Saturable Metabolism in the GI Tract and Liver

After oral absorption, saturable metabolism potentially occurs in the GI tract, and then in the liver. See:

• Saturable GI tract metabolism

• Saturable liver metabolism

Saturable GI tract metabolism

Figure 1-8 is a representation of the different competing linear and non-linear absorption processes in the GI tract that participate in drug transfer from the lumen to the bloodstream. Drug transfer across the apical membrane can be active or passive, or both. Saturable GI tract metabolism, saturable GI tract efflux, and basolateral transport are competing processes that occur in the enterocytes.

Figure 1-8:  Competing linear and non-linear absorption processes in the GI tract

GI tract metabolism is assumed to follow Michaelis-Menten kinetics. Equation 1-61 is the calculation for the total rate of GI tract metabolism in all GI enterocyte compartments (index j) due to all enzymes (index i).

Equation 1-61: Saturable GI tract metabolism rate

where:

Only the free drug concentration in the enterocyte is available for GI extraction. If the enzyme is also present in the liver and if V_max and K_m data are available only from liver microsomes (as is typically the case), then you can use the same V_max and K_m for the GI tract, as long as the regional distribution of enzymes in the GI tract is expressed as an amount relative to the whole liver amount of the same enzyme. This is the method used for the GI tract enzyme distribution factors where the numbers represent the following ratio:

where the typical default value for liver weight is 1800g.

Saturable liver metabolism

Traditional linear predictions of hepatic clearance using the venous equilibrium model for the liver make one or more of the following assumptions:

• No drug accumulates in the liver, that is, the liver behaves as a reactor at steady state.

• Extraction proceeds in the linear regime of Michaelis-Menten kinetics, that is, the intrinsic clearance is independent of concentration.

• Binding of drugs to erythrocytes does not affect hepatic clearance.

GastroPlus® includes a physiologically-based, non-steady-state, non-linear hepatic extraction model that you can use if you suspect non-linear hepatic clearance. In this model, the liver is treated as a separate extraction compartment, perfused by the hepatic blood flow. Before absorbed drug can become systemically available, it must pass from the portal vein through the liver. Systemic drug is also extracted during passage through the liver. Hepatic blood flow and the apparent volume of the liver control the residence time of drug in the liver. Figure 1-9 is a schematic of the GastroPlus® Hepatic Extraction model.

Figure 1-9:  GastroPlus® Hepatic Extraction model

In GastroPlus®, the liver is assumed to behave as a well-stirred tank, which means that extraction occurs at the exit drug concentration. Equation 1-62 is the differential equation for liver extraction.

Equation 1-62: GastroPlus® Hepatic Extraction model, differential equation

where:

Equation 1-63: Sum total rate of metabolism for all liver enzymes

where:

The purpose of the two scale factors for V_max and K_m, respectively, is to allow optimization of these values to fit simulated metabolic rates to observations without changing the individual enzyme V_max and K_m values, which allows for comparison with experimental data. As a result, you can estimate the net effective V_max and K_m from plasma concentration-time data for several doses, which gives you two options:

• You can adjust the maximum velocity and concentration sensitivity for liver metabolism while maintaining proportionally correct ratios among enzymes from their experimental data.

• You can fit a net “lumped” GI metabolic rate for a single “effective” enzyme.