STUDIES ON THE METABOLISM AND DISPOSITION OF THE NEW RETINOID TRAHYDRO-5,5,8,8-TETRAMETHYL-2-NAPHTHYL)CARBAMOYL] BENZOIC-ACID .4. ABSORPTION, METABOLISM, EXCRETION AND PLASMA-PROTEIN BINDING IN VARIOUS ANIMALSAND MAN

o-5,5,8,8-tetramethyl-2-naphthyl)carbamoyl]benzoic acid (GAS 94497-51- 5, Am-80) is a new synthetic retinoid which has been shown to have a p otent topical antipsoriatic activity. Pharmacokinetic profiles of Am-8 0 were studied in dogs, mice and rabbits after percutaneous or subcuta neous administration of C-14-Am-80. Plasma protein binding of C-14-Am- 80 was also studied in rats, dogs and humans. After topical applicatio n of C-14-labeled Am-80 by occlusive dressing technique at a dose of 1 mg C-14-Am-80/1,000 mg ointment/kg, the blood and plasma levels of ra dioactivity were below the detection limit in normal-skin dogs. In nor mal 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, respectiv ely. Percutaneous absorption of C-14-Am-80 was less than 2 % of the do se for dogs, 34 % for mice and 23 % for rabbits. After subcutaneous ad ministration at a dose of 1 mg/kg to mice, dogs and rabbits, plasma le vels of radioactivity peaked at 1, 4 and 4 h after dosing with a conce ntration 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 exc retion 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 mi ce and 43.5 and 45.6 % in rabbits. A possible gastrointestinal secreti on, which might lead to excretion into feces, was suggested from the r esults with bile-duct-cannulated dogs. Unchanged Am-80 was present in high amounts in the plasma and bile or feces of all animal species tes ted except in rat bile, in which Am-80 was predominantly detected in t he form of its taurine conjugate (M-6). Hydroxylation of Am-SO to yiel d 7-hydroxy-Am-80 (M-4) and 6-hydroxy-Am-80 (M-3), which lead to the f ormation of 6-oxo-Am-80 (M-5), were commonly observed in all animal sp ecies. Taurine conjugation reaction of unchanged Am-80 and hydroxy-Am- SO (to form M-6 and both M-1 and M-2, respectively) was distinct in ra ts and dogs, but, hardly detected in mice and rabbits. The presence of tetrahydro-tetramethyl-naphtylamine (TTNA) was most marked in mice, f ollowed by rabbits and rats, but it was almost absent in dogs. HPLC-RI A analysis of human samples obtained from the phase II and phase III c linical trials of Am-80 ointment suggested that fecal excretion was th e major elimination route, and that hydroxylation and taurine conjugat ion reaction of unchanged and hydroxy-Am-80 also occured. Unchanged Am -80 was preodominant in human plasma as compared with metabolites M-l to M-6. In vitro binding of C-14-Am-80 to the plasma protein was found to be more than 99 % in rats, dogs and humans. In vivo plasma protein binding of C-14-Am-80 and/or its radioactive metabolites was also fou nd to be more than 98 % in rats and dogs after subcutaneous administra tion of C-14-Am-80. In both dogs and humans, in vitro, C-14-Am-80 appe ared to be bound predominantly to serum albumin. The binding of C-14-A m-80 to human serum albumin was scarcely affected in the presence of d iazepam, digitoxin or warfarin, indicating that there are no specific binding sites for Am-80 on serum albumin.