Pharmacokinetic evidence for the occurrence of extrahepatic conjugative metabolism of p-nitrophenol in rats.

p-Nitrophenol (PNP), as a model compound for the study of conjugative metabolism, was administered intravenously to rats. PNP and its conjugated metabolites, i.e. PNP-glucuronide (PNP-Glu) and PNP-sulfate (PNP-Sul), were determined in body fluids by reversed-phase high-performance liquid chromatography using ion-pair systems. Linear pharmacokinetics was applicable in the dose range of 1.6 to 8 mg/kg. The metabolic clearance which was obtained from the area under the PNP blood concentration curve (AUCiv) and from the excretion ratio of the total conjugates as PNP-Glu and PNP-Sul was so close to the hepatic blood flow that the PNP conjugation reactions seemed to be limited by the hepatic blood flow, that is the hepatic extraction ratio (EH) was expected to be 1. However, AUCpv, following portal vein administration of PNP (4 mg/kg), was not zero but was significantly different from AUCiv after the same dosing (P less than 0.05). Consequently, comparison between the AUC values from both dosing routes and the excretion ratio of PNP-Glu and PNP-Sul gave and EH of 0.43. Such a difference in EH obtained by the two methods suggested a contribution by extrahepatic conjugative metabolism. It was shown that the intrinsic hepatic clearance obtained, assuming exclusively hepatic conjugative metabolism, was certainly overestimated. Furthermore, the results of the conjugation reaction in tissue homogenates suggested a contribution by extrahepatic glucuronidation.