Drug Elimination

Drug elimination refers to the process by which drugs are removed from the body after they have been administered. The elimination of drugs can occur through various pathways, including renal excretion (in the urine), hepatic metabolism (in the liver), and excretion through the bile and feces.

The rate at which a drug is eliminated from the body can have a significant impact on its pharmacokinetics, including its duration of action and its potential for accumulation in the body. Factors that can affect drug elimination include age, weight, liver and kidney function, as well as other factors such as drug-drug interactions and genetic differences in drug-metabolizing enzymes.

In order to optimize the safe and effective use of drugs, it is important to understand the pharmacokinetics of drug elimination, including the half-life of the drug (the time it takes for the concentration of the drug to decrease by half), and the rate of elimination. This information can be used to adjust dosing regimens as needed, to minimize the risk of adverse effects and maximize the therapeutic benefits of the drug.

The drug eliminated from body either through:

1. Metabolism (biotransformation) in which the drugs undergo a chemical reactions convert them to  a metabolites (some drugs not).
2. Excretion in which the metabolites or drugs are excreted outside the body  

Drug Metabolism 

Drug metabolism refers to the biotransformation of drugs in the body, which involves a series of chemical reactions that alter the pharmacokinetic properties of the drugs. These reactions can include oxidation, reduction, hydrolysis, and conjugation, and they serve to make the drugs more water-soluble and easier for the body to excrete.

Drug metabolism occurs primarily in the liver, but other tissues such as the gut, lung, and kidney can also contribute to the process. The enzymes responsible for drug metabolism are collectively referred to as cytochrome P450 enzymes, and they play a crucial role in determining the pharmacokinetics of a drug, including its efficacy, safety, and potential for drug-drug interactions.

Variability in drug metabolism can result from genetic differences in the expression of drug-metabolizing enzymes, as well as from other factors such as age, gender, liver and kidney function, and concomitant use of other drugs that can affect enzyme activity. Understanding the role of drug metabolism in the pharmacokinetics of a drug is important for optimizing safe and effective use, and for predicting potential adverse effects.

Drug metabolism it is non-selective detoxification process by which the body adapts drugs (Xenobiotics). It called also drug biotransformation: chemical changing of the drug by the body.

Main aim of drug metabolism: Convert lipophilic drug to less lipid soluble form to be easily excreted.

The main site of drug metabolism is:

-Liver.

-Other sites include:

• Intestinal wall.
• Lung.
• Skin.
• Plasma and kidney.

Drug metabolism involve 2-phases which often, but not always, occur sequentially:

Phase 1; Non synthetic (chemical change):

• Which occur first (more commonly) and convert drug to more polar metabolite through oxidation, reduction or hydrolysis reactions  by a microsomal or non-microsomal enzymes.
• Result in: less active –more active or toxic metabolite.

Phase 2; Synthetic (conjugation):

• Which occurs second  and convert insufficient polar metabolites from phase 1 to sufficient polar one to be excreted through conjugation with endogenous substances by transferase enzymes.
• Usually results in inactive metabolite.

Drug Elimination 

Consequence of Drug Metabolism 

Drug metabolism can have a number of important consequences for the pharmacokinetics and pharmacodynamics of a drug. Some of the key consequences of drug metabolism include:

1. Determining drug efficacy: The rate and extent of drug metabolism can affect the concentration of the drug in the bloodstream and its ability to reach the target site in the body, thus impacting its efficacy.
2. Modifying drug safety: Some drugs and their metabolites can be toxic or produce adverse effects, and the rate and extent of drug metabolism can affect the exposure of the body to these harmful substances.
3. Predicting drug-drug interactions: The metabolism of drugs can be affected by other drugs that are taken simultaneously, leading to changes in the pharmacokinetics of the drugs involved and potentially increasing the risk of adverse effects.
4. Genetic variability: The activity of the enzymes responsible for drug metabolism can vary between individuals, due to genetic differences. This variability can lead to differences in the pharmacokinetics and pharmacodynamics of a drug between individuals, including differences in efficacy and toxicity.
5. Change solubility: Convert lipophilic drug to less lipid soluble to be easily excreted metabolites.
6. Change the pharmacological activity:

• Active to inactive (inactivation process)
• Inactive (or less active) to active (activation process) →prodrug 
• Active or toxic (toxification process)

Type of metabolizing enzyme system

1. Microsomal drug metabolizing enzymes. 

The major enzyme system responsible for drug metabolism is the cytochrome P450 (CYP450) enzyme system. CYP450 enzymes are a family of heme-containing enzymes that are found primarily in the liver, but also in other tissues such as the gut and kidney.

CYP450 enzymes play a crucial role in the biotransformation of drugs, including the oxidation, reduction, hydrolysis, and conjugation of drugs. There are several different subfamilies of CYP450 enzymes, each with distinct substrate specificity and thus responsible for the metabolism of different classes of drugs.

