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Research ArticleArticle

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
Drug Metabolism and Disposition November 2004, 32 (11) 1293-1298; DOI: https://doi.org/10.1124/dmd.104.000752
Jeevan R. Kunta
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Sung-Hack Lee
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Barbara A. Perry
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Yong-Hee Lee
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Patrick J. Sinko
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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 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.

Footnotes

  • This work was supported by Grant AI42007 from the National Institutes of Health.

  • Article, publication date, and citation information can be found at http://dmd.aspetjournals.org.

  • doi:10.1124/dmd.104.000752.

  • ABBREVIATIONS: PK, pharmacokinetic; PV, portal venous; P-gp, P-glycoprotein; IVAP, intestinal and vascular access-ported; USI, upper small intestinal; VL, verapamil; BA, bioavailability; HPLC, high-performance liquid chromatography; AUC, area under the concentration curve; EH, hepatic extraction ratio; EI, gut extraction ratio; CL, clearance.

    • Received May 26, 2004.
    • Accepted August 5, 2004.
  • The American Society for Pharmacology and Experimental Therapeutics
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Drug Metabolism and Disposition: 32 (11)
Drug Metabolism and Disposition
Vol. 32, Issue 11
1 Nov 2004
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Research ArticleArticle

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
Drug Metabolism and Disposition November 1, 2004, 32 (11) 1293-1298; DOI: https://doi.org/10.1124/dmd.104.000752

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Research ArticleArticle

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
Drug Metabolism and Disposition November 1, 2004, 32 (11) 1293-1298; DOI: https://doi.org/10.1124/dmd.104.000752
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