Pharmacokinetics: Drug's Journey in the Body

• The central theme focuses on pharmacokinetics, which involves quantitatively examining what happens to an active principle within an organism after administration, essentially studying the drug's journey in the body.

Introduction

• Pharmacodynamics and pharmacokinetics are interconnected.
• The system reaches a plateau, indicating the whole medicine is in the bloodstream after five half-lives (97%).
• The medicine is almost entirely eliminated after seven half-lives (99%).

Objectives

• To quantify drug presence in blood and action sites
• To analyze drug distribution among organs and tissues
• To understand the body's mechanisms for drug elimination
• To maintain effectiveness, ensuring benefits without toxicity from accumulation
• To consider influence from diet and lifestyle
• To account for effect variations due to physiological states like age and sex
• To acknowledge effect changes based on pathological conditions
• To address drug interactions related to ADME

Pharmacokinetics in Research and Development

• Digestibility: Does the active ingredient pass through the digestive epithelium?
  • Implications for administration route (oral) and future formulation and overall drug viability
• Metabolism: How is the active principle metabolized?
  • Guides future dosage, pharmacochemistry (prodrugs, modulation), animal species selection, preclinical studies, and safety assessment
• Tissue Targeting: Can the active principle reach the target tissue?
  • Influences biopharmaceutics, vector form, and overall drug effectiveness.
• Elimination: How is the active principle eliminated?
  • Reveals saturation potential and accumulation
  • Impact on inter-individual variability, safety and the need for future dosage adjustments
• Dosage Determination: What will the posology be?
  • Dosage determined by PK parameters
  • Understanding pharmacokinetics/pharmacodynamics and identifying subpopulations

Pre-Pharmaceutical Considerations

• Active principles must be released and solubilized
• Factors include galenic form and physicochemical properties of molecules.

Drug Movement in the Body

• Administration via oral route involves these stages:
  • Absorption, distribution, metabolism and excretion
• Resorption is essentially absorption plus dissolution.

Drug Passage to General Circulation

• Drug passage across biological membranes and degradation occurs upon first contact with an organ is key
• Membrane structure consists of a phospholipid bilayer with or without transporters.
• Passage Mechanisms: involving diffusion and gradient concentration.

Fick's Law

• Explains drug diffusion across membranes, factoring in diffusion coefficient (D), surface area (S), concentration difference (C1-C2), and membrane thickness (E).
• $dQ/dt = (D * S * (C1 - C2)) / E$
• For good drug absorption, there needs to be an active principle that is soluble (hydrophilic, ionized) and capable of crossing