Pharmacokinetics: FAR 381 Lecture

• Pharmacology Department Lecture, FAR 381 covers Pharmacokinetics

Suggested Use of Notes

• Study (patho)physiology to understand how pharmacology works
• Integrate physiology and pharmacology for rational pharmacotherapy decisions
• Research or ask for clarification if something is unclear
• Use notes with narrated presentations and activities, acknowledging questions might have multiple answers

Pharmacokinetics Defined

• Pharmacokinetics studies the time course of drug concentration in the body
• The body's effect on the drug dictates aspects of drug input and output

LADMET

• LADMET stands for Liberation, Absorption, Distribution, Metabolism, Excretion, and Toxicity.

Pharmacokinetic Profile

• Pharmacokinetics involves concentration versus time
• It is useful to examine a pharmacokinetic profile that contains the:
  • Absorptive phase
  • Cmax (maximum drug concentration)
  • Cmin (minimum drug concentration)
  • Tmax (Time to maximum drug concentration)
  • T 1/2 (Half-life)
  • Duration of action
  • Therapeutic range
  • Subtherapeutic range
  • Toxicity range

ADME Scheme: Simultaneous Events

• Absorption: drug movement from administration site to blood circulation
• Distribution: drug diffusion/transport from intravascular to extravascular space
• Metabolism: chemical conversion/transformation of drugs for easier elimination
• Excretion: elimination of unchanged drug/metabolite from the body

Absorption

• Absorption involves the movement of a solubilized drug from the administration site into systemic circulation across biological membranes
• It affects the onset, duration, and intensity of a drug's action.
• Passive transport, which does not require energy, includes simple diffusion, facilitated diffusion, filtration, osmosis, and bulk flow
• Active transport requires energy

Passive Transport

• Drug molecules directly penetrate the lipid bilayer along a concentration gradient without cellular energy
• Simple diffusion and facilitated diffusion are the most frequently used routes for drugs

Factors Affecting Simple Diffusion

• Lipophilic molecules pass through lipid bilayers more easily
• Small, low-molecular weight molecules pass easily through lipid bilayers
• The ionized state of a compound alters its solubility
• Lipophilic molecules dissolve easily in lipids and tend to cross lipid bilayers freely with higher permeation into cells, needing only to dissolve slightly in water
• Extremely lipophilic molecules cannot dissolve in aqueous compartments, reducing their absorption.
• Hydrophilic molecules dissolve easily in water via hydrogen bonds but cannot dissolve in lipophilic compartments, resulting in reduced absorption.

Ionization Affects Diffusion

• Weak acids and bases ionize at different pH ranges
• Unionized/uncharged molecules are more lipophilic and have higher membrane permeability
• Ionized/charged molecules are more hydrophilic and have low membrane permeability
• The pKa is the pH at which a drug is equally ionized and unionized
• Weak acids ionize when pKa is less than pH
• Weak bases ionize when pKa is greater than pH
• pH partitioning and cell retention are important for drugs needing to accumulate in specific locations like local anesthetics
• Small intestines provide the best absorptive surface, due to the structure of villi and microvilli, therefore
• Most GIT absorption occurs in small intestines, regardless of ionization state

Facilitated Diffusion

• Drug molecules are transported across a bilayer along a concentration gradient without cellular energy, requiring facilitators like carriers or transporters

Active Transport

• Drug molecules penetrate the lipid bilayer against a concentration gradient using facilitators and energy (ATP)
• Movement occurs from low to high concentration
• It is classified into primary and secondary
• Primary involves the direct usage of ATP
• Secondary involves the indirect usage of ATP

Specialized Transport

• Active and facilitated transport are specific towards molecules, recognizing only specific structures
• These systems are saturable as they have finite amounts of facilitators
• Drugs are transported if transporters are available; without them, no transport occurs
• Non-diffusible or hydrophilic drugs are transported via this pathway

Bioavailability

• Bioavailability is the fraction of an administered drug that reaches systemic circulation unchanged
• It is a relative comparison, with IV administration always being 100% bioavailable.
• All ADME processes may alter a drug's presence
• Bioavailability measures the amount of unchanged drug available after absorption into the systemic compartment, not its activity
• Dosage is needed to be effective, along with it's importance
• Changes in bioavailability can lead to clinical consequences and can be altered due to disease or interactions
• Pro-drugs only become active once metabolized

