Effect of H2-receptor antagonists on steady-state extraction of indocyanine green and lidocaine by the perfused rat liver

Roderick K. Roberts, Carolyn A. Heath, Raymond F. Johnson, K. Vincent Speeg, Steven Schenker

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8 Scopus citations

Abstract

Variable effects of cimetidine on the clearance in humans of the high-clearance compounds lidocaine and indocyanine green have been reported, some investigators finding a reduction and others no change. We measured the extraction of indocyanine green, which is not metabolized and of lsidocaine, which is metabolized by the perfused rat liver, in an open system with a fixed flow rate. The extraction ratios of both indocyanine green (ERICG) and lidocaine (ERL) were determined under control conditions and during continuous infusion of cimetidine and other H2-receptor antagonists (ranitidine, nizatidine, and ICI 125,211) on separate occasions. The effects of increasing concentrations of cimetidine and ranitidine were measured, and single concentrations of nizatidine and ICI 125,211 were used. Indocyanine green was measured spectrophotometrically or by high-performance liquid chromatography (HPLC). Lidocaine concentrations in perfusate were measured by gas chromatography, and H2-receptor antagonist levels in perfusate and in liver by HPLC. The perfused rat liver extracted indocyanine green (ERICG = 0.43 ± 0.04) and lidocaine (ERL = 0.78 ± 0.01) with steady state being reached within 5 minutes. Neither cimetidine nor ranitidine altered steady-state indocyanine green extraction. In contrast, ERL was decreased by all four H2-receptor antagonists but with differing potencies. In this system, cimetidine was the most potent agent, reducing ERL by 28.5% at a cimetidine concentration of 56 μmol/L. The other H2-receptor antagonists also decreased ERL: ICI 125,211 by 20% (49 μmol/L), ranitidine by 13% (38 μmol/L), and nizatidine by 9% (43 μmol/L). A dose-response relationship for cimetidine and ranitidine was developed, confirming the greater potency of cimetidine. These data indicate a dose-related reduction of lidocaine extraction by cimetidine and ranitidine in the perfused rat liver at constant flow. This effect on lidocaine but not indocyanine green extraction in this experimental model suggests that inhibition of mixed function oxidases accounts for the observed decreased extraction of lidocaine, although impaired hepatocyte uptake cannot be excluded.

Original languageEnglish (US)
Pages (from-to)112-117
Number of pages6
JournalThe Journal of Laboratory and Clinical Medicine
Volume107
Issue number2
StatePublished - Feb 1986

ASJC Scopus subject areas

  • Pathology and Forensic Medicine

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