INTRAPERITONEAL AND INTRAPORTAL ADMINISTRATION OF DROLOXIFENE TO THE SPRAGUE-DAWLEY RAT - ASSESSING THE FIRST-PASS EFFECT

1. Employing droloxifene as a probe substrate, we have compared the us e of intraperitoneal injection and intraportal infusion, where the rat e and duration of intraportal drug administration were designed to app roximate those observed after oral drug delivery, as methods of discri minating between high first-pass hepatic extraction and poor oral abso rption. 2. Intraperitoneal injection of droloxifene (1 mg/kg) yielded an AUC(0-infinity) approximately twice that observed following intrapo rtal infusion or oral delivery of equal doses. 3. Our findings suggest chat hepatic first-pass metabolism may have been saturated following intraperitoneal drug administration due to the rapid rate of absorptio n and the corresponding high drug concentrations achieved. 4. Applicat ion of a model in which intraportal drug infusion rates are designed t o mimic the oral absorption rate appears warranted under such circumst ances.