The liver is the major body site for xenobiotic metabolism, the biotransformation of chemicals not normally present in biological systems, such as environmental pollutants and medications. It determines the disposition of many drugs.

The liver has a dual blood supply, receiving blood from the hepatic artery and the portal veins. After trans-coursing through the liver, blood returns to the systemic circulation via the hepatic vein and into the vena cava. The extraction ratio is a measure of the efficiency of the liver in removing drug from hepatic inflow. High-extraction drugs are absorbed from the gut and delivered to the liver, where they may be metabolized before reaching the systemic circulation. This is known as first-pass metabolism.

Drugs with a high extraction ratio and significant first-pass metabolism have a low oral bioavailability. That is, much of the administered drug does not reach the systemic circulation. An extraction ratio of 1 would indicate that all of the drug is metabolized before it can reach the systemic circulation. The portion of drug reaching the systemic circulation does return to the liver for metabolism. It is important to remember that the hepatic extraction ratio is a measure of the efficiency of the extraction rather than the extent of the extraction.

The metabolism of high-extraction drugs is affected by liver blood flow and by the functional ability of liver enzymes. A decrease in liver blood flow will decrease the first-pass metabolism and increase bioavailability, making more drug available to the systemic circulation.

Low-extraction drugs reach the systemic circulation and are brought back to the liver for metabolism. An extraction ratio of zero would indicate that none of the drug is metabolized by the liver. The metabolism of low-extraction drugs is minimally affected by liver blood flow but is extensively affected by the functional capacity of hepatocytes.

The capacity for the liver to metabolize drugs depends on hepatic blood flow and liver enzyme activity.1Hepatic metabolic enzymes are diverse. They are classified as:

• Phase I, involved in non-synthetic or functionalization metabolism, which includes oxidation, reduction, and hydrolysis reactions

• Phase II, involved in synthetic or conjugation metabolism, which includes glucuronidation, methylation, and acetylation reactions

Multiple forms of cytochrome P-450 are involved in Phase I metabolism. There may be genetic polymorphic distribution of these enzymes. Therefore, some individuals may be inherently fast or slow metabolizers. It has become critical to know which of the isoenzymes of cytochrome is involved in a specific drug’s metabolism and whether there is genetic polymorphism for metabolism.

Drug-metabolizing enzymes may also be induced or inhibited. When enzymes are induced, drugs are metabolized more quickly. This increases the clearance, shortens the half-life, and decreases the bioavailability. Conversely, when drug-metabolizing enzymes are inhibited, drugs are metabolized more slowly, which decreases the clearance, increases the half-life, and increases the bioavailability.

The liver produces albumin and alpha glycoprotein, to which some drugs are extensively bound. An alteration in the ability of the liver to synthesize proteins decreases the amount of bound drug and increases the drug’s free fraction, which binds at receptor sites, exerting its pharmacologic activity. Liver disease also may alter the binding characteristics of plasma proteins in a manner similar to what happens with renal disease, so that even if plasma proteins are normal, plasma protein binding may be decreased. By altering the binding characteristics, the percent bound will be changed. An increase in free fraction also makes more drug available for metabolism, which increases clearance if the hepatocytes are functioning. If the hepatocytes are not functioning, there is an increase in the free drug concentration.

Several patient factors alter the liver’s ability to metabolize drugs:

• food consumption (For example, the presystemic clearance of high-extraction drugs such as propranolol is significantly reduced and bioavailability significantly increased when taken within 3 hours after eating.)

• age

• sex

• race

• pregnancy

• hormones

• circadian variability

Another factor is concurrently administered medications. Drugs have the ability to induce and inhibit the enzymes responsible for drug metabolism. Drug interactions may occur when new drugs are added or if a concurrent drug is discontinued. Concurrent drug administration also may change protein binding.

Liver disease causes multiple pathophysiologic changes that influence drug disposition. Decreased hepatic blood flow, extrahepatic and intrahepatic blood shunting, and loss of hepatocytes alter the ability to metabolize drugs. The bioavailability of administered medications increases, effectively increasing the dose. Decreased protein synthesis decreases the percentage of drug bound to plasma proteins and increases the amount of “free” or unbound drug. The increase in free fraction makes more drug available to the receptor site and more drug available for metabolism, thereby increasing its clearance. Increased clearance does not occur if hepatocytes are not capable of metabolizing the drug, however. An increase in free fraction and a decrease in hepatocyte function result in an increase in free drug concentration.

Liver diseases that alter drug disposition include:

• chronic liver disease (e.g., cirrhosis)

• acute hepatitis

• drug-induced hepatotoxicity

• cholestasis

• infiltrative or neoplastic disease

• In liver disease, there is no measure of residual liver function comparable to creatinine clearance in renal disease. Endogenous biochemical markers such as AST, ALT, bilirubin, and INR are qualitative but not quantitative for liver function Clearance tests of exogenous markers such as aminopyrine, indocyanine green, and lorazepam have not proved to be clinically useful. The Child-Pugh classification of liver disease can be used clinically to indicate mild (type A), moderate (type B), or severe (type C) disease, but this does not predict drug metabolism.

Patients with both liver disease and kidney disease may have further changes in the protein binding of drugs because patients with renal failure retain a high-molecular-weight protein that displaces drugs such as phenytoin. They also may have a low albumin. There is thus a significant potential for liver disease to alter the pharmacokinetics of AEDs, as well as their pharmacodynamics. For example, some patients with chronic liver disease (e.g., alcoholic cirrhosis) may have chronic mild to moderate encephalopathy, which could make these patients more sensitive to the CNS side effects of AEDs.