Pharmacokinetics

Pharmacokinetics = cellular process by which ions and molecules move across the cell membrane.

Cell membrane = barrier that separates the interior of the cell (cytoplasm) from the outside environment.

Drug Absroption

The process by which drug is absorbed in systemic circulation from the site of administration.

Factors affecting drug Absroption

1. Physicochemical Properties of the Drug:

• Solubility: A drug needs to be dissolved in the surrounding fluid (e.g., stomach juices) for absorption. Poorly soluble drugs are absorbed slower or not at all.
• Size and shape: Smaller molecules with simpler shapes generally pass through cell membranes more easily, leading to faster absorption.
• Ionization: The charge of a drug molecule (ionized or non-ionized) affects its ability to pass through cell membranes. Lipid-soluble, non-ionized drugs typically penetrate membranes better.
• pKa (acid dissociation constant): This value determines the extent of ionization at a specific pH. Drugs with a pKa close to the pH of the absorption site (e.g., stomach for oral drugs) will have a higher concentration of the non-ionized form, facilitating absorption.
• Partition Coefficient (P): This value reflects the drug’s relative solubility in n-octanol (a fat-like solvent) and water. A higher P indicates greater lipophilicity (preference for fat or lipids). Drugs with higher P values tend to passively diffuse through cell membranes more readily, leading to faster absorption. However, an extremely high P could lead to trapping in membranes and hinder absorption.

2. Dosage Form:

• Disintegration and dissolution: Tablets, capsules, etc., need to disintegrate and dissolve into the surrounding fluid for the drug to be released and absorbed. Formulations with faster disintegration and dissolution rates generally lead to quicker absorption.
• Excipients: Inactive ingredients can influence absorption. For example, certain fillers or binders might slow down dissolution.

3. Route of Administration:

• Oral: The most common route, but absorption can be affected by stomach emptying rate, presence of food, and first-pass metabolism (drug breakdown before reaching systemic circulation).
• Sublingual/Buccal: Drugs placed under the tongue or between the cheek and gum are absorbed directly into the bloodstream, bypassing first-pass metabolism but offering limited surface area for absorption.
• Injection (Intravenous, Intramuscular, Subcutaneous): Bypasses absorption altogether, delivering the drug directly into the bloodstream for the fastest effect. The specific site of injection influences absorption rate (e.g., intramuscular slower than intravenous).
• Topical: Drugs applied to the skin or mucous membranes may have limited systemic absorption depending on the skin’s permeability and the drug’s properties.
• Inhalation: Drugs delivered through the lungs can be rapidly absorbed into the bloodstream.

4. Physiological Factors:

• Age: Absorption can be slower in infants and older adults due to changes in body composition and gastrointestinal function.
• Gastrointestinal motility: Faster motility can decrease absorption time for oral drugs.
• Blood flow: Blood flow at the absorption site can affect the rate at which drug enters the bloodstream.
• Diseases: Certain gastrointestinal diseases can impair absorption.

5. Other Factors:

• Food: Food in the stomach can delay gastric emptying and slow down absorption of oral medications.
• Drug interactions: Certain medications can compete for the same absorption pathways, potentially reducing absorption of one another.

Types of Membrane Transport

Passive Diffusion:

• Definition: Movement of drug molecules from an area of high concentration to low concentration across a cell membrane without the use of energy.
• Characteristics:
  • No energy required.
  • Moves down the concentration gradient.
  • Lipid-soluble and non-ionized drugs pass through more easily.

Facilitated Diffusion:

• Definition: Similar to passive diffusion but involves specific carrier proteins in the cell membrane.
• Characteristics:
  • No energy required.
  • Moves down the concentration gradient.
  • Transported via carrier proteins.
  • Can be saturated if all carrier proteins are occupied.

Active Transport:

• Definition: Movement of drug molecules against their concentration gradient, requiring energy (usually ATP).
• Characteristics:
  • Requires energy.
  • Moves against the concentration gradient.
  • Involves specific carrier proteins (transporters).
  • Can be saturated.

Endocytosis and Exocytosis:

• Endocytosis: The process by which cells engulf substances into a pouch which then becomes a vesicle.
  • Pinocytosis: Engulfing of liquid.
  • Phagocytosis: Engulfing of solid particles.
• Exocytosis: The process by which cells expel substances contained in vesicles to the outside of the cell.

Factors Affecting Membrane Transport:

Drug Properties:

• Molecular Size: Smaller molecules pass through membranes more easily.
• Lipophilicity: Lipid-soluble drugs pass through lipid membranes more readily.
• Ionization: Non-ionized forms of drugs are more easily transported across membranes.

Membrane Properties:

• Thickness and Composition: Thinner and lipid-rich membranes facilitate easier transport.
• Presence of Transport Proteins: Specific transporters can facilitate or inhibit drug movement.

Concentration Gradient:

• The difference in drug concentration across the membrane drives passive and facilitated diffusion.

Energy Availability:

• Adequate ATP levels are necessary for active transport mechanisms.

