A study of the metabolism and kinetics of SK&F 94120 and two structural analogues in rat hepatocytes and in vivo.
The major route of metabolism of 5-(4-acetamidophenyl)pyrazin-2(1H)-one (SK&F 94120) was by glucuronidation at the oxygen of the pyrazinone ring. Other metabolites originated from metabolism by gut microflora with subsequent hepatic metabolism (Ross et al., 1988). SK&F 94120 was metabolized by cultures of rat hepatocytes to a glucuronide conjugate and was rapidly cleared in the hepatocyte system (Cl(int) = 0.320 ml/hr/mg protein). A structural analogue (SK&F 94467) was not glucuronidated by rat hepatocytes and therefore its clearance in vitro could not be detected. In vivo SK&F 94120 was rapidly cleared from the plasma. Plasma clearance was greater for SK&F 94120 than for SK&F 94467, which is consistent with data from the hepatocyte system. Thus the mean retention time of SK&F 94467 in vivo is longer than for SK&F 94120.
Dean
A J
AJ
Smith Kline & French Research Ltd, The Frythe, Welwyn, UK.
Chenery
R J
RJ