CORRELATION OF DRUG CONJUGATIVE METABOLISM RATES BETWEEN IN VIVO AND IN VITRO : GLUCURONIDATION AND SULFATION OF p-NITROPHENOL AS A MODEL COMPOUND IN RAT

Abstract

The correspondence of conjugative metabolism rates in vivo and in vitro was studied in rat using p-nitrophenol (PNP) as a model compound. In PNP-glucuronide conjugation, the hepatic intrinsic clearance calculated from K_m and V_max obtained in the isolated liver cells was approximately three times larger than that calculated by the in vivo blood concentration on the basis of the linear pharmacokinetic concepts, but this difference was not considered essential. On the other hand, in PNP-sulfate conjugation, some inhibition in the isolated liver cells, which was not expected in the in vivo blood concentration, was found at more than 5 μM PNP. Such inhibition mechanism could not be elucidated by the inorganic sulfate concentration in the reaction medium. Accordingly, it was suggested that some unknown reaction mechanism still remained to be studied for the applicability of the conjugation rates in the isolated liver cells, especially sulfation rates, to the pharmacokinetic study in vivo.