Hepatocytes well-stirred model

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 2 Comparison between the uptake clearance obtained in vivo and that extrapolated from the in vitro transport study of endothelin antagonists. In vivo uptake clearance of endothelin antagonists (BQ-123, BQ-518, BQ-485, compound A) was evaluated by integration plot analysis using the plasma concentration-time profile after intravenous administration (500 nmol/kg) and the amount of drug in the liver and that excreted in the bile. In vitro hepatic uptake clearance was measured using isolated rat hepatocytes and was extrapolated to the in vivo uptake clearance assuming the well-stirred model. Source From Ref. 5.

The well-stirred model [eqn (13.5)] is a simplified model of hepatic drug clearance and relates in vivo intrinsic clearance, which is the clearance of the drug experiences at the enzyme level, to blood flow and liver distribution. The in vivo C/int can be estimated from an in vitro C/ nt measurement by scaling the in vitro measurement to the in vivo situation, using estimates of microsomal protein yield per gram of liver and liver weights (for microsomal estimates of C/int) or hepatocyte numbers per gram of liver for in vitro C/int values derived from hepatocytes. See eqn (13.5). 

Transporters are involved in biliary and renal excretions that are the two common routes of drug elimination. In the liver, a drug is first taken up into hepatocytes, then either secreted back to the systemic circulation or excreted to the bile in an intact form or as metabolites via Phase I and/or Phase II enzymes. Given the involvement of transporters in both uptake at the sinusoidal membrane and efflux at the sinusoidal and canulicular membranes (Fig. 6.1c), the hepatic clearance can be expressed based on well-stirred model as the following equation (Shitara et al., 2005 Yamazaki et al., 1996) ... 

Steady state the hepatic intrinsic clearance of pravastatin, a substrate for OATP2 and MRP2 (Tokui et al., 1999 Yamazaki et al., 1997), was regulated by the uptake process, followed by rapid metabolism and/or biliary excretion with minimal efflux to the systemic circulation in rats after infusion. The total hepatic elimination rate at steady state exhibited Michaelis-Menton saturation with the drug concentration and the and V ax obtained in rats with different mathematical models (i.e., well stirred, parallel tube, and dispersion models) were comparable with the initial uptake velocity measured from in vitro hepatocytes (Tokui et al., 1999). 

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