Mechanisms of hepatic drug metabolism and excretion

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Mechanisms of hepatic drug metabolism and excretion

Wolf H. Stapelfeldt, MD

Drug clearance is defined as the theoretical volume of blood from which a drug is completely removed in a given time interval. Total drug clearance (CLtotal) is the sum of clearances based on a variety of applicable elimination pathways (hepatic, renal, pulmonary, intestinal, plasma, other). A drug is considered to be hepatically eliminated if hepatic clearance (CLhepatic) assumes a large proportion of the total body clearance (CLhepatic ≈ CLtotal). This method is the case for most drugs metabolized in humans. Examples of a minority of drugs for which the metabolism is independent of hepatic function include esmolol (metabolized by esterases located in erythrocytes), remifentanil (metabolized by nonspecific esterases in muscle and intestines), and cisatracurium (metabolized by Hoffman elimination in plasma). However, most drugs depend, either directly or indirectly, on adequate hepatic function for metabolism and elimination.

Hepatic clearance

CLhepatic is the volume of blood from which a drug is removed as it passes through the liver within a given time interval. Therefore, CLhepatic is limited by the volume of blood flowing through the liver within the same time interval (imagehepatic). 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" />CLintrinsic = Vm/km

image

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 (imagehepatic) of the drug, which determines the extraction ratio (ER) of the drug (ER = CLhepatic/imagehepatic) according to the following formula (Figure 50-1):

ER=CLintrinsic /(Q˙hepatic+CLintrinsic)

image

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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