Abstract
The application of the axial dispersion model to diazepam hepatic elimination was evaluated using data obtained for several conditions using the single-pass isolated perfused rat liver preparation. The influence of alterations in the fraction unbound in perfusate (fu) and perfusate flow (Q) on the availability (F) of diazepam was studied under steady conditions (n=4 in each case). Changes in fu were produced by altering the concentration of human serum albumin (HSA) in the perfusion medium while maintaining diazepam concentration at 1 mg L−1. In the absence of protein (fu = 1), diazepam availability was 0.011 ±0.005 (¯x±SD). >As fu decreased, availability progressively increased and at a HSA concentration of 2% (g/100 ml), whenfu was 0.023, diazepam availability was 0.851 ±0.011. Application of the axial dispersion model to the relationship betweenfu andF provided estimates for the dispersion numbe (D N) of 0.337±0.197, and intrinsic clearance (CL int) of 132±34 ml min−1. The availability of diazepam during perfusion with protein-free media was also studied at three different flow rates (15, 22.5, and 30 ml min−1). Diazepam availability always progressively increased as perfusate flow increased, with the axial dispersion model yielding estimates forD N of 0.393 ± 0.128 andCL int of 144 ±38 ml min−1. The transient form of the two-compartment dispersion model was also applied to the output concentration versus time profile of diazepam after bolus input of a radiolabeled tracer into the hepatic portal vein (n=4), providingD N andCL int estimates of 0.251 ±0.093 and 135±59 ml min−1, respectively. Hence, all methods provided similar estimates forD N andCL int. Furthermore, the magnitude of DNis similar to that determined for noneliminated substances such as erythrocytes, albumin, sucrose, and water. These findings suggest that the dispersion of diazepam in the perfused rat liver is determined primarily by the architecture of the hepatic microvasculature.
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References
G. R. Wilkinson. Clearance concepts in pharmacology.Pharm. Rev. 39:1–47 (1987).
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 the hepatocellular enzymatic activity on hepatic drug clearance.J. Pharmacokin. Biopharm. 5:625–653 (1977).
M. S. Roberts and M. Rowland. A dispersion model of hepatic elimination. 1. Formulation of the model and bolus considerations.J. Pharmacokin. Biopharm. 14:227–260 (1986).
L. Bass, P. Robinson, and A. J. Bracken. Hepatic elimination of flowing substances: The distributed model.J. Theoret. Biol. 72:161–184 (1978).
E. L. Forker and B. Luxon. Hepatic transport kinetics and plasma disappearance curves: Distributed modelling versus conventional approach.Am. J. Physiol. 235:E648-E660, (1978).
Y. Sawada, Y. Sugiyama, Y. Miyamoto, T. Iga, and M. Hanano. Hepatic drug clearance model: Comparison among the distributed, parallel-tube and well-stirred models.Chem. Pharm. Bull. 33:319–326 (1985).
M. S. Roberts and M. Rowland. Hepatic elimination. Dispersion model.J. Pharm. Sci. 74:585–587 (1985).
L. Bass, M. S. Roberts, and P. J. Robinson. On the relation between extended forms of the sinusoidal perfusion and the convection-dispersion models of hepatic elimination.J. Theorel. Biol. 126:457–482 (1987).
M. S. Roberts and M. Rowland. A dispersion model of hepatic elimination. 2. Steadystate considerations. Influence of hepatic blood flow, binding within blood and hepatocellular enzyme activity.J. Pharmacokin. Biopharm. 14:261–288, (1986).
M. S. Roberts, J. D. Donaldson, and M. Rowland. Models of hepatic elimination: Comparison of stochastic models to describe residence time distribution and to predict the influence of drug administration, enzyme heterogeneity and systemic recycling on hepatic elimination.J. Pharmacokin. Biopharm. 16:41–83 (1988).
A. M. Evans, Z. Hussein, and M. Rowland. A two-compartment dispersion model describes the hepatic outflow profile of diclofenac in the presence of its binding protein.J. Pharm. Pharmacol. 43:709–714, (1991).
R. H. Smallwood, D. J. Morgan, G. W. Mihaly, D. B. Jones, and R. A. Smallwood. Effect of plasma protein binding on elimination of taurocholate by isolated perfused rat liver: Comparison of venous equilibrium, undistributed and distributed sinusoidal, and dispersion models.J. Pharmacokin. Biopharm. 16:377–396 (1988).
M. S. Ching, D. J. Morgan, and R. A. Smallwood. Models of hepatic elimination: Implications from studies of the simultaneous elimination of taurocholate and diazepam by isolated rat liver under varying conditions of binding.J. Pharmacol. Exp. Ther. 250:1048–1054 (1989).
