Differentiation of gut and hepatic first-pass effect of drugs: 1. Studies of verapamil in ported dogs.

Abstract

To investigate the relative contributions of the gut and liver to the first-pass loss of verapamil (VL) using an in vivo intestinal-vascular access port (IVAP) dog model. Basic pharmacokinetics of VL were determined after intravenous (IV: 0.5 mg/kg), portal venous (PV: 2 mg/kg), and duodenal (ID: 2 mg/kg) administration in IVAP dogs. Serial blood samples were collected for 8 h after dosing, and plasma was analyzed for unchanged drug by a high-performance liquid chromatography-fluorescence method. Extraction ratios in the liver and intestinal tract were determined from the area under the concentration-time curves for ID, PV, and IV administration. The functional role of CYP450 or secretory transporters such as P-gp on the gut and liver first-pass loss of VL was further studied using ritonavir, a known substrate or inhibitor of these processes. The liver had a high intrinsic capacity for clearing VL because the absolute bioavailability (BA) of VL was 21.7% after PV administration. The BA of VL after ID administration was 23.5%; therefore, intestinal absorption was complete and intestinal extraction was negligible (ER(GI) approximately 0). The BA of VL increased from 23.5% to 66.2% in the presence of ritonavir primarily due to a reduction in hepatic extraction. Although the liver had a high intrinsic capacity for extracting VL, the contribution of gut to the first-pass loss of VL was negligible. Because of the additive effects of intestinal CYP3A-mediated metabolism and secretory transport, a significant gut first-pass effect was expected, but not observed in dogs. These studies demonstrate the utility of the in vivo IVAP dog model for evaluating the relative contribution of the gut and liver to the first-pass loss of drugs and for characterizing the functional role that CYP450 metabolism and/or secretory transporters play in drug-drug interactions and reduced oral bioavailability.