Role of the Liver in Drug Metabolism

Role of the Liver in Drug Metabolism:

Reabsorbed drugs are picked up by the liver cells and transformed into metabolites by enzymes located in the cells. Metabolites are less capable of being reabsorbed and are emitted in the urine.

As a drug is carried to the liver some is cleared from the blood by the liver cells, processed into by- products and returned to the blood stream. The metabolites are then carried to the kidneys, filtered, poorly reabsorbed and remain in the urine until expelled.

The Cytochrome P450 enzyme family is the major system involved in drug metabolism. They are responsible for the purification of chemicals, food toxins and drugs. This enzyme system has developed over 3.5 billion years and can detoxify a chemically diverse group of substances. CYP-1, CYP-2, CYP-3 are responsible for encoding the enzymes involved in most drug biotransformation.

Genetic, environmental, cultural and physiological factors can alter the rate at which drugs are metabolized. Genetic DNA testing can now identify how a person’s body may break down a drug. Results provide a scientific basis for understanding why a person might have an unexpected toxic reaction or might fail to respond to what was thought to be a therapeutic dose.

A Normal Metabolizer: the genes produce a typical amount of enzyme and the prescribed drug works the way it should. Helping the condition and causes few side effects.

A Slow Metabolizer: the genes produce too little enzyme and the prescribed drug builds up in the body causing intolerable side effects.

The Fast Metabolizer: the genes produce too much enzyme and the prescribed drug is eliminated too quickly providing little or no improvement in the illness.

If more than one drug is present in the body, the drugs may interact with one another in a beneficial way or in a way that has adverse effects. In the liver, one drug can either increase or reduce the rate of metabolism of the second drug, reducing or increasing the blood level of the second drug.

Enzyme induction is a process that induces an apparent tolerance to other drugs metabolized by the enzyme CYP-3A3/4. Metabolic drug tolerance develops as the blood level of drug falls more rapidly than would be expected if tolerance had not developed. So any other drug that is metabolized by the same enzyme will also be broken down more rapidly. The second drug becomes less effective because it is metabolized quickly as a result of the increased amount of metabolic enzyme. When the drug has less of an effect it is called cross tolerance.

Concept of Drug Half Life:

Half life of a drug is the duration of action in the body. It’s the time required for the drug concentration to be reduced by 1 half and it determines the length of time necessary to reach the steady state or the full effective concentration. It is important to know because it tells us how long a drug remains in the body. Even though the blood level of a drug is reduced by 75% after two half-lives, the drug persists in the body a low levels for at least six half lives. This causes the hangover effect. Most drug half lives are measured in hours others in days and recovery from the drug may take a week or more.

Knowing about the relationship between the time course of drug action in the body and its pharmacological effects is essential for:

- Predicting the correct dosage and dose intervals needed to reach a therapeutic effect

- Maintain a therapeutic drug level for the desired period of time

- Determining