Studies on the metabolism and disposition of the new retinoid 4-[(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)carbamoyl] benzoic acid. 4th communication: absorption, metabolism, excretion and plasma protein binding in various animals and man

Abstract

4-[(5,6,7,8-Tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)carbamoyl]benzoic acid (CAS 94497-51-5, Am-80) is a new synthetic retinoid which has been shown to have a potent topical antipsoriatic activity. Pharmaco-kinetic profiles of Am-80 were studied in dogs, mice and rabbits after percutaneous or subcutaneous administration of 14C-Am-80. Plasma protein binding of 14C-Am-80 was also studied in rats, dogs and humans. After topical application of 14C-labeled Am-80 by occlusive dressing technique at a dose of 1 mg 14C-Am-80/1,000 mg ointment/kg, the blood and plasma levels of radioactivity were below the detection limit in normal-skin dogs. In normal skin mice and rabbits, the plasma radioactivity peaked at 8 h (40.8 ng eq./ml) and at 12 h (34.0 ng eq./ml) after application, respectively. Percutaneous absorption of 14C-Am-80 was less than 2% of the dose for dogs, 34% for mice and 23% for rabbits. After subcutaneous administration at a dose of 1 mg/kg to mice, dogs and rabbits, plasma levels of radioactivity peaked at 1, 4 and 4 h after dosing with a concentration of 614.0, 902.9 and 757.7 ng eq./ml and then it declined with half-lives of 2.4, 7.2 and 4.1 h, respectively. Urinary and fecal excretion of radioactivity after subcutaneous administration at a dose of 1 mg/kg was 3.5 and 94.7% of the dose in dogs, 27.0 and 73.2% in mice and 43.5 and 45.6% in rabbits. A possible gastrointestinal secretion, which might lead to excretion into feces, was suggested from the results with bile-duct-cannulated dogs. Unchanged Am-80 was present in high amounts in the plasma and bile or feces of all animal species tested except in rat bile, in which Am-80 was predominantly detected in the form of its taurine conjugate (M-6). Hydroxylation of Am-80 to yield 7-hydroxy-Am-80 (M-4) and 6-hydroxy-Am-80 (M-3), which lead to the formation of 6-oxo-Am-80 (M-5), were commonly observed in all animal species. Taurine conjugation reaction of unchanged Am-80 and hydroxy-Am-80 (to form M-6 and both M-1 and M-2, respectively) was distinct in rats and dogs, but, hardly detected in mice and rabbits. The presence of tetrahydro-tetramethyl-naphtylamine (TTNA) was most marked in mice, followed by rabbits and rats, but it was almost absent in dogs. HPLC-RIA analysis of human samples obtained from the phase II and phase III clinical trials of Am-80 ointment suggested that fecal excretion was the major elimination route, and that hydroxylation and taurine conjugation reaction of unchanged and hydroxy-Am-80 also occurred. Unchanged Am-80 was predominant in human plasma as compared with metabolites M-1 to M-6. In vitro binding of 14C-Am-80 to the plasma protein was found to be more than 99% in rats, dogs and humans. In vivo plasma protein binding of 14C-Am-80 and/or its radioactive metabolites was also found to be more than 98% in rats and dogs after subcutaneous administration of 14C-Am-80. In both dogs and humans, in vitro. 14C-Am-80 appeared to be bound predominantly to serum albumin. The binding of 14C-Am-80 to human serum albumin was scarcely affected in the presence of diazepam, digitoxin or warfarin, indicating that there are no specific binding sites for Am-80 on serum albumin.