Liver hepatic intrinsic clearance

In turn the steady-state enzyme concentration in the liver determines the baseline hepatic intrinsic clearance, CLint, for the metabolism of a drug substrate by the enzyme. When substrate concentration, S, is low relative to the Michaelis constant, Km, for a particular biotransformation,... 

Variables in addition to liver blood flow that may influence the capacity of the liver to extract a drug from the blood for elimination by hepatic processes (biotransformation and/or biliary excretion of unchanged drug) are the unbound fraction in blood and the hepatic intrinsic clearance, which is a measure of the maximal ability of the liver to eliminate the drug. The hepatic clearance (with respect to blood concentrations) is determined by the following relationship between the variables which affect drug elimination by the liver ... 

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.

Note that the effect of the inhibitor in the liver is independent of blood flow. This is not the case for the intestine, where the relative magnitude of mucosal blood flow compared with the baseline mucosal intrinsic clearance and the apparent intrinsic clearance in the presence of inhibitor must be considered. When the baseline mucosal intestinal intrinsic clearance is negligible compared to mucosal blood flow (i.e., negligible mucosal extraction), Eq. (11) will collapse into a much simpler and better recognized equation for a hepatic inhibitory interaction (3). 

For a drug that is eliminated exclusively by the liver and that is completely absorbed following oral administration, the intrinsic clearance can be related to the area under the plasma concentration-time curve (AUCp0) if the well-stirred model of hepatic elimination is assumed (81,82) ... 

The O-deethylation of phenacetin is CYPlA2-mediated and results in the liberation of acetaldehyde that is subsequently metabolized to acetate and then CO2. Thus, a breath test based on the use of phenacetin labeled with 14C in the 1-position of the ethyl side chain could function to assess CYP1A2 activity. Early studies demonstrated the feasibility of this approach and its potential application to evaluating hepatic function (65,66). No extensive validation was attempted, so it is difficult to determine how well this test reflects the enzyme s intrinsic clearance, rather than perhaps some other determinant, such as liver blood flow. However, the situation appears to be moot since phenacetin is no longer an approved dmg worldwide because of its renal side effects following chronic dosing accordingly, further studies of this approach are unlikely. 

The extent to which the liver successfully eliminates a xenobiotic from the blood is determined by the intrinsic clearance of the liver (Clh) and the rate at which the xenobiotic is presented to it (i.e., the hepatic blood flow Qh ). This gives the overall hepatic extraction ratio (E) for the compound, as shown in Equation 11.3 ... 

However, in severe hepatic disease, not only is hepatic blood flow reduced but the degree of liver damage may influence intrinsic clearance to the extent that it also affects total drug clearance. Consequently, patients with hepatic disease are at particular risk of developing adverse effects to high extraction ratio drugs. 

The factors that affect hepatic clearance include blood flow to the liver (Q), the fraction of drug not bound to plasma proteins (fu), and intrinsic clearance (CGjjf) (1, 2). Intrinsic clearance is simply the hepatic clearance that would be observed in the absence of blood flow and protein binding restrictions. As discussed in Chapter 2, hepatic clearance usually can be considered to be a first-order process. In those cases, intrinsic clearance represents the ratio of Vmax l m, and this relationship has been used as the basis for correlating in vitro studies of drug metabolism with in vivo results (3). However, for phenytoin and several other drugs, the Michaelis-Menten equation is needed to characterize intrinsic clearance. 

Vmax and Km for MDZ 1 -liydroxylation. V,nax determined for each biopsy sample was then scaled to the estimated total liver mass and intrinsic clearance estimated as total liver Vmax/Kn- Hepatic clearance then was predicted from Equation 7.6 in Chapter 7. Figure 30.13 compares the observed total elimination clearance with predicted hepatic clearance based on the assumption that the E-hydroxylation pathway accounts for 70% of the substrate loss. The prediction is quite good. The average absolute deviation between the five observed data points and their predicted values is only 28% and the differences are uniformly distributed. 

Boxenbaum, H. Interspecies variation in liver weight, hepatic blood flow, and antipyrine intrinsic clearance extrapolation of data to benzodiazepines and phenytoin. J. Pharmacokinet. Biopharm. 1980, 8, 165-176. 

Using liver microsomes from different species, the intrinsic clearance (Cl nt) for each species can be determined and then scaled to hepatic clearance. This is typically done by first determining in vitro Km (the Michaelis-Menten constant) and Vmax (the... 

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. 

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). 

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