma ³H present as the parent compound fell from 82% 30 min after i.v. dosing to 12% after 24 h. After oral dosing, the fraction of plasma ³H present as unchanged Z-7760 was < 5% and this was essentially unaltered throughout the study. The long terminal elimination phase evident from 6 h was notable after both routes of administration. 3. The bile duct-cannulated rat was given ³H-Z-7760 p.o. (0.4 mg and 40 μCi/kg) and bile was collected for up to 22 h. Biliary excretion accounted for 30% of the dose. No parent compound was detected in the bile. 4. In further studies, other rats were dosed p.o. or i.v. with ³H-Z-7760 (0.4 mg and 400 μCi/kg) and urine and faeces were collected daily for 3 days. The major route of excretion was the faeces with 94-97% ³H recovered after oral and 70-73% after i.v. dosing. A further 4-7% was recovered in the urine after oral and 12-13% after i.v. dosing. 5. After oral administration of Z-7760 (100 mg/kg, 40 μCi/kg) to rats, the major metabolites in the urine were identified as the 5-O-methyl and glucuronic acid conjugates of Z-7760 by LC and MS. The glucuronide was only seen in urine after oral administration but 5-O-methyl-Z-7760 was present in urine and faeces after both routes of administration. 6. The low bioavailability of Z-7760 is the consequence of its poor absorption from the gastrointestinal tract as well as extensive first-pass metabolism that further reduces systemic blood concentrations after oral administration.