Pharmacokinetics: Clearance and Bioavailability

Clearance (CL)

• Clearance is a critical ADME parameter reflecting the rate at which compounds are removed from systemic circulation.
• Primary organs involved are the liver (metabolism and biliary excretion) and kidneys (urinary excretion).
• Drug clearance does not change and is a quantitative measure of drug elimination.
• Routes of drug elimination include hepatic biotransformation, kidney and bile excretion, exhalation, and fecal excretion.
• Clearance is expressed in terms of volume of body fluid cleared of a drug per unit time.

Bioavailability

• Bioavailability measures the percentage of unchanged drug entering the systemic circulation post-administration.
• AUC (area under the curve) reflects drug absorption and is calculated as:
  • Bioavailability = [AUC (oral) / AUC (IV)] x 100%
• Factors affecting bioavailability include:
  • Drug formulation affecting dissolution time.
  • Drug interactions in the GI tract, such as complex formation.
  • Biotransformation before entering systemic circulation.

Kinetics of Drug Metabolism

• First Order Kinetics:
  • Drug metabolism is concentration-dependent with a constant percentage metabolized and constant half-life.
• Zero Order Kinetics:
  • Metabolism is independent of concentration with a constant amount metabolized; half-life varies, leading to overdose risks with large initial doses (e.g., alcohol).

Polypharmacy

• Defined as concurrent use of multiple medications (over five), which can raise the risk of adverse drug reactions.
• Important to balance between needed therapies and avoiding unnecessary medications.

Cytochrome P450 (CYP)

• A superfamily of membrane-bound hemoprotein isozymes crucial for xenobiotic (e.g., drug) metabolism.
• Predominantly functions in the liver, intestines, and kidneys with highest levels in the liver.
• Defective metabolism may affect drug dosing significantly (e.g., debrisoquine affected by CYP2D6).

Genetic Factors in Drug Responses

• Genetic variations can impact drug metabolism leading to adverse reactions (e.g., G-6-PD deficiency).
• Over 400 million people carry G-6-PD deficiency, increasing hemolytic reactions to certain drugs.
• Pharmacogenetics helps predict individual drug responses based on genetic makeup.

Therapeutic Misadventures

• Alcohol interactions with other medications can lead to toxicity even at so-called "safe" doses.
• 13% of drug-related fatalities involve alcohol and other drugs.
• Anxiolytics are frequently implicated in fatal interactions, particularly regarding respiratory and cardiac functions.

Toxic Interactions

• Toxic interactions with substances like alcohol can occur via:
  • Physicochemical: Prior to administration.
  • Pharmacokinetic: Altered absorption or elimination (e.g., gastric pH, plasma binding).
  • Pharmacodynamic: Changes in drug effects on the body (e.g., acetaminophen toxicity leads to acute liver failure).

Dose Determination

• Dose impacts whether a substance is beneficial or toxic:
  • Example beneficial doses: Aspirin (300-1000 mg), Vitamin A (300-1000 mg), Oxygen (20% air).
  • Toxic doses significantly exceed beneficial ones.

Maximum Tolerated Dose (MTD)

• MTD refers to the highest dose that produces the desired effect without unacceptable toxicity.
• Helps in assessing long-term health effects of chemical exposure without leading to premature mortality.

Environmental Factors in Drug Therapy

• Microsomal enzyme inducers (e.g., tobacco smoke) lead to increased drug metabolism rates.
• Pollution can also induce P450 enzymes influencing drug efficacy and safety.

Food-Drug Interactions

• Certain foods can affect drug absorption:
  • Calcium foods inhibit tetracycline absorption.
  • High-calorie meals can enhance drug absorption (e.g., saquinavir).
  • Grapefruit juice can significantly increase blood levels of drugs like felodipine by inhibiting CYP3A.

Importance of Pharmacogenetics

• Aids in identifying individuals' variability in drug responses and optimizing dosage.
• Genetic polymorphisms relate to ADME processes - affecting pharmacokinetics and dynamics.
• Differences can stem from monogenic (single gene) or multigenic (multiple gene) variations.

Genetic Variants

• Monogenic variants often lead to significant drug metabolism issues due to enzyme absence.
• Multigenic traits impact complex phenotypes influenced by both genetics and environment.

This quiz covers essential concepts in pharmacokinetics, focusing on clearance and bioavailability. It examines how drugs are eliminated from the body, the significance of various organs, and the factors influencing bioavailability. Test your understanding of these critical pharmacological parameters.