Hepatic kinetics of SCP-1 ( N-[ α-(1,2-benzisothiazol-3(2 H)-ona-1,1-dioxide-2-yl)-acetyl]- p-aminophenol) compared with acetaminophen in isolated rat liver

The hepatic disposition of a new analgesic, SCP-1, a derivative of acetaminophen, was studied in the isolated perfused rat liver using a recirculating system. The aim of this study was to compare the kinetic parameters of this molecule with those of acetaminophen. Sprague–Dawley rat (230–330 g) livers were perfused for 2 h with 250 ml Krebs–Henseleit bicarbonate buffer containing SCP-1 or acetaminophen, 0.07 mmol l −1 ( n=4), 0.28 mmol l −1 ( n=4), and 0.8 mmol l −1 ( n=4) (approximately one, four and ten times the therapeutic doses in man, respectively). Perfusate samples were collected from the efflux at various times. The SCP-1 and acetaminophen perfusate concentrations were assayed by a HPLC method. Pharmacokinetic analysis was carried out using a computer program. There were significant differences between the hepatic kinetics of SCP-1 and those of acetaminophen. Thus, SCP-1 elimination half-life (mean 14.8±10.0 min) was shorter than that of the acetaminophen (186.1±27.7 min) ( t=11.6, P=0.0001). While the half-life of SCP-1 increases with concentration, the half-life of acetaminophen remains constant as the concentration increases. The hepatic clearance was higher for SCP-1 than acetaminophen (mean 19.01±14.5 ml min −1 vs. 1.29±0.08 ml min −1, respectively) ( t=2.44, P