ADME: Distribution of Drugs in the Body

ADME Scheme

• The ADME scheme refers to the Absorption, Distribution, Metabolism, and Excretion of drugs in the body.

Distribution

• Distribution involves the movement of drugs from the systemic circulation to the site(s) of action.
• The extent of distribution can be widespread, organ-specific, or localized.
• Distribution occurs in the following major fluid compartments:
  • Plasma (circulatory fluid)
  • Interstitial fluid (fluid between cells)
  • Intracellular fluid (fluid in cells)
• The circulatory system is the first compartment to which distribution occurs.
• Factors affecting distribution include:
  • Patient characteristics (e.g., blood flow to area, weight, age)
  • Drug characteristics (e.g., formulation, route of administration, solubility, ionization)
  • Physiological conditions (e.g., co-morbidities, drug/food interactions)

Transport in Circulatory System

• Drugs are transported in the circulatory system by binding to plasma proteins or dissolving in plasma.
• Plasma proteins involved in drug binding include:
  • Albumin
  • Lipoproteins
  • Acid glycoprotein
  • α, β, and γ-globulin
• Albumin maintains colloidal osmotic pressure of blood, carries hydrophobic molecules, and is the most important protein involved in drug binding.
• Plasma protein binding can be affected by:
  • Hydrophilic or lipophilic properties of the drug
  • Free and bound fractions of the drug
• Clinical implications of plasma protein binding include:
  • Decreased free fraction and biological activity if highly bound
  • Increased free fraction and biological activity if plasma proteins are saturated or depleted
  • Drug displacement during drug interactions

Body Fat Partitioning

• Body fat consists of a large, non-polar compartment with a poor blood supply.
• Only drugs with high lipophilicity accumulate easily in body fat.
• Chronic administration of lipophilic drugs can lead to accumulation of parent compound and metabolites.

Metabolism

• Metabolism is the process by which drugs are broken down into smaller molecules.
• First-pass metabolism occurs in the liver and affects the bioavailability of oral drugs.
• Clinical implications of first-pass metabolism include:
  • Higher dosage required with oral administration
  • Inter-individual variation in enzyme systems
  • Susceptibility to drug-drug interactions

Michaelis-Menten Kinetics

• Michaelis-Menten kinetics is a model of enzyme kinetics that describes the rate of enzyme reaction.
• The model relates the rate of enzyme reaction (V) to the concentration of substrate (S).
• Parameters of the model include:
  • Vmax: maximum rate of enzymatic reaction
  • Km: Michaelis-Menten constant, which is the substrate concentration at which ½Vmax is defined
• The model allows for the interpretation of inhibition of enzyme function, including:
  • Competitive inhibition: alters the amount of substrate needed
  • Non-competitive inhibition: alters the maximum rate that can be achieved

Excretion

• Excretion is the removal of drugs or metabolites from the body through excretory organs.
• Main routes of excretion include:
  • Kidneys (as urine)
  • Hepatobiliary system (as bile and faecal matter)
  • Lungs (as volatile gases)
• Factors affecting renal excretion include:
  • Patient characteristics (e.g., age, co-morbidities, urinary pH)
  • Drug characteristics (e.g., lipophilicity, plasma protein binding)
  • Physiological conditions (e.g., renal blood flow, urinary volume)

Elimination Rate Constant (kel)

• Elimination rate constant (kel) is the rate of drug elimination from the body per unit time.
• It is a measure of the rate of drug clearance from the body.

Pharmacokinetic Concepts

• Absorption is affected by ionization, which affects the ability of drugs to cross membranes.
• Passive transport involves the movement of drugs across membranes without the use of cellular energy.
• Active transport involves the movement of drugs across membranes against a concentration gradient, using cellular energy.
• Specialized transport mechanisms, such as facilitated diffusion and active transport, can be specific to certain molecules and can be saturated.