Received for publication June 2, 2004.
Revised August 4, 2004.
Accepted for publication August 5, 2004.

Differentiation of Gut and Hepatic First-Pass Loss of Verapamil in Intestinal and Vascular Access Ported (IVAP) Rabbits

Abstract

Low and varied oral bioavailability (BA) of some drugs has been attributed to extraction by the intestine and liver. However, the role of the intestine is difficult to directly assess. We recently developed an in vivo IVAP rabbit model that allows for a direct assessment of the contributions of the gut and the liver to the first pass loss of drugs. The current studies validate the utility of the IVAP rabbit model using verapamil (VL). VL pharmacokinetics (PK) were determined after intravenous (IV), portal venous (PV), and upper small intestinal (USI) administration. In the IV dose range studied, VL exhibited linear PK. The PV concentration of VL was significantly lower than systemic concentrations after IV administration suggesting significant intestinal second pass extraction. The intestinal and hepatic extraction of VL, calculated directly from area under the curve (AUC) measurements, were 79% and 92%, respectively, and are in contrast to our previous dog results that showed VL intestinal extraction to be negligible. Assessing the role of intestinal extraction using an "indirect" method was not predictive further showing the utility of this direct measurement model. The BA of VL after USI administration was 1.65%, much lower than that reported for rats, dogs or humans. However, humans and rabbits behave similarly in that the contribution of intestinal extraction for VL is high. In conclusion, the current results demonstrate the utility of the rabbit IVAP model in studying the first- and second-pass intestinal and hepatic loss of drugs and other xenobiotics.

Key words: absorption, bioavailability, drug secretion, first-pass metabolism, gastrointestinal cytochrome P450, hepatic elimination, intestinal bioavailability, intestinal transport, oral absorption, pharmacokinetics