Pharmacokinetic (I)

1. Drug Permeation and Disposition Processes (ADME)

Drug permeation and disposition involve several processes that determine the pharmacokinetics of a drug. The major processes are:

• Absorption: Absorption refers to the movement of a drug from its site of administration into the bloodstream. The rate and extent of absorption can be influenced by factors such as the physicochemical properties of the drug (lipophilicity, molecular weight, degree of ionization), the route of administration (oral, intravenous, topical, etc.), blood flow to the absorption site, and the formulation of the drug.

• Distribution: Distribution is the transportation of a drug throughout the body to its target site(s) of action. Factors affecting drug distribution include blood flow to tissues, drug-protein binding, tissue permeability, and the physicochemical properties of the drug. Lipophilic drugs tend to distribute more extensively into tissues, while hydrophilic drugs may be more confined to the vascular space.

• Metabolism: Metabolism involves the biotransformation of a drug into metabolites, usually occurring in the liver. Drug metabolism can involve Phase I reactions (oxidation, reduction, hydrolysis) and Phase II reactions (conjugation). The liver is the primary site of drug metabolism, but other organs and tissues can also contribute. Enzyme activity, particularly cytochrome P450 enzymes, plays a significant role in drug metabolism.

• Excretion: Excretion is the elimination of a drug and its metabolites from the body, primarily through urine and feces. The kidneys play a crucial role in renal excretion, while hepatic/biliary excretion contributes to drug elimination via the bile into the feces. Other routes of excretion include sweat, saliva, and breast milk. Drug clearance, which represents the rate at which a drug is eliminated, is an important parameter in determining dosing regimens.

2. First Pass Metabolism and Bioavailability

First pass metabolism refers to the initial metabolism of a drug in the liver before it reaches systemic circulation. The liver can metabolize a significant portion of an orally administered drug, resulting in reduced bioavailability. Bioavailability is the fraction of the administered dose that reaches the systemic circulation unchanged and is available to exert its pharmacological effects.

Factors affecting first pass metabolism and bioavailability include:

• Liver enzyme activity: Enzymes in the liver, such as cytochrome P450 enzymes, can metabolize drugs and reduce their bioavailability. Genetic variations in these enzymes can lead to interindividual differences in drug metabolism and response.

• Gut metabolism: Some drugs may undergo metabolism in the gut wall or intestinal lumen before reaching the liver. This “pre-systemic” metabolism can also contribute to the overall reduction in bioavailability.

• Drug formulations: The formulation of a drug can affect its absorption and bioavailability. Different formulations, such as immediate-release or extended-release formulations, may have varying rates and extents of absorption.

• Drug interactions: Concurrent use of other drugs or substances can affect the metabolism of a drug and its bioavailability. Drug-drug interactions can result in inhibition or induction of metabolic enzymes, altering the pharmacokinetics and therapeutic effects of the drugs involved.

The clinical significance of first pass metabolism and bioavailability lies in understanding the factors that influence the systemic exposure and therapeutic response to orally administered drugs. It is crucial for determining appropriate dosing regimens and ensuring optimal drug efficacy.

3. Plasma Protein Binding, Drug Distribution, and Duration of Action

Plasma protein binding refers to the reversible binding of drugs to proteins, primarily albumin, in the blood. Bound drugs are inactive and less available for distribution to tissues, while unbound (free) drugs are pharmacologically active. Protein binding affects drug distribution and can influence the duration of action of a drug.

• Drug distribution: Protein-bound drugs have limited ability to distribute into tissues compared to unbound drugs. Only unbound drugs can cross cellular membranes and reach their target sites. Changes in plasma protein levels or displacement of drugs from protein binding sites by other drugs can alter the distribution of drugs and their pharmacological effects.

• Drug redistribution: Drugs that are extensively bound to plasma proteins can be displaced from protein binding sites, leading to drug redistribution. This can result in changes in drug concentration over time, affecting the duration of action.

• Enterohepatic circulation: Some drugs can undergo enterohepatic circulation, which involves the reabsorption of drugs from the intestine back into the liver via the bile. This recycling process can extend the duration of action of certain drugs as they undergo repeated cycles of elimination and reabsorption.

Understanding the influence of plasma protein binding on drug distribution and the potential for drug redistribution and enterohepatic circulation is important in determining dosing regimens, predicting drug interactions, and managing drug concentrations within the therapeutic range.

4. Phases of Biotransformation and Clinical Significance

Biotransformation, or drug metabolism, occurs in two main phases:

• Phase I reactions: Phase I reactions involve the introduction or exposure of functional groups on the drug molecule. These reactions typically include oxidation, reduction, and hydrolysis. Phase I reactions can convert prodrugs into active forms or inactive drugs into active metabolites. They can also generate reactive metabolites that may contribute to drug toxicity or adverse effects.

• Phase II reactions: Phase II reactions involve the conjugation of drugs or their Phase I metabolites with endogenous molecules, such as glucuronic acid, sulfate, or amino acids. Conjugation reactions increase the water solubility of drugs, facilitating their excretion. Phase II reactions play a crucial role in the elimination of drugs from the body.

The clinical significance of biotransformation lies in its impact on drug efficacy, safety, and elimination. Drug metabolism can determine the onset, duration, and intensity of pharmacological effects. It can also lead to the formation of metabolites with different pharmacological properties or toxicity profiles. Understanding the metabolic pathways and potential drug-drug interactions is essential for appropriate dosing and minimizing the risk of adverse reactions.

5. Processes of Drug Excretion and Clinical Significance

Excretion is the process by which drugs and their metabolites are eliminated from the body. The two primary routes of drug excretion are renal excretion and hepatic/biliary excretion.

• Renal excretion: The kidneys filter drugs from the blood and excrete them into urine. Renal excretion is influenced by factors such as glomerular filtration, tubular secretion, and tubular reabsorption. Impaired renal function can result in drug accumulation and potential toxicity. Adjustments in drug dosing are often required in patients with renal dysfunction.

• Hepatic/biliary excretion: Drugs and their metabolites can be excreted into bile and eliminated in feces. Hepatic/biliary excretion contributes to the elimination of lipophilic drugs and their metabolites. Some drugs can undergo enterohepatic circulation, where they are reabsorbed from the intestine back into the liver via the bile. This process can prolong the duration of drug action and affect dosing regimens.

• Drug clearance: Clearance represents the rate at which a drug is eliminated from the body and is a crucial parameter in determining dosing regimens. Clearance is influenced by various factors, including renal and hepatic function, protein binding, and metabolic enzyme activity. Understanding drug clearance helps optimize drug dosing and maintain therapeutic drug levels.

The processes of drug excretion play a vital role in terminating drug action, preventing drug accumulation, and minimizing the risk of toxicity. Monitoring renal and hepatic function, considering drug interactions, and adjusting dosing regimens in patients with impaired excretory function are essential for safe and effective drug therapy.