Hepatic kinetics of SCP-1 (N-[alpha-(1,2-benzisothiazol-3(2H)-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<0.05), and it behaved according to dose-dependent kinetics. The SCP-1 extraction ratio was higher (mean 0.63+/-0.49) than for acetaminophen (0.04+/-0.01) (t=2.41, P<0.05) and this parameter tended to decrease as the perfusate concentrations of SCP-1 increased. It was concluded that the hepatic kinetics of SCP-1 behaved according to dose-dependent kinetics, and statistically significant differences were found between pharmacokinetics parameters of both drugs studied.
González-Martin
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Catholic University of Chile, Santiago, Chile. ggonzale@puc.cl
Lyndon
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Sunkel
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D000082:Acetaminophen / Q000031:analogs & derivatives* / Q000493:pharmacokinetics*; D018712:Analgesics, Non-Narcotic / Q000493:pharmacokinetics*; D000818:Animals; D019540:Area Under Curve; D004305:Dose-Response Relationship, Drug; D008099:Liver / Q000378:metabolism*; D008297:Male; D010477:Perfusion; D051381:Rats; D017207:Rats, Sprague-Dawley; D012439:Saccharin / Q000031:analogs & derivatives* / Q000493:pharmacokinetics
D018712:Analgesics, Non-Narcotic; C118048:SCP 1; D000082:Acetaminophen; D012439:Saccharin