Hepatic intrinsic clearance Clint

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,... 

The principle for the bioavailability estimate is as follows [84], Hepatic intrinsic clearance (CLint) is measured in hepatocytes by measuring the half-life (t1/2) in the following equation ... 

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.

Table 4.1 Dependence of hepatic clearance on intrinsic clearance (Clint) and blood flow to the liver (Qh)...

This situation could have two causes very large Qh or very small Clint- The former is theoretical since Qh has an upper physiological limit of 0.8Lmin . The latter (very small Clmt) does occur for many drugs where the liver has little inherent ability to metabolize them. In this case, hepatic clearance can approximately equal the drug s intrinsic clearance. The proof follows. 

Cl or Cls systemic clearance of a drug CIh hepatic clearance of a drug Clint intrinsic clearance of a drug Cl int intrinsic free (unbound) clearance of a drug... 

The species differences in biotransformation pathways, rates of elimination, and intrinsic hepatic clearance of esfenvalerate and deltamethrin using rat and human liver microsomes were examined [33]. Esfenvalerate was eliminated primarily via NADPH-dependent oxidative metabolism in both rat and human liver microsomes. The CLint of esfenvalerate was estimated to be threefold greater in rodents than in humans on a per kg body weight basis. Deltamethrin was also eliminated primarily via NADPH-dependent oxidative metabolism in rat liver microsomes however, in human liver microsomes, deltamethrin was eliminated almost entirely via... 

Hepatic clearance can also be estimated from in vitro intrinsic metabolic CL obtained by incubation of a compound with hepatocytes or liver microsomes. This method requires fewer resources than the in vivo approach and is more suitable for screening a large number of compounds however, there are documented cases when in vitro clearance does not accurately predict in vivo. Intrinsic metabolic CL (CLint) is a parameter that only reflects the intrinsic ability of liver to metabolize... 

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