Pharmacokinetics: Drug ADME and Absorption

• Pharmacokinetics (PK) studies drug movement into, around, and out of the body.
• Key properties (ADME) determine a drug's onset, intensity, and duration of action.

ADME

• Absorption
• Distribution
• Metabolism
• Excretion
• Clinicians use pharmacokinetic parameters to design optimal drug regimens, considering route, dose, frequency, and duration of treatment.

Absorption

• Absorption involves movement of a drug from its administration site into systemic circulation or lymph, usually across a membrane.
• Absorption rate and extent relies on the environment, drug characteristics, and administration route, which impacts bioavailability.
• Routes of administration other than intravenous may result in partial absorption and lower bioavailability.

Mechanisms of Absorption of Drugs from the GI tract

• Passive diffusion is driven by concentration gradients, doesn't require a carrier, isn't saturable, has low specificity and is how most drugs are absorbed.
• Facilitated diffusion involves transmembrane carrier proteins for large molecules from high to low concentrations without energy.
• Active transport needs energy and specific carrier proteins against concentration gradients.
• Endocytosis/exocytosis transports large drugs across membranes.
• Endocytosis involves engulfing the drug via vesicles (e.g., Vitamin B12) and exocytosis is vesicle-mediated release (e.g., norepinephrine).

Factors Influencing Absorption

• Physicochemical properties like solubility, pKa, ionization, and particle size affect absorption.
• Solutions absorb more efficiently than suspensions or tablets.
• Intestines' greater blood flow favors absorption over the stomach.
• Shock reduces blood flow, limiting absorption.
• Intestines' microvilli-rich brush borders provide a greater (1000x) surface area than the stomach, increasing efficiency.
• Rapid GI transit reduces absorption time, limited drug exposure.
• Delayed gastric emptying slows movement to the small intestine.
• Food can dilute drug concentration and delays gastric emptying.
• P-glycoprotein transports drugs back into the blood, also contributing to multidrug resistance, and reduces drug absorption.

Bioavailability

• Bioavailability is the rate and extent an administered drug reaches systemic circulation.
• Determined by comparing plasma levels after a route of administration with levels achieved by IV.
• Bioavailability of PO is the ratio of the area of drug under the curve following oral administration to the area under the curve following IV administration
• Area under the curve is measured by plotting plasma concentrations versus time.

Factors Influencing Bioavailability

• First-pass hepatic metabolism in the portal circulation reduces the amount of active drug reaching its target.
• Poorly water-soluble drugs and oil-loving drugs are poorly absorbed, so optimal absorption requires a balance.
• Drugs are unstable in gastric pH.
• Formulation factors like particle size, salt form, crystal polymorphism, enteric coatings, and excipients affect dissolution and absorption.

Bioequivalence & Therapeutic Equivalence

• Bioequivalent drugs have comparable bioavailability and similar times to peak blood concentrations.
• Therapeutic equivalence means they have similar clinical and safety profiles and have the same dosage, active ingredient, and administration route.
• Two drugs that are bioequivalent may not be therapeutically equivalent.

Distribution

• Distribution is the process where a drug reversibly leaves the bloodstream and enters the interstitium and tissues.
• For IV drugs, absorption is not a factor, the distribution phase is when the drug rapidly leaves the circulation and enters the tissues.

Factors Influencing Drug Distribution

• Blood flow: highest in brain, liver, kidney; moderate in muscle; lowest in adipose tissue.
• Capillary permeability: Liver and spleen have large capillaries.
• The brain has capillaries with no slit junctions to form the blood-brain barrier.

Capillary Permeability - Drug Entry into the Brain

• Must pass through endothelial cells.
• Lipid-soluble drugs can dissolve in the lipid membranes.
• Ionized/polar drugs cannot pass into the CNS.
• CNS capillaries lack slit junctions, and juxtaposed cells creating the blood-brain barrier.

Factors Influencing Drug Distribution

• Plasma protein binding slows transfer and sequesters drugs, acting as a drug reservoir, and maintaining free-drug concentration.
• Drugs can accumulate in tissues via binding or active transport, prolonging its action or causing local toxicity.
• Apparent Volume of Distribution (Va) is the fluid volume needed to contain the drug in the body at the same concentration measured in the plasma.
• A high molecular weight or extensive protein binding results in a low Vd.
• Vd can be usefel to compare the distribution of a drug with the volumes of the water components in the body.
• Va influences drug half-life, as elimination depends on the drug amount delivered to excretory organs per time unit.
• Drugs with large Va are mostly in the extraplasmic space, making them less available for elimination.

Metabolism

• Metabolism is the body's processing of drugs into subsequent compounds.
• Often converts drugs into more water-soluble forms for renal clearance.
• Prodrugs are activated by metabolism.
• Metabolism mainly happens in the liver.
• Phase I reactions use CYP450 enzymes, transforming drugs into polar metabolites.
• Phase II reactions use UGT enzymes, conjugating metabolites to make them hydrophilic.

Factors Influencing Drug Metabolism

• Drug Interactions: Competitive Inhibition
• Genetic Variation: Genetic polymorphisms affect drug metabolism.
• Nutritional State influences conjugating agents.
• Dosage: High doses can saturate metabolic enzymes.
• Drug metabolism is slower in extremes of age.

Excretion

• Excretion eliminates leftover parent drugs and metabolites after absorption, distribution, and metabolism.
• The kidneys filter drugs and metabolites from the bloodstream.
• The liver excretes byproducts and waste via bile.
• The lungs eliminate volatile substances.

Kinetics of Elimination

• Clearance (CL) is the theoretical volume of plasma from which drug is completely moved in unit time (CL = Rate of elimination (RoE)/C).
• First Order Kinetics (exponential) is when the drug elimination is directly proportional to drug concentration
• In first order kinetics, a constant fraction of drug is eliminated per unit time.
• Zero Order Kinetics (linear): The rate of elimination remains constant irrespective of drug concentration
• In zero order kinetics, the clearance decreases with increase in concentration.
• Zero order kinetics applies in to alcohol, theophyline & tolbutmide

Plasma Half-Life (t½)

• Time required to decrease to half of its original value (t = 0.693 × V/CL).
• Directly proportional is the volume of distribution and is inversely proportional to clearance.
• Changes in CL (due to disease or aging) can alter the drug's t½.
• The steady state is when the rate of drug administration equals the rate of drug elimination.
• It takes approximately 4-5 half-lives for a drug to reach steady state.
• The time to steady state is independent of the drug dose, but depends on the drug's half-life.