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Formed and preformed metabolite excretion clearances in liver, a metabolite formation organ: Studies on enalapril and enalaprilat in the single-pass and recirculating perfused rat liver

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Abstract

Single-pass and recirculating rat liver perfusion studies were conducted with [14C]enalapril and [3H] enalaprilat, a precursor-product pair, and the data were modeled according to a physiological model to compare the different biliary clearances for the solely formed metabolite, [14C]enalaprilat, with that of preformed [3H]enalaprilat. With single-pass perfusion, the apparent extraction ratio (or biliary clearance) of formed [14C]enalaprilat was 15-fold the extraction ratio of preformed [3H] enalaprilat, an observation attributed to the presence of a barrier for cellular entry of the metabolite. Upon recirculation of bolus doses of [14C]enalapril and [3H]enalaprilat, the biliary clearance, estimated conventionally as metabolite excretion rate/midtime metabolite concentration, for formed [14C]enalaprilat was again 10-to 15-fold higher than the biliary clearance for preformed [3H]enalaprilat, but this decayed with perfusion time and gradually approached values for preformed [3H]enalaprilat. The decreasing biliary clearance of formed enalaprilat with recirculation was explained by the dual contribution of the circulating and intrahepatic metabolite (formed from circulating drug) to excretion. Physiological modeling predicted (i) an influx barrier (from blood to cell) at the sinusoidal membrane as the rate-limiting process in the overall removal of enalaprilat, (ii) a 15-fold greater extraction ratio or biliary clearance for formed [14C]enalaprilat over [3H]enalaprilat during single-pass perfusion, and (iii) the time-dependent and declining behaviour of the biliary clearance for formed [14C]enalaprilat during recirculation of the medium. In the absence of a direct knowledge of eliminating organs in vivo, this variable pattern for excretory clearance of the formed metabolite within the organ is indicative of a metabolite formation organ.

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Abbreviations

C R :

denotes the reservoir concentration

C In andC Out,L :

respectively, denote the input and output concentrations.

Q L :

is the total hepatic plasma flow rate.

Q Bile :

is the bile flow rate

f p and fL :

denote the unbound fractions in plasma and liver tissue, respectively

Cp :

is the concentration in renal plasma; CL is the concentration in liver;

C Bile :

is the concentration in bile.

v R,V p,V L, andV Bile :

denote the reservoir plasma, hepatic plasma, tissue, and bile volumes, respectively

CL ind andCL efd :

denote the influx and efflux clearances, respectively

CL mint,L ,L:

represents the hepatic metabolic intrinsic clearance of the drug

CL bint,L L:

denotes the biliary intrinsic clearance

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Author notes

  1. Ines A. M. de Lannoy

    Present address: Medical Research Council Group in Membrane Biology, Faculty of Medicine, University of Toronto, M5S 1A8, Toronto, Ontario, Canada

Authors and Affiliations

  1. Faculty of Pharmacy, Univeristy of Toronto, 19 Russell Street, M5S 2S2, Toronto, Ontario, Canada

    Ines A. M. de Lannoy, Ford Barker III & K. Sandy Pang

  2. Department of Pharmacology, Faculty of Medicine, University of Toronto, M5S 2S2, Toronto, Ontario, Canada

    K. Sandy Pang

Authors
  1. Ines A. M. de Lannoy
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  2. Ford Barker III
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  3. K. Sandy Pang
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Additional information

This work was supported by the Medical Research Council of Canada. I. A. M. de Lannoy was a recipient of the Ontario Graduate Fellowship from the Ontario Ministry of Health; K. S. Pang was a recipient of the Faculty Development Award, Medical Research Council, Canada.

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de Lannoy, I.A.M., Barker, F. & Pang, K.S. Formed and preformed metabolite excretion clearances in liver, a metabolite formation organ: Studies on enalapril and enalaprilat in the single-pass and recirculating perfused rat liver. Journal of Pharmacokinetics and Biopharmaceutics 21, 395–422 (1993). https://doi.org/10.1007/BF01061689

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