In vivo assessment of extrahepatic conjugative metabolism in first pass effects using the model compound phenol

Jt has been known for a number of years that the liver is not the only site where drugs and other xenobiotics undergo conjugation reactions (Hartiala 1973; Dutton & Burchell 1978; Hook & Bend 1978). In vitro studies have shown that a number of extrahepatic tissues including the intestinal mucosa and lung contain significant glucuronyl transferase (Chhabra & Fouts 1974, 1976; Litterst et al 1975;) and sulphotransferase (Bostrom 1965; Hook & Bend 1978). However, little attempt has been made to quantify the role of extrahepatic metabolism in the in vivo disposition of drugs and xenobiotics. We have evaluated the relative contribution of the intestinal mucosa, liver and lung in the in vivo disposition of phenol in rat. This compound was selected for investigation because it is essentially completely biotransformed to phenyl glucuronide and phenyl sulphate and very little oxidative metabolism occurs (Capel et a1 1972; Weitering et a1 1979). Blood concentration-time profiles for phenol and its metabolites have been obtained following administration of phenol by a number of different routes. First pass considerations (Rowland 1973; Gibaldi & Perrier 1974) have been used to assess the relative conjugative ability of hepatic, intestinal and pulmonary enzymes. When administered intra-arterially (La.) a compound is immediately distributed throughout the body and may be regarded as being 100% available. The area under the blood concentration-time curve between zero and infinity (AUC,.,) is governed by the dose administered (D) and the systemic clearance of the drug (CL).