Mechanisms of hepatic drug metabolism and excretion
Hepatic clearance
hepatic). Disease-induced or anesthetic-induced reductions in total hepatic blood flow are the principal causes for diminished hepatic clearance for a large number of drugs; the elimination of these drugs is termed flow-limited. Other factors affecting hepatic clearance include maximal hepatic metabolic activity, expressed as intrinsic clearance:< ?xml:namespace prefix = "mml" />
where Vm = maximal metabolic rate (mg/min) and km (Michaelis constant) = drug concentration producing the half-maximal metabolic rate (mg/L). In this case drug elimination is termed capacity-limited. In this situation, unlike the flow-limited condition, drug elimination may change as a function of free-drug concentration that is available for hepatic metabolization and may, thus, be affected by the amount of protein binding and disease-induced changes in protein binding. Whether the hepatic elimination of a drug is flow-limited or capacity-limited depends on the ratio of the free plasma concentration of the drug to km (flow-limited if < 0.5) and that of the CLintrinsic to total hepatic blood flow (
hepatic) of the drug, which determines the extraction ratio (ER) of the drug (ER = CLhepatic/
hepatic) according to the following formula (Figure 50-1):
Depending on these ratios, different types of hepatic ERs have been described (Table 50-1).
Table 50-1
Flow-Limited Versus Capacity-Limited Elimination of Drugs by the Liver
| Type of Hepatic Elimination | Extraction Ratio (ER) | Rate of Hepatic Drug Metabolism |
| Flow-limited | High: At clinically relevant concentrations, most of the drug in the afferent hepatic blood is eliminated on first pass through the liver. | Rapid: Because drugs with a high ER are metabolized so rapidly, their hepatic clearances roughly equal their rates of transport to the liver (i.e., hepatic flow). |
| Capacity-limited | Low
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