Residence time distributions of solutes in the perfused rat liver using a dispersion model of hepatic elimination: 2. Effect of pharmacological agents, retrograde perfusions, and enzyme inhibition on evans blue, sucrose, water, and taurocholate
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The effect of altered physiological conditions on the residence time distributions of sucrose, water, and taurocholate in the rat liver were studied using a bolus injection and quantifying fraction of total outflow per ml-time profiles. Retrograde perfusions increased the residence times of sucrose and water markedly and were associated with very low hepatic availabilities for taurocholate. Resistance by the inlet sinusoids sphincters, which become outlet sphincters during retrograde perfusions, is suggested as the explanation for the observation. Infusions of noradrenaline, propranolol, and lidocaine resulted in relatively small changes in the mean residence times for sucrose and water with no apparent relationship existing between the efficiency number of taurocholate and volumes of either water or sucrose. Taurochenodeoxycholate resulted in an increase in the availability and mean residence time for taurocholate relative to no infusion.
Key wordsliver metabolism hepatic models residence time distribution dispersion model drug infusions enzyme inhibition retrograde perfusion rat liver
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- 1.K. S. Pang and M. Rowland. Hepatic clearance of drugs: I. Theoretical considerations of a “well-stirred” model and a “parallel tube” model. Influence of hepatic blood flow, plasma and blood cell binding and hepatocellular enzymatic activity on hepatic drug clearance.J. Pharmacokin. Biopharm. 5:625–653 (1977).CrossRefGoogle Scholar
- 3.K. S. Pang and M. Rowland. Hepatic clearance of drugs: III. Additional experimental evidence supporting the “well-stirred” model, using metabolite (MEGX) generated from lidocaine under varying hepatic blood flow rates and linear conditions in the perfused liver in situ preparation.J. Pharmacokin. Biopharm. 5:681–699 (1977).CrossRefGoogle Scholar
- 5.D. B. Jones, D. J. Morgan, G. W. Mihaly, L. K. Webster, and R. A. Smallwood. Discrimination between the venous equilibrium and sinusoidal models of hepatic drug elimination in the isolated perfused rat liver by perturbation of propranolol protein binding.J. Pharmacol. Exp. Ther. 229:522–526 (1984).PubMedGoogle Scholar
- 9.M. Rowland, K. Leitch, G. Fleming, and B. Smith. Protein binding and hepatic clearance: Discrimination between models of hepatic clearance with diazepam, a drug of high intrinsic clearance, in the isolated perfused rat liver preparation.J. Pharmacokin. Biopharm. 12:129–147 (1984).CrossRefGoogle Scholar
- 19.M. S. Roberts, J. D. Donaldson, and M. Rowland. Models of hepatic elimination: Comparison of stochastic models to describe residence time distributions and to predict the influence of drug distribution, enzyme heterogeneity and systemic recycling or hepatic elimination.J. Pharmacokin. Biopharm. 16:41–84 (1988).CrossRefGoogle Scholar
- 20.M. S. Roberts, S. Fraser, A. Wagner, and L. J. McLeod. Residence time distributions of solutes in the perfused rat liver using the dispersion model of hepatic elimination: 1. Effect of changes in perfusate flow and albumin concentration on sucrose and taurocholate.J. Pharmacokin. Biopharm. 18: 209–234 (1990).CrossRefGoogle Scholar
- 25.K. S. Pang, H. Koster, I. C. M. Halsema, E. Scholters, G. J. Milder, and R. N. Stillwell. Normal and retrograde perfusion to probe the zonal distribution of sulfation and glucuronidation activities of harmol in the perfused rat liver preparation.J. Pharmacol Exp. Ther. 224:647–653 (1983).PubMedGoogle Scholar
- 30.J. L. Campra and T. B. Reynolds. The hepatic circulation. In I. Arias, D. Popper, D. Schatchter, and D. A. Shafritz (eds.),The Liver Biology and Pathobiology, Raven, NY, chap. 37, pp. 627–645 (1982).Google Scholar