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

1. Z-7760 (S(-)-N-[N-2-phenylethyl)-6-hesylamino]-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 failu re. Reported is the fate of the drug in rat. 2. H-3-Z-7760 was administered p.o, and i.v. to male Sprague--Dawley rats ( 0.4 mg and 400 mu Ci/kg in 0.1 % ascorbic acid) and venous blood samples co llected at intervals up to 48 h. Comparison of the AUC for total H-3 showed that 37 % of an oral dose of Z-7760 was absorbed. The percentage plasma H- 3 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 H-3 present as unchanged Z-7760 was < 5 % and this was essentially unaltered throughout th e study. The long terminal elimination phase evident from 6 h was notable a fter both routes of administration. 3. The bile duct-cannulated rat was given H-3-Z-7760 p.o. (0.4 mg and 40 <m u>Ci/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 H-3-Z-7760 ( 0.4 mg and 400 mu Ci/kg) and urine and faeces were collected daily for 3 da ys. The major route of excretion was the faeces with 94-97 % H-3 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 mu Ci/kg) to rats, th e major metabolites in the urine were identified as the 5-O-methyl and gluc uronic acid conjugates of Z-7760 by LC and MS. The glucuronide was only see n in urine after oral administration but 5-O-methyl-Z-7760 was present in u rine and faeces after both routes of administration. 6. The low bioavailability of Z-7760 is the consequence of its poor absorpt ion from the gastrointestinal tract as well as extensive first-pass metabol ism that further reduces systemic blood concentrations after oral administr ation.