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Drug Metabolism and Disposition Fast Forward
First published on August 10, 2004; DOI: 10.1124/dmd.104.000752

0090-9556/04/3211-1293-1298$20.00
DMD 32:1293-1298, 2004

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DIFFERENTIATION OF GUT AND HEPATIC FIRST-PASS LOSS OF VERAPAMIL IN INTESTINAL AND VASCULAR ACCESS-PORTED (IVAP) RABBITS

Jeevan R. Kunta, Sung-Hack Lee, Barbara A. Perry, Yong-Hee Lee, and Patrick J. Sinko

Department of Pharmaceutics, Ernest Mario School of Pharmacy, Rutgers, The State University of New Jersey, Piscataway, New Jersey (J.R.K., S.-H.L., P.J.S.); Mechanism and Extrapolation Technologies, Drug Metabolism and Pharmacokinetics (DMPK), GlaxoSmithKline, King of Prussia, Pennsylvania (J.R.K.); Department of Surgery, Robert Wood Johnson Medical School, University of Medicine and Dentistry of New Jersey, New Brunswick, New Jersey (B.A.P.); and DMPK, Ligand Pharmaceuticals Inc., San Diego, California (Y.-H.L.)

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 intestinal and vascular access-ported (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 (i.v.), portal venous (PV), and upper small intestinal (USI) administration. In the i.v. dose range studied, VL exhibited linear PK. The PV concentration of VL was significantly lower than systemic concentrations after i.v. administration, suggesting significant intestinal second-pass extraction. The intestinal and hepatic extraction of VL, calculated directly from area under the curve 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.

Address correspondence to: Dr. Patrick J. Sinko, Rutgers, The State University of New Jersey, Ernest Mario School of Pharmacy, 160 Frelinghuysen Road, Piscataway, NJ 08854. E-mail: sinko{at}rci.rutgers.edu






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