• Synthesized in endoplasmic reticulum.
• Also called cytochrome (contain heme) p450.
• Concentrated mainly in liver but may be in other tissue.
• Stored in microsome.
• Non selective (metabolize many drugs)
• Mainly implicated in oxidation-reduction reaction.
• There are multiple isoforms.

Some of the most important CYP450 enzymes involved in drug metabolism include:

1. CYP1A2: responsible for the metabolism of drugs such as caffeine and theophylline
2. CYP2C9: involved in the metabolism of drugs such as warfarin and losartan
3. CYP2D6: involved in the metabolism of drugs such as codeine, tamoxifen, and dextromethorphan
4. CYP3A4: responsible for the metabolism of a wide range of drugs, including calcium channel blockers, anti-infectives, and immunosuppressants

Variability in the expression and activity of CYP450 enzymes can result from genetic differences, as well as from other factors such as age, gender, liver function, and drug-drug interactions. Understanding the role of CYP450 enzymes in drug metabolism is important for optimizing safe and effective use, and for predicting potential adverse effects.

2. Non microsomal enzymes.

In addition to the cytochrome P450 (CYP450) enzyme system, there are several other non-microsomal enzyme systems involved in drug metabolism, including:

1. Flavin-containing monooxygenases (FMOs): These enzymes are primarily located in the liver and gut and play a role in the biotransformation of drugs such as trimethylamine.
2. Aromatic amine N-acetyltransferases (NATs): These enzymes are primarily located in the liver and play a role in the biotransformation of drugs such as isoniazid.
3. Glucuronosyltransferases (UGTs): These enzymes are found in the liver and other tissues and play a role in the conjugation of drugs, making them more water-soluble and easier for the body to excrete.
4. Sulfotransferases (SULTs): These enzymes are found in the liver and other tissues and play a role in the sulfation of drugs, making them more water-soluble and easier for the body to excrete.
5. Methyltransferases (MTs): These enzymes play a role in the methylation of drugs, altering their pharmacokinetic properties.

Each of these non-microsomal enzyme systems has distinct substrate specificity and may play a role in the biotransformation of specific classes of drugs. Understanding the role of these enzyme systems in drug metabolism is important for optimizing safe and effective use, and for predicting potential adverse effects.

Enzyme induction

Enzyme induction is a process by which the expression and activity of drug-metabolizing enzymes, such as the cytochrome P450 (CYP450) enzyme system, is increased in response to exposure to certain drugs or other chemical compounds.

Enzyme induction can have important implications for the pharmacokinetics and pharmacodynamics of drugs. For example, the induction of CYP450 enzymes can increase the rate of drug metabolism, leading to decreased drug concentration in the bloodstream and reduced efficacy. Conversely, the induction of CYP450 enzymes can also increase the rate of metabolism of other drugs taken concurrently, leading to increased clearance and reduced adverse effects.

Enzyme induction can occur as a result of exposure to drugs such as rifampin, phenobarbital, and carbamazepine, which are known to induce CYP450 enzymes. Other chemicals such as alcohol and certain dietary compounds can also induce CYP450 enzymes.

Enzyme inhibition

Enzyme inhibition is a process by which the expression and activity of drug-metabolizing enzymes, such as the cytochrome P450 (CYP450) enzyme system, is decreased in response to exposure to certain drugs or other chemical compounds.

Enzyme inhibition can have important implications for the pharmacokinetics and pharmacodynamics of drugs. For example, the inhibition of CYP450 enzymes can decrease the rate of drug metabolism, leading to increased drug concentration in the bloodstream and increased efficacy. Conversely, the inhibition of CYP450 enzymes can also decrease the rate of metabolism of other drugs taken concurrently, leading to decreased clearance and increased adverse effects.

Enzyme inhibition can occur as a result of exposure to drugs such as cimetidine, ketoconazole, and erythromycin, which are known to inhibit CYP450 enzymes. Other chemicals such as grapefruit juice and certain dietary compounds can also inhibit CYP450 enzymes.

 Determinant of drug metabolism

The rate and extent of drug metabolism can be influenced by several factors, including:

1. Genetic factors: Variations in the genes that code for drug-metabolizing enzymes, such as the cytochrome P450 (CYP450) enzyme system, can result in differences in the rate and extent of drug metabolism among individuals.
2. Age: The activity of drug-metabolizing enzymes can change with age, with some enzymes becoming less active and others becoming more active with aging.
3. Sex: Differences in hormone levels and the activity of drug-metabolizing enzymes can result in differences in drug metabolism between men and women.
4. Body size and composition: The amount of drug-metabolizing enzymes in the body can vary based on body size and composition, affecting the rate and extent of drug metabolism.
5. Diet: Certain dietary compounds can induce or inhibit drug-metabolizing enzymes, affecting the rate and extent of drug metabolism.
6. Disease state: Certain disease states, such as liver or kidney disease, can affect the activity of drug-metabolizing enzymes, altering the rate and extent of drug metabolism.
7. Drug interactions: Concurrent use of multiple drugs can result in drug-drug interactions, as some drugs can induce or inhibit the activity of drug-metabolizing enzymes.