Pharmacokinetics involves studying a drug’s absorption, distribution, metabolism, and excretion. Bioavailability refers to the percentage of a drug that reaches the blood after absorption. The volume of distribution (Vd) is an indication of how much a drug is distributed out of the blood. The half-life of a drug is the time it takes for the concentration in the blood to drop by half. Drug metabolism occurs in organs such as the liver, kidneys, gastrointestinal tract, and lungs. The final step of pharmacokinetics is the elimination of the drug from the body, mainly done by the kidneys.
When drugs are used to treat or prevent disease, doses must be given that achieve the concentrations necessary for the desired effects, while remaining at levels in the blood that do not cause excessive toxicity. The processes that bring about this are collectively called pharmacokinetics. This involves studying the drug’s absorption into the body, distribution throughout the body, and metabolism and excretion to eliminate the drug from the body. Many factors contribute to the variability of a given drug’s pharmacokinetics, including age, gender, body weight, and medical conditions. Sometimes, the pharmacokinetics is referred to as clinical pharmacokinetics.
When a drug is administered by any means other than intravenously, it must be absorbed through biological membranes to reach the blood. Most often, this refers to oral drugs absorbed from the gastrointestinal (GI) tract. The percentage of a dose that reaches the blood after absorption is called the bioavailability.
The most common reason for low oral bioavailability is first pass metabolism. All drugs absorbed from the gastrointestinal tract first pass through the liver. Here, drugs can be significantly broken down or metabolized before reaching the blood. Other reasons for the reduced oral bioavailability include destruction of the drug by gastric acid and inhibition of absorption by food. Some drugs have saturable absorption, meaning that only a certain amount can be absorbed at one time.
Once the drug is in the blood, it can stay there or enter various tissues throughout the body. The volume of distribution (Vd) is an indication of the extent to which a drug is distributed out of the blood. It is a mathematical relationship between the amount of drug in the body and the concentration in the blood. This is a virtual volume, rather than a physiological one, and expresses the volume that would be required to contain all of the drug in the body at any one time.
In practice, Vd is used to calculate a loading dose for a drug. This is the amount of drug that will quickly reach effective concentrations in the blood. It’s the dose that completely fills the tank, if you will. A loading dose will be higher for drugs with a large Vd than for one with a small Vd.
The half-life of a drug is the time it takes for the concentration in the blood to drop by half. It is usually expressed in hours, but for some drugs it can be a matter of minutes or several days. Half-life is taken into consideration when determining how often to dose a drug. A longer half-life means the drug can be administered less frequently.
Different organs in the body have the ability to break down drugs. This is called drug metabolism. Organs with metabolic capabilities include the liver, kidneys, gastrointestinal tract, and lungs. Blood also contains enzymes that can metabolize drugs.
Enzymes in the liver that metabolize drugs evolved long before humans intentionally took drugs. These enzymes inactivate toxins that are inadvertently ingested, thus preventing damage to the body. Since many drugs are derivatives of natural substances, they are also susceptible to degradation by liver enzymes. Liver disease, such as cirrhosis or hepatitis, can reduce the body’s ability to metabolize drugs.
Two separate processes characterize liver metabolism: phase I reactions and phase II reactions. Phase I reactions usually inactivate or detoxify drugs. After inactivation, phase II reactions add molecules that make the drug more water soluble. This improves the elimination of the drug by the kidneys.
The most common phase I enzymes in the liver are called cytochrome P450 enzymes. Some drugs can increase the production of these enzymes by the liver, leading to a decrease in the concentration of the metabolized drug in the blood. This is called enzyme induction. Other drugs can inhibit cytochrome P450 enzymes. These drugs are called enzyme inhibitors and can cause an increase in the concentration of the metabolized drug.
The final step of pharmacokinetics is the elimination of the drug from the body, also called excretion or clearance. For most drugs, clearance is a constant factor, regardless of how much drug is left in the body. This is called linear pharmacokinetics. For some drugs, however, clearance is saturable, usually because metabolizing enzymes can only break down a fixed amount of drug at a time. Drugs with saturable metabolism and/or clearance exhibit non-linear pharmacokinetics.
Elimination of drugs is mainly done by the kidneys. Inactivated drugs are excreted in the urine and eliminated from the body. Decreased kidney function, whether due to age or diseases such as diabetes or high blood pressure, can reduce the body’s ability to eliminate drugs. The liver also excretes drugs, usually in the bile which is eliminated in the stool.
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