Absorption is the movement of a drug from its site of administration into the bloodstream. The rate and extent of absorption depend on the route of administration, drug solubility, pH at the absorption site, blood flow, surface area, and the drug's formulation. Bioavailability refers to the fraction of an administered dose that reaches the systemic circulation in active form. Intravenous administration delivers the drug directly into the bloodstream and therefore has 100 percent bioavailability, while oral drugs typically have lower bioavailability because of incomplete absorption and the first-pass effect, in which the drug is absorbed from the gastrointestinal tract into the portal circulation and metabolized by the liver before reaching the rest of the body. Common routes of administration include oral, intravenous, intramuscular, subcutaneous, sublingual, transdermal, inhalation, rectal, topical, and intrathecal, each with characteristic absorption rates, bioavailabilities, and clinical uses.
Once in the bloodstream, a drug is distributed to body tissues. The rate and extent of distribution depend on blood flow to tissues, the drug's lipophilicity, the extent of plasma protein binding (mainly to albumin), tissue permeability, and specialized barriers such as the blood-brain barrier. Only the unbound or free fraction of a drug is pharmacologically active, and competition between drugs for protein binding sites can lead to clinically important drug interactions. The volume of distribution (Vd) is a theoretical volume that relates the total amount of drug in the body to its plasma concentration, calculated as Vd = dose / plasma concentration. A large Vd indicates extensive distribution into tissues, while a small Vd suggests that the drug remains largely confined to the plasma.
Drug metabolism, also called biotransformation, primarily occurs in the liver and converts lipophilic drugs into more water-soluble metabolites that can be more readily excreted. Phase I reactions involve oxidation, reduction, or hydrolysis and are largely carried out by the cytochrome P450 enzyme system, with CYP3A4 being the most important enzyme because it metabolizes roughly half of all drugs, followed by CYP2D6, CYP2C9, CYP2C19, and CYP1A2. Phase II reactions conjugate the drug or its Phase I metabolite with a polar group such as glucuronic acid, sulfate, acetyl, methyl, or glutathione, further increasing water solubility. CYP enzyme activity can be increased by inducers such as rifampin, carbamazepine, phenytoin, and St. John's Wort, which accelerate drug metabolism and can reduce therapeutic effect, or decreased by inhibitors such as ketoconazole, erythromycin, grapefruit juice, and fluoxetine, which slow metabolism and can lead to toxic accumulation. Finally, excretion removes drugs and metabolites from the body, principally through the kidneys via glomerular filtration, tubular secretion, and tubular reabsorption, with secondary contributions from bile, feces, the lungs (for volatile anesthetics), sweat, saliva, and breast milk.