Hepatic clearance model

Tirona RG, Schwab AJ, Geng W, Pang KS. Hepatic clearance models comparison of the dispersion and Goresky models in outflow profiles from multiple indicator dilution rat liver studies. Drug Metab Dispos 1998 26 465-75. Bassingthwaighte JB, Sparks HV. Indicator dilution estimation of capillary endothelial transport. Anna Rev Physiol 1986 48 321-34. 

When the extraction ratio is high, clearance is so efficient that fu. Cl int dominates the denominator of the hepatic clearance model and Q becomes negligible. As fu. Clyint then cancels out, hepatic blood flow becomes the most important factor influencing drug elimination (Panel... 

KS Pang, 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 5/6 625-653, 1977. 

Lau, Y.Y. et al. 2002. Development of a novel in vitro model to predict hepatic clearance using fresh, cryopreserved, and sandwich-cultured hepatocytes. Drug Met. Disp. 30 1446. 

The analysis was completed for 12 compounds for which protein binding, renal and hepatic clearances and microsomal data were available. Plasma concentration versus time profiles in the rat were also available for these compounds. The approach taken was to simulate the individual processes (metabolic clearance, renal clearance, distribution, pharmacological activity). The ability of the PBPK model to simulate the in vivo behavior of the compound was verified in the rat. Thus, the metabolic clearance of the compounds could be reasonably well simulated, based on microsomal data and assuming no binding to microsomes less than twofold deviation between the observed and predicted clearance was achieved for about eight of the... 

Figure 6 Well-stirred model of hepatic clearance. The exchange of a drug between plasma and hepatocyte and its removal from this cell involves an unbound compound. Intrinsic clearance, CLint, relates the rate of the elimination (by formation of metabolites, CLint>f, and secretion of unchanged compound into bile, CLint5ex) to the unbound drug in the cell, CUr Cbout and CUout are the bound and unbound concentrations of the drug leaving the liver at total concentration Cout.

Figure 7 Influence of changes in (a) organ blood flow on clearance, (b) fraction of the drug unbound in plasma (/u) on extraction ratio, and (c) intrinsic clearance on extraction ratio as predicted by the well-stirred model of hepatic clearance.

Due to its mathematical simplicity, most in vitro-in vivo correlations are based on a homogeneous, well-stirred model for the liver such that all metabolic enzymes in the liver are exposed to the same drug concentration [266]. Under steady-state conditions, the predicted hepatic clearance CLh for this model is... 

Niro, R., Byers, J., Fournier, R., and Bachmann, K., Application of a convective-dispersion model to predict in vivo hepatic clearance from in vitro measurements utilizing cryopreserved human hepatocytes, Current Drug Metabolism, Vol. 4, No. 5, 2003, pp. 357-369. 

It has been demonstrated that hepatic extraction ratio (ER) is also influenced by blood flow. A number of mathematical models have been proposed to explain this observation, but the simplest model, and the one that is easiest to apply to clinical practice, is the well stirred or venous equilibrium model (Equation 5.3). This model relates hepatic clearance to hepatic blood flow (Q), the fraction of drug concentration that is unbound in plasma (fu) and the intrinsic clearance of the unbound drug (Clyint) [1]. Intrinsic clearance represents the maximum clearance of drug in the absence of any restrictions caused by blood flow, binding or access to the metabolising enzymes. The model states that ... 

The well-stirred model, shown in Figure 7.1, is the model of hepatic clearance that is used most commonly in pharmacokinetics. If we apply the Pick equation (see Chapter 6) to this model, hepatic clearance can be defined as follows (2) ... 

In addition to the well-stirred model that is the basis for Equation 7.6, several other kinetic models of hepatic clearance have been developed (4). However, the following discussion will be based on the relationships defined by Equation 7.6, and the limiting cases represented by Equations 7.7 and 7.8. 

Other models of hepatic clearance include the sinusoidal model and the dispersion model. All these... 

Table 8.1 Equations for predicting hepatic clearance using the well-stirred model...

Pelkonen O, Turpeinen M (2007) In vitro-in vivo extrapolation of hepatic clearance biological tools, scaling factors, model assumptions and correct concentrations. Xenobiotica 37 1066-1089... 

Oxidative Biotransformation in Microsomes The rapid determination of pharmacokinetic parameters, solubility, permeability, and in vitro stability in plasma or liver tissue can often provide a reasonable explanation of the mechanisms limiting oral bioavailability. An approach that is often used is to extrapolate the in vitro rate of metabolism to estimate the hepatic clearance using in vitro-in vivo correlation methods.82-86 These methods use in vitro kinetic parameters, usually Vmllx/Km or in vitro t ji, to determine the intrinsic clearance, which is then scaled to hepatic clearance using the amount of tissue in the in vitro incubation, the weight of the liver, and the well-stirred model for hepatic clearance. 

Rosenbaum SE. Effect of variability in hepatic clearance on the bioequivalence parameters of a drug and its metabolite simulations using a pharmacostatistical model. Pharm Acta Helv 1998 73 135-144. 

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