Biopharmaceutics

The ADME Process

ADME is an acronym in pharmacology for four simultaneously occurring processes; absorption, distribution, metabolism, and excretion. The four processes, working together, are responsible for blood concentrations of a drug within the body. When viewed altogether, the four processes are called disposition.

Absorption

For a drug to reach its intended site of action, it must be taken into the bloodstream. The process of releasing a drug from its dosage formulation and transferring it into the bloodstream is called absorption. This process occurs to some extent regardless of formulation or route of administration; drugs injected directly into the bloodstream must still be absorbed.

Three factors affect the absorption of a drug: its water solubility, its fat solubility, and the transport mechanisms of the body. It is imperative that you understand that all drugs must be in solution before they can be absorbed.

All body fluids are water based. Therefore, a drug must be soluble in water in order to be absorbed. Dissolution of the drug in aqueous (water) solution is dependent on the pH of the solution and the disintegration of the drug. The speed at which a dosage form disintegrates is dependent upon the type of solid dosage form and the manufacturing process used to make that dosage form. Solid dosage forms can be a tablet, suppository, capsule, powder, or a suspension. Take for example a tablet. The manufacturer may add starch to a tablet in order to make it swell when added to water. A tablet may be a sublingual tablet made to rapidly dissolve in the mouth. The contents of a tablet could be compressed under great pressure so that it will dissolve more slowly. Further, an enteric coating may be applied to a tablet so that it will pass through the stomach and dissolve in the intestine. In the case of some capsules, "extended release capsules" systematically dissolve over a period of time, prolonging the effect of the drug.

The acidity or basicity of the fluids into which a drug is placed will affect how rapidly it will dissolve. The pH of the stomach can be as low as 1.0 (very acidic), the pH of the small intestine can range from 6.9 to 7.4 (slightly acidic to slightly basic), while the pH of the blood plasma is approximately 7.4 (slightly basic). Weakly acidic drugs such as aspirin are more soluble in a basic or alkaline solution like the small intestine (pH above 7.4). Weakly basic drugs, such as tetracycline hydrochloride, are more soluble in an acidic solution like the stomach (pH below 7.0). As drugs dissolve, or dissociate (come apart), they will associate, or attach to other chemicals, in solution. When acids dissociate, they become ionized. When bases dissociate they become unionized. Ionization is simply the process whereby a substance breaks down into positively and negatively charged particles. For example, when hydrochloric acid ionizes, it forms hydrogen ions (H+) and chloride ions (Cl-).

Almost, all biological membranes are lipid (fatty) in nature. Membranes separate the various water compartments of the body and are selectively permeable. That is, the membranes will only allow certain materials to pass through them. In particular, membranes favor the absorption of unionized particles (particles which have neither a positive nor a negative charge). Unionized drugs penetrate biological membranes more easily because electrical charges on the membranes either bind or repel ionized drug particles. Ionized particles also associate (attach) with water molecules which creates large particles unable to pass through biological membranes.

The third factor affecting the absorption of a drug is the transport mechanisms of the body, either passive or active. Passive transport follows a concentration gradient. That is, if there is a high concentration of a substance on one side of the biological membrane and a low concentration of that substance on the other, nature tries to balance the two concentrations so that one is equal to the other. This equalization can occur in one of two ways. One way is for the liquid containing the substance to move from the side with fewer particles to the side with more particles. This process is called osmosis and will ultimately result in the two sides having the same concentration. The second option is for the drug particles to move from the side of higher concentration to the side of the lower concentration. This process is called diffusion and will also ultimately result in the two sides having the same concentration. Most drugs are absorbed via diffusion, particles moving from a higher concentration to a lower concentration.

To understand active transport imagine a roller coaster. You have probably observed that a car on a roller coaster does not have an engine. Common sense dictates that the car does not need an engine to go down hill, but up hill . . . well, that's a different story. You have probably observed that a mechanism exists for pulling the car up hill. Active transport works much the same way. Some proteins that make up the linings of the cells of biological membranes have a particular affinity, or attraction, for particular drugs. When the drug molecules meet the cell wall, these proteins called "carrier molecules" attach themselves to the drug, carry it across the cell membrane, and release it on the other side. The drug then enters the circulation and is distributed throughout the body.

Distribution

Once a drug is absorbed, it enters the circulation and is carried throughout the body. The destination within in the body varies from drug to drug. The drug may be stored in bone or fat, bound to the proteins in the blood plasma, or circulate freely as the unbound drug. The drug will find its way into many organs. Yet finally, some of the drug will reach the target tissue where it can cause the effect for which it was administered.

The distribution of a drug within the body happens in a very systematic way.

Assume that 10 mg of a drug have been absorbed and distributed based on the percentages in the illustration above. Of the 10 mg absorbed, only 0.2 mg of the drug will arrive at the target tissue to give the desired pharmacological effect. If 0.2 mg is enough drugs to produce the desired effect, all is well. However, if the amount of drug required to produce the effect is 1 mg, the desired effect will not be obtained. The dose can be increased so that 50 milligrams of the drug can be absorbed, thus providing the amount of drug needed to give the desired effect. However, increasing the dose may present problems. Increasing the dose would also increase the amount of drug in the other areas of the body. Perhaps this increased dosage may produce some response by another body organ. For example, the patient may become nauseous, vomit, lose his hair, or go into convulsions. These are all side effects of the drug. It is important to remember that the whole body must be taken into account when a drug is administered.

Another area of concern in the distribution of drugs is the crossing of the placental barrier. Drugs may actively or passively cross the placental barrier and enter the fetal circulation. The enzyme systems of a developing fetus may not be able to adequately metabolize certain drugs and toxic effects can result.

Metabolism

The process of drug absorption and distribution is dynamic. That is, it is continually changing. Even as the drug is being distributed, the individual cells of the body begin to chemically change or alter the drug. This metabolic process of changing the drug is called metabolism or biotransformation. The majority of small-molecule drug metabolism is carried out in the liver by redox enzymes, termed cytochrome P450 enzymes. The liver changes drugs to make them more water-soluble so that they may be more easily excreted from the body. As metabolism occurs, the initial drug is converted to new compounds called metabolites. When metabolites are pharmacologically inert, metabolism deactivates the administered dose of drug and this usually reduces the effects on the body. Drugs can undergo one of four potential biotransformations: Active Drug to Inactive Metabolite, Active Drug to Active Metabolite, Inactive Drug to Active Metabolite, Active Drug to Toxic Metabolite (biotoxification). Metabolites may also be pharmacologically active, sometimes more so than the parent drug.

Excretion

Excretion is the process of eliminating a drug or its metabolites from the body. The major organ of excretion is the kidney. The kidneys filter blood and remove waste materials. As blood flows through the kidney, some of the plasma water is filtered from it into the nephron tubule in a process called glomerular filtration. As the water moves along the tubule, additional wastes products and drug can be secreted into the fluid. Some drugs can be reabsorbed back into the blood during a process called urinary reabsorption. After glomerular filtration, renal secretion, and urinary reabsorption are completed, the resulting fluid is excreted from the body as urine.

Secondary routes of excretion are hepatic (liver), through the bile into the feces, lungs, saliva, sweat, and breast milk. The inability of a patient to excrete drugs and other waste can be life threatening. Patients who have limited liver and kidney function usually require lower doses of medication, due to the fact that more of the drug tends to stay in the body.