The liver is the primary organ involved in drug metabolism. Under normal conditions, it receives approximately 1.2–1.4 L of blood per minute, which is roughly 25% of cardiac output. Seventy five percent of blood arriving to the liver is from the portal vein, whereas the remaining 25% is from the hepatic arteries.
The route of administration of a drug has significance with regard to its metabolism. When medications are given by mouth, they are absorbed by the gut, enter the hepatic portal system, and are transported to the liver where they undergo metabolism before entering the systemic circulation. This process sharply decreases the concentration of drug that is available to enter the systemic circulation, a phenomenon called the first-pass effect. Other routes of administration such as intravenous, intramuscular, inhalation, transdermal, and sublingual undergo significantly less of a first-pass effect because they enter the systemic circulation before arriving at the liver. Two related terms, bioavailability and hepatic extraction ratio, can be viewed as quantitative descriptors of the first-pass effect.
Bioavailability refers to the fraction of drug administered that reaches the systemic circulation. When a drug is administered intravenously, its first-pass effect is minimal, and its bioavailability is often close to 100%. The hepatic extraction ratio is the fraction of drug that is removed from the blood by the liver. It is calculated by dividing the rate at which the liver removes drug from the plasma by the rate at which the drug arrives at the liver. The hepatic extraction ratio is dependent on many factors, including hepatic blood flow, liver disease, the induction and/or inhibition of metabolizing enzymes by other drugs, genetic predisposition, and protein binding. Generally, if a drug has a high liver extraction ratio, it will have a high first-pass effect and low bioavailability. Conversely, if the drug has a low extraction ratio, it will have a low first-pass effect and a high bioavailability.
Most active drugs are lipophilic, enabling them to cross cell membranes and exert their effect by binding to active sites. It can be difficult for the body to excrete lipophilic compounds. When they are filtered at the glomerulus of the kidney and enter tubular fluid, lipophilic compounds easily diffuse out of the renal tubules, into capillaries lining the nephron, and return to systemic circulation. A fundamental concept and purpose of drug metabolism by the liver is the biotransformation of lipophilic compounds into water-soluble compounds. Water solubility enables excretion from the body via urine and bile.
The smooth endoplasmic reticulum of hepatocytes contains microsomal enzymes (cytochrome P450 system) which are responsible for conversion of lipid-soluble drugs into more water soluble and pharmacologically less active metabolites. These chemical reactions are classified as phase I reactions in which reactive chemical groups are modified through mixed function oxidases or the cytochrome P450 system, and phase II reactions, which involve ...