Distribution

• Distribution involves drug movement from systemic circulation throughout the body and to the site(s) of action
• It's affected by the drug's physicochemical properties and determines the extent of distribution, which can be widespread, organ-specific, or localized
• The distribution spreads to major fluid compartments of the body: plasma (circulatory fluid), interstitial fluid (fluid between cells), and intracellular fluid (fluid in cells)
• The circulatory system is the initial site of distribution

Transport in Circulatory System

• Drugs dissolve in plasma and/or bind to plasma proteins
• Plasma proteins include albumin, lipoproteins, acid glycoprotein, and α, β, and γ-globulin
• Albumin maintains colloidal osmotic pressure and acts as a carrier for hydrophobic molecules with drug or molecule binding abilities

Plasma Protein Binding

• Involves free and bound fractions of a drug
• Hydrophilic drugs are transported freely in plasma
• Lipophilic drugs dissolve to a lower degree and undissolved drugs bind to hydrophobic pockets of plasma proteins
• Bound fraction releases as free fraction is excreted and replaces free fraction.

Free vs Bound Fractions

• The free fraction is pharmacologically active, eliciting biological effects, transported across cellular systems, and either metabolized or excreted
• The bound fraction is pharmacologically inert, unable to fit into active sites, not transported/metabolized/excreted, and is only released once the free fraction is cleared

Plasma Protein-Bound Drugs

• Plasma protein-bound drugs have clinical implications; it is important to evaluate if:
  • Free fraction decreases if highly bound
  • Free fraction increases if plasma proteins are saturated or depleted
  • Drug displacement may occur during drug interactions

Factors Affecting Plasma Protein Binding

• Plasma protein concentration dictates the amount available to be bound and can be saturated
• Free drug concentration influences the release of bound drug to maintain equilibrium
• Affinity for binding sites affects how easily drugs bind; high-affinity drugs displace low-affinity drugs

Body Fat Partitioning

• Body fat is a large, non-polar compartment with poor blood supply leading to drug accumulation
• Drugs with high lipophilicity accumulate easily
• Chronic administration of lipophilic drugs or low metabolic clearance drugs, will accumulate in obese patients, which leads to long lasting toxicity

Blood-Brain Barrier

• The blood-brain barrier (BBB) is a continuous layer of endothelial cells joined by tight junctions and surrounded by pericytes with the purpose of;
• Preventing toxin entry into brain
• Transport across BBB occurs via passive diffusion (water, lipophilic molecules/drugs, some gasses) Selective transport with facilitators (drugs that fit transporters/carriers, amino acids and glucose)
• Functionally-permeable areas have different permeability, such as the chemo-emetic trigger zone (toxin sensor)
• Elements that increase permeability include certain molecules (e.g., bradykinin and enkephalins), barrier inflammation, and stress.

Volume of Distribution (Vd)

• Vd is a measure of drug distribution in the body, referencing the theoretical volume into which a drug must dissolve to yield plasma concentration (Cp)
• It's an indication of the lipophilicity and plasma protein binding
• An inverse relationship exists between Vd and Cp
• Vd shows a direction relationship to half-life
• Used to determine the loading dose for emergency treatment
• Low Vd (<15 L) drugs are confined to systemic circulation and have a higher Cp with penicillin as an example
• High Vd (>40 Vd) drugs spread throughout the body, and have a lower Cp with tricyclic antidepressants as an example

Loading Dose

• Used to determine loading dose higher dosage achieve target Cp and reach steady state earlier

Metabolism

• Metabolism is the chemical conversion of substrates to metabolites by enzymes
• The detoxification of molecules helps the removal of unwanted chemicals in urine
• Occurs mainly in the liver but also in the intestines, plasma, and lungs
• Can be catabolic (break-down) or anabolic (build-up)
• Process is controlled by enzymes, such as CYP450 enzymes
• Metabolism can deactivate active drugs, activate inactive pro-drugs, convert active drugs, or form reactive/toxic metabolites/carcinogens
• Each metabolite produces a different effect

Drug Properties

• Lipophilic drugs are metabolized often because they cross a membrane to reach enzymes and are reabsorbed by the kidney
• Reactions create more reactive, hydrophilic metabolites
• Hydrophilic drugs aren't metabolized, unless transported
• Hydrophilicity allows for urinary excretion

