Explain the liver’s detoxifying and first-pass, metabolic functions

Explain the liver’s detoxifying and first-pass, metabolic functions.

Other liver catabolic functions include the degradation of hemoglobin, production and elimination of bilirubin, clearance of fibrin split products and activated coagulation factors, and elimination of potential xenobiotics (alcohol/ drugs) and toxins (e.g., endotoxin) absorbed from the gas-trointestinal tract. While one of the main functions of the gastrointestinal tract is to absorb nutrients, it can also absorb toxins and other foreign material including drugs and other xenobiotics. Venous drainage from the gastro-intestinal tract is channeled to the portal system which empties into the liver. With the exception of absorption that occurs in the mouth and in the distal part of the rec-tum, everything that is absorbed by the gastrointestinal tract must pass through the liver. The liver plays an active role in detoxifying foreign materials absorbed via the gastrointestinal tract. It is also responsible for first-pass metabolism of orally administered drugs. The bioavailabil-ity of a drug is the fraction of a given dose that reaches the general circulation. There are several factors than can influ-ence bioavailability. One of the most important of these is first-pass metabolism. The cytochrome P450 (CYP) system found in the liver plays a significant role in first-pass metab-olism and bioavailability of many drugs. However, when portal inflow into the liver is impeded, as seen in cirrhosis, collateral connections may constitute an important alterna-tive route that bypasses the liver, thereby decreasing first-pass metabolism and increasing the bioavailability of drugs as well as increasing the risk of exposure to toxins.

CYPs are hemoprotein isoforms that are responsible for biotransformation of numerous endogenous and exoge-nous compounds. Isoforms that held the interest of many investigators are CYP2E1 and CYP3A. These isoforms are induced by ethanol. CYP2E1 is important in the metabo-lism of ethanol, toxins and potent inhaled anesthetics. In humans, the CYP3A family is the most abundant isoform and is involved in metabolizing numerous drugs, such as cyclosporine, midazolam, alfentanil, and lidocaine. Other drugs or substrates, such as phenobarbital and glucocorti-coids, can also induce the CYP3A isoform. Since ethanol can induce CYP2E1 and CYP3A, its role in the metabolism, interaction, and toxicity of drugs that are regularly used by anesthesiologists and other physicians, and the impact of enzyme induction on these roles, are of immense interest. Management of patients with chronic and/or acute alcohol intake can be extremely challenging. Acute intoxication is analogous to partly anesthetizing a patient. However, the induction of CYP may cause drugs to be metabolized at an accelerated rate. A third consideration is that CYP induc-tion may be offset by alcohol inhibiting drug metabolism by acting as a competitive substrate. Furthermore, the metabolic effects of CYP induction may be outweighed by alcohol-induced hepatic dysfunction. The great clinical importance of the interactions of drugs used in anesthesia (or any other area of medicine) with ethanol at the CYP level is further accentuated by the fact that 1 in 10–20 people consume ethanol on a daily basis.

The liver is a major site for the biotransformation of drugs and environmental toxins. Lipophilic compounds are transformed into hydrophilic compounds by a series of reactions. The ultimate goal of this process is excretion in either the bile or the urine. Phase 1 reactions, oxidation, reduction, dehalogenation, hydrolysis, etc., are mostly catalyzed by cytochrome P450. Products of phase I reactions can be inactive (transformation of fentanyl to norfentanyl) or active (transformation of diazepam to temazepam and oxazepam). Occasionally, phase I reactions will transform a compound into toxins (transformation of halothane to trifluoroacetyl (TFA) halide intermediate or of acetaminophen to N-acetyl-p-benzoquinone). Phase II biotransformations occur in the cytosol. They are conjuga-tion reactions in which a covalent link between either the parent drug or metabolite (after a phase I transformation) and glucuronic acid, sulfate, glutathione, amino acids, or acetate is formed.

Pharmacokinetics can be altered by changes in absorp-tion, first-pass metabolism, distribution, and elimination. In patients with liver disease, some or all of these kinetic mechanisms can be changed. In order to fully understand how liver disease affects pharmacokinetic parameters, one must understand the interactions of drug metabolism and how the liver extracts drugs from blood.

Drugs may be classified according to their liver extrac-tion. The extraction ratio is defined as: E = (C_a − C_v)/C_a, where C_a is defined as the concentration in the hepatic artery and C_v is the concentration in the hepatic vein. High-extraction drugs usually have extraction ratios greater than 70%, whereas low-extraction drugs usually have extraction ratios that are less than 30%. Classification of drugs according to their extraction ratio is useful. Drugs with high extraction ratios are highly dependent on liver blood flow. Their clearance is independent of plasma protein binding and independent of liver metabolism. Induction or inhibition of P450 usually will not change clearance; however, extremely high inhibition will markedly decrease clearance of high (and low) extraction drugs by the liver. Scarring and abnormal architecture associated with cirrhosis leads to hepatic blood flow obstruction. Obstruction of portal flow produces shunting away from the liver. Portal blood accounts for approxi-mately 70% of liver blood flow. Therefore, this will have a major effect on clearance of high-extraction drugs and first-pass metabolism. The clearance of low-extraction drugs is independent of liver blood flow. The amount of drug delivered to the liver under normal blood flow far exceeds the liver’s intrinsic capacity to metabolize it. Low-extraction drugs are dependent on the intrinsic ability of the liver to metabolize the drug; therefore, induction or inhibition of cytochrome P450 usually will have a parallel change in clearance. Furthermore, low-extraction drugs are usually dependent on binding to plasma proteins. Drugs that are highly bound will have increased clearance in disease states that decreased the binding proteins and the fraction of bound drug, e.g., albumin. The liver is a major organ of the reticuloendothelial system (RES) and accounts for 85% of RES activity. The RES is a functional rather than an anatomic system that serves as an important bodily defense mechanism. In the liver, Kupffer cells, highly phagocytic macrophages that line the sinuses of the liver, take up large foreign particles and act as a first-line defense against bacteria absorbed from the gastrointestinal tract. Therefore, portal flow obstruction can lead to the shunting of toxins and bacteria absorbed by the gastrointestinal system directly into the systemic circulation.