Importance of membrane transport:

Absorption, distribution, metabolism, and excretion

Membrane transporters:

Transporter	Function	Locations
Efflux Transporters
Efflux Transporters	Pumps drugs out of cells, reducing drug absorption and increasing drug elimination.	Intestinal epithelium, blood-brain barrier, liver, kidney, and placenta.
Multidrug Resistance-associated Proteins (MRPs) (ABCC family)	Transport a wide range of substrates, including drugs and their metabolites, out of cells.	Liver, kidney, intestines, and brain.
Breast Cancer Resistance Protein (BCRP) (ABCG2)	Similar to P-gp, it limits drug absorption and promotes drug excretion.	Intestines, liver, brain, and placenta.
Uptake Transporters
Organic Anion Transporting Polypeptides (OATPs) (SLCO family)	Mediate the uptake of a broad range of drugs, including statins and anticancer agents.	Liver, kidney, intestines, and brain.
Organic Anion Transporters (OATs) (SLC22 family)	Involved in the renal excretion of various drugs.	Kidney, liver, and other tissues.
Organic Cation Transporters (OCTs) (SLC22 family)	Facilitate the uptake of organic cations, including drugs and endogenous compounds.	Kidney, liver, intestines, and brain.

Few additional points:

• There are some drugs which affect the absorption and distribution of other drugs by inhibiting P-gp
• ABCC are a family of transport proteins. These are called ATP binding casette transporters

Drug Distribution

Movement of a drug molecule from the bloodstream to various tissues throughout the body.

Factors affecting drug distribution

Blood Flow: Highly perfused organs (liver, kidneys, heart) receive drugs faster.Tissue Permeability:

• High Permeability: Drugs easily enter tissues like muscle.
• Low Permeability: Blood-brain barrier restricts drug entry to the brain.
• Fat Solubility: Lipid-soluble drugs can accumulate in fat tissue, affecting distribution time.

Protein Binding: As mentioned earlier, higher protein binding reduces the amount of free drug available for distribution.Body Composition:

• Muscle: High water content allows for good drug distribution.
• Fat: Stores drugs, leading to a larger volume of distribution and potentially slower action.

Bound vs Unbound

• Drugs can bind to plasma proteins (mainly albumin) in the bloodstream.
• Only the unbound drug is free to diffuse out of the bloodstream and reach tissues.
• The higher the protein binding, the less drug is available for distribution and action.

Protein Binding

Protein binding = Reversible binding of drug to plasma proteins. Major plasma protein is Albumin.

Impact on Distribution:

• Only the unbound fraction of the drug is free to diffuse out of the bloodstream and reach target tissues.
• Higher protein binding translates to a larger proportion of the drug being bound and less available for distribution and action.

Factors Affecting Binding:

• Drug Properties: Chemical structure, charge, and hydrophobicity of the drug influence its affinity for binding sites on proteins.
• Plasma Protein Concentration: Changes in albumin levels (e.g., due to illness) can affect the amount of drug bound and available for distribution.
• Competition for Binding Sites: Multiple drugs can compete for the same binding sites on proteins. This competition can displace a bound drug, increasing its free fraction and potentially leading to altered effects.

Plasma proteins involved in protein binding

1. Albumin

• Function: Albumin is the most abundant plasma protein and plays a major role in maintaining oncotic pressure (colloid osmotic pressure) and transporting various endogenous and exogenous substances.
• Binding Characteristics:
  • Primary Binding Sites: Two major drug-binding sites (Site I and Site II).
  • Drugs Bound: Weak acids and neutral drugs (e.g., warfarin, phenytoin, ibuprofen).
• Significance: The binding of drugs to albumin is reversible and can be influenced by factors such as pH, the presence of other drugs, and disease states.

2. α1-Acid Glycoprotein (AAG)

• Function: AAG, also known as orosomucoid, is an acute-phase protein whose levels increase in response to inflammation and stress.
• Binding Characteristics:
  • Primary Binding Site: One primary binding site.
  • Drugs Bound: Basic (cationic) and neutral drugs (e.g., lidocaine, propranolol, imipramine).
• Significance: The levels of AAG can vary significantly in different physiological and pathological conditions, affecting drug binding and availability.

3. Lipoproteins

• Function: Lipoproteins are complexes of lipids and proteins that transport lipids through the bloodstream.
• Binding Characteristics:
  • Types: High-density lipoprotein (HDL), low-density lipoprotein (LDL), very low-density lipoprotein (VLDL).
  • Drugs Bound: Highly lipophilic drugs (e.g., cyclosporine, amiodarone).
• Significance: The binding of drugs to lipoproteins can influence their distribution, particularly to tissues with high lipid content.

4. Globulins

• Function: Globulins are a diverse group of proteins involved in various functions, including immune responses and hormone transport.
• Binding Characteristics:
  • Types: α, β, and γ globulins.
  • Drugs Bound: Steroid hormones, vitamins, and other specific drugs.
• Significance: Different globulins bind specific endogenous substances and drugs, impacting their pharmacokinetics and dynamics.