Phases of Metabolism

• Drugs go through different phases to get metabolized
• Phase I involves Functionalization reactions to increase reactivity
• Phase II involves Conjugation reactions to increase hydrophilicity
• Phase III involves Excretion/uptake by transporter systems
• Molecule is made reactive for subsequent metabolism using Cytochrome P450 monooxygenase (CYP450) enzymes
• CYP450 Enzymes are found in the liver, GIT, and other tissues
• They are microsomal enzymes that are haem proteins
• Are related, but each is distinct
• Have some substrate specificity overlaps, but differ in sensitivity and rate of conversion

CYP450 Enzyme Percentages

• CYP3A4 is the largest contributor to drug metabolism at 36%
• CYP2D6 is the second largest contributor to drug metabolism at 19%
• CYP2C8/9 is responsible for 16%

Phase I reactions

• Oxidation reactions involve oxygen addition to form a hydroxyl group facilitated by CYP450 enzymes
• Reduction reactions involve electron addition via CYP450 enzymes
• Hydrolysis reactions involve molecule cleavage through water addition, not involving hepatic microsomal enzymes.

Phase II reactions

• Anabolic conjugation of molecules with large, hydrophilic groups forms less lipophilic, more hydrophilic molecules facilitating excretions occurring in the liver, lungs, kidneys

Examples of Phase II reactions

• Glucoronidation (primary)
• Sulfation
• Acetylation
• Amino acid conjugation
• Glutathionation

Enzyme Activity Modifiers

• The inhibition of CYP450 enzymes decreases enzyme activity and can occur through direct enzyme inhibition and reduced enzyme expression involving genetic alterations
• Induction of CYP450 enzymes increases activity, and can occur through increased enzyme expression.

First-Pass Metabolism

• Sum of all metabolic effects in the GIT and liver that reduce Cp of a drug before reaching systemic circulation
• Blood flow from intestines passes to the liver
• Then distributed to the rest of the systemic circulation
• Requires higher dosages to increase effect
• Leads to inter-individual variation in the enzyme systems because of genetic variability causing an unpredictable first-pass
• Susceptibility to drug-drug interactions may alter bioavailability effects

Excretion Routes

• Excretion System involves the removal of a drug or metabolite through excretory organs.
• Primary excretion routes include the kidneys (as urine), hepatobiliary system (as bile and faecal matter), and the lungs (as volatile gasses)
• Negligible excretion routes include milk, tears, saliva, semen, and sweat and can potentially cause side effects

Renal Excretion

• Renal Plasma is filtered to remove hydrophilic molecules.
• It is assisted by several mechanisms: Glomerular filtration / Active tubular secretion / Passive diffusion

Biliary Excretion

• Large, charged, usually, hydrophilic phase II conjugates, or amphipathic drugs may be excreted by hepatocytes into the duodenum, eventually becoming faecal matter
• The excretion is facilitated via passive or facilitated diffusion

Half Life

• In pharmacokinetics, half-life (t₁₂) is the time necessary for a drug's Cp to decrease by half and is used to determine steady state and dosing intervals.
• Provides an index for: time-course of drug accumulation and elimination, and for dosing intervals
• Half Life is Time taken for a drug to be eliminated, considering combination of metabolism and excretion pathways
• Dependent on Volume of Distribution and affected by Genetic profile/Drug or food interactions: Influences elimination and Metabolism

Steady State

• Steady-state is achieved when the rate of drug absorption equals the rate of drug elimination, and Cp plateaus and depends on half-life
• Drugs with a short t₁/₂ achieve steady state earlier, while those with a long t₁/₂ reach it later;
• Missing a dosage can drop Cp below the therapeutic range, potentially impacting drugs with a narrow therapeutic index.

Order Classifications

• Classification depends the characteristics of drug's plasma concentration as a function of drug's time in the body

First-Order Kinetics

• A constant fraction of drug is eliminated per unit of time, where its value is constant and concentration-independent; doubling the dose doubles Cp, undergoing exponential decline
• Most drugs follow first-order kinetics, accumulating under normal circumstances, with predictable profiles

Zero-Order Kinetics

• Constant amount of drug is eliminated per unit of time
• This is variable and concentration-dependent where saturable kinetics are present; higher Cp requires more time to clear, and is affected with high volume usage
• The process undergoes linear decline and is evident in few drugs
• saturable parameters such as enzymes are present
• the ADME processes are rate-limiting factors