O. Levenspiel.Chemical Reaction Engineering, Wiley, New York, 1972, pp. 253–315.
Y. Yano, K. Yamaoka, Y. Aoyama, and H. Tanaka. Two-compartment dispersion model for analysis of organ perfusion system of drugs by fast inverse Laplace transform (FILT).J. Pharmacokin. Biopharm. 17:179–202 (1989).
K. Yamaoka, T. Nakagawa, and T. Uno. Statistical moments in pharmacokinetics.J. Pharmacokin. Biopharm. 6:547–558 (1978).
V. A. Raisys, P. N. Friel, P. R. Graaff, K. E. Opheim, and A. J. Wilensky. High performance liquid chromatography and gas liquid chromatographic determination of diazepam and nitrazepam in plasma.J. Chromatog. 183:441–448 (1980).
K. S. Pang and M. Rowland. Hepatic clearance of drugs. II. Experimental evidence for acceptance of the “well stirred” model over the “parallel-tube” model using lidocaine in the perfused rat liver in situ preparation.J. Pharmacokin. Biopharm. 5:655–680 (1977).
Y. Yano, K. Yamaoka, and H. Tanaka. A non-linear least squares program, MULTI-(F1LT), based on fast inverse Laplace transforms for microcomputers.Chem. Pharm. Bull. 37:1535–1538 (1989).
M. S. Roberts, S. Fraser, A. Wagner, and L. McLeod. Residence time distribution of solutes in the perfused rat liver using a 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).
S. C. Tsao, Y. Sugiyama, Y. Sawada, S. Nagase, T. Iga, and M. Hanano. Effect of albumin on hepatic uptake of warfarin in normal and analbunemic mutant rats: Analysis by multiple indicator dilution method.J. Pharmacokin. Biopharm. 14:51–64 (1986).
S. C. Tsao, Y. Sugiyama, Y. Sawada, T. Iga, and M. Hanano. Kinetic analysis of albumin-mediated uptake of warfarin by perfused rat liver.J. Pharmacokin. Biopharm. 16:165–181 (1988).
C. A. Goresky. A linear method for determining liver sinusoidal and extravascular volumes.Am. J. Physiol. 204:626–640 (1963).
A. Buse. The likelihood ratio, Wald, and Lagrange multiplier tests: An expository note.Am. Statist. 36:153–157 (1982).
Y. Yano, K. Yamaoka, T. Minamide, T. Nakagawa, and H. Tanaka. Evaluation of protein binding effect on local disposition of oxacillin in rat liver by a two-compartment dispersion model.J. Pharm. Pharmacol. 42:632–636 (1990).
M. Rowland, D. 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).
J. F. Cumming and G. J. Mannering. Effect of phenobarbital administration on the oxygen requirement for hexobarbital metabolism in the isolated perfused rat liver preparation and the intact rat.Biochem. Pharmacol. 19:973–978 (1970).
K. S. Pang, W-F. Lee, W. F. Cherry, V. Yuen, J. Accaputo, S. Fayz, A. J. Schwab, and C. A. Goresky. Effects of perfusate flow rate on measured blood volume, Disse space, intracellular water space, and drug extraction in the perfused rat liver preparation: Characterization by the multiple indicator dilution technique.J. Pharmacokin. Biopharm. 16:595–632 (1988).
A. B. Ahmad, P. N. Bennett, and M. Rowland. Models of hepatic drug clearance: discrimination between the “well-stirred” and “parallel-tube” models.J. Pharm. Pharmacol. 35:219–224 (1983).
L. P. Rivory, M. S. Roberts, and S. M. Pond. Axial tissue diffusion can account for the disparity between current models of hepatic elimination for lipophilic drugs.J. Pharmacokin. Biopharm. 20:19–62 (1992).
L. Bass and S. M. Pond. The puzzle of rates of cellular uptake of protein-bound ligands. In A. Pecile and A. Rescigno (eds.),Pharmacokinetics: Mathematical and Statistical Approaches to Metabolism and Distribution of Chemicals and Drugs, Plenum Press, London, 1988, pp. 245–269.
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This work was supported by the Commission of the European Communities and the Medical Research Council. One of us (A.M.E.) was partially supported by a Merck, Sharp & Dohme Fellowship. We are grateful to Roche (Switzerland) for the supply of diazepam and 2-[14C]-diazepam, and Kabi AB (Sweden) for the supply of human serum albumin.
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Diaz-Garcia, J.M., Evans, A.M. & Rowland, M. Application of the axial dispersion model of hepatic drug elimination to the kinetics of diazepam in the isolated perfused rat liver. Journal of Pharmacokinetics and Biopharmaceutics 20, 171–193 (1992). https://doi.org/10.1007/BF01071000
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DOI: https://doi.org/10.1007/BF01071000