Clinical pharmacokinetics is the discipline that describes the absorption, distribution, metabolism, and elimination of drugs in patients requiring drug therapy.
Clearance is the most important pharmacokinetic parameter because it determines the steady-state concentration for a given dosage rate. Physiologically, clearance is determined by blood flow to the organ that metabolizes or eliminates the drug and the efficiency of the organ in extracting the drug from the bloodstream.
The volume of distribution is a proportionality constant that relates the amount of drug in the body to the serum concentration. The volume of distribution is used to calculate the loading dose of a drug that will immediately achieve a desired steady-state concentration. The value of the volume of distribution is determined by the physiologic volume of blood and tissues and how the drug binds in blood and tissues.
Half-life is the time required for serum concentrations to decrease by one-half after absorption and distribution are complete. It is important because it determines the time required to reach steady state and the dosage interval. Half-life is a dependent kinetic variable because its value depends on the values of clearance and volume of distribution.
The fraction of drug absorbed into the systemic circulation after extravascular administration is defined as its bioavailability.
Most drugs follow linear pharmacokinetics, whereby steady-state serum drug concentrations change proportionally with long-term daily dosing.
Some drugs do not follow the rules of linear pharmacokinetics. Instead of steady-state drug concentration changing proportionally with the dose, serum concentration changes more or less than expected. These drugs follow nonlinear pharmacokinetics.
Pharmacokinetic models are useful to describe data sets, to predict serum concentrations after several doses or different routes of administration, and to calculate pharmacokinetic constants such as clearance, volume of distribution, and half-life. The simplest case uses a single compartment to represent the entire body.
Factors to be taken into consideration when deciding on the best drug dose for a patient include age, gender, weight, ethnic background, other concurrent disease states, and other drug therapy.
Cytochrome P450 is a generic name for the group of enzymes that are responsible for most drug metabolism oxidation reactions. Several P450 isozymes have been identified, including CYP1A2, CYP2C9, CYP2C19, CYP2D6, CYP2E1, and CYP3A4.
Membrane transporters are protein molecules concerned with the active transport of drugs across cell membranes. The importance of transport proteins in drug bioavailability, elimination, and distribution is continuing to evolve. A principal transport protein involved in the movement of drugs across biologic membranes is P-glycoprotein. P-glycoprotein is present in many organs, including the gastrointestinal (GI) tract, liver, and kidney. Other transport protein families include the organic cation transporters, the organic anion transporters, and the organic anion transporting polypeptides.
When deciding on initial doses for drugs that are renally eliminated, the patient’s renal function should be assessed. A common, useful way to do this is to measure the patient’s serum creatinine concentration and convert this value into an estimated creatinine clearance (CLcr est...