Abstract
In vivo metabolism of[3, 4-di(4-methoxyphenyl)-5-isoxazolyl]acetic acid (mofezolac) was studied in mice, rats, dogs and monkeys following intravenous injection or oral administration, and serum protein binding of mofezolac and its metabolites were studied in rats, mice, dogs, monkeys and human.
Obtained results were as follows;
1. Following metabolites were identified in the rat urine and bile and dog bile ; [3-(4-hydroxyphenyl)-4-(4-methoxyphenyl)-5-isoxazolyl]acetic acid (3-DM-mofezolac), [4-(4-hydroxyphenyl)-3-(4-methoxyphenyl)-5-isoxazolyl]acetic acid (4-DM-mofezolac), [3, 4-di(hydroxyphenyl)-5-isoxazolyl]acetic acid (3, 4-DM-mofezolac), 4-[4-(4-methoxyphenyl)-5-carboxymethyl-3-isoxazolyl]phenyl hydrogen sulfate (3-DM-mofezolac-sulfate), 4-[(4-hydroxyphenyl)-5-carboxymethyl-3-isoxazolyl]phenyl hydrogen sulfate (3, 4-DM-mofezolac-sulfate), β-D-glucopyranuronic acid 1-[3, 4-di(4-methoxyphenyl)-5-isoxazolyl]acetate (mofezolac-glucuronide).
2. After administration to various animal species, plasma levels of mofezolac reached Cmax rapidly except monkeys. Area under concentration time curve (AUC) of mofezolac shows the species related differences with the highest AUC value found in dogs. Main metabolite in mice and monkeys plasma were 3-DM-mofezolac and 3-DM-mofezolac and 3-DM-mofezolacsulfate was found only in rats. In dogs plasma only a small quantities of metabolites were observed in the plasma. AUC of 3-DM-mofezolac-sulfate in male rats was about three times higher than female rats.
3. After oral administration of mofezolac to rats, the residue of mofezolac in the stomach was about 60% at 0. 5hr, 33% at 2hr. And at 8hr, the residue in the stomach was slightly detected. In the small intestine, its content consisted mainly of 3-DM-mofezolac-sulfate. In the large intestine, the content of 3-DM-mofezolac was increased when compared with that of the small intestine.
4. After oral administration, main metabolites found in the urine were 3-DM-mofezolac in mice, 3-DM-mofezolac and 3-DM-mofezolac-sulfate in rats, 3-DM-mofezolac and unchanged drug in monkeys, and unchanged drug in dogs. Total amount of urinary excretion was the lowest in dogs among examined animal species.
5. In the feces after oral administration, main metabolites were 3-DM-mofezolac in mice and rats, and unchanged drug in dogs.
6. Mofezolac, 3-DM-mofezolac and 4-DM mofezolac were strongly bound to serum proteins of all species studied. Mofezolac was mainly bound to albumin of human serum.
7. After administration to rats, total amount excreted with bile was about 39% in bile within 24 hours. Main metabolite was 3-DM-mofezolac-sulfate.
