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An enzyme-distributed system for lidocaine metabolism in the perfused rat liver preparation

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Abstract

The influence of enzymic distribution on lidocaine metabolism was investigated in the once-through perfused rat liver preparation. Low input concentrations of14C-lidocaine (1–2 μM) and preformed monoethylglycine xylidide (MEGX; 2.3–2.8 μM) were delivered by normal and retrograde flow directions to the liver preparations at 10 ml/min per liver. Upon reversal of normal to retrograde delivery of lidocaine, the rates at which lidocaine, MEGX, and glycine xylidide (GX) left the liver almost doubled, whereas the rates of appearance of (total) hydroxylated lidocaine and MEGX in bile and perfusate increased to lesser extents. Upon reversal of normal to retrograde delivery of preformed MEGX, the rates of appearance of MEGX and GX were virtually unchanged. Computer simulations on lidocaine and preformed MEGX metabolism were performed on both evenly distributed (“parallel tube” model) and enzyme-distributed systems. An even or parallel distribution of N-deethylation and hydroxylation activities for lidocaine metabolism failed to predict the observed increased hepatic availability of lidocaine. Rather, the distribution of a low-affinity, high-capacity N-deethylation system anterior to a high-affinity, lowcapacity hydroxylation system for lidocaine metabolism adequately predicted the increased hepatic availability of lidocaine. Further extension of these consistent enzyme-distributed models on the metabolism of lidocaine metabolites suggests that the N-deethylation and hydroxylation activities for the metabolism of lidocaine, MEGX, 3-hydroxyidocaine, and 3-hydroxy MEGX are not identically distributed. When these enzymedistributed models were appraised with reference to the “parallel tube” and “wellstirred” models of hepatic drug clearance, predictions from these.enzymedistributed models proved to be superior to the “parallel tube” and “well-stirred” models for the present data on lidocaine metabolites with normal and retrograde perfusions. Previously published data on lidocaine and MEGX metabolism after inputting 4 μg/ml (17 μM) lidocaine at flow rates of 10, 12, 14, and 16 ml/min were reexamined with respect to the adequacy of these enzyme-distributed models. They were found to be superior to the evenly-distributed or “parallel tube” model in predicting hepatic availability of lidocaine and the rate of appearance of MEGX. However, the enzyme-distributed systems were not as consistent as the “well-stirred” model in predicting lidocaine hepatic availability in these flow experiments.

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Authors and Affiliations

  1. Faculty of Pharmacy, University of Toronto, M5S 1A1, Toronto, Ontario, Canada

    K. Sandy Pang & Julia A. Terrell

  2. Department of Pharmacology, University of Toronto, M5S 1A1, Toronto, Ontario, Canada

    K. Sandy Pang, Kathleen F. Feuer, Mary-Jean Clements & Laszlo Endrenyi

  3. School of Pharmacy, University of Washington, 98105, Seattle, Washington

    Sidney D. Nelson

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  1. K. Sandy Pang
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  2. Julia A. Terrell
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Additional information

This work was supported in part by U.S. HHS grant GM-27323 and a Research Career Development Award from the National Institute of Arthritis, Diabetes, Digestive and Kidney Diseases (AM-01028) as well as grants from the Canadian Medical Research Council (development grants DG-262, 263, and 264) (K.S.P.).

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Pang, K.S., Terrell, J.A., Nelson, S.D. et al. An enzyme-distributed system for lidocaine metabolism in the perfused rat liver preparation. Journal of Pharmacokinetics and Biopharmaceutics 14, 107–130 (1986). https://doi.org/10.1007/BF01065257

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  • DOI: https://doi.org/10.1007/BF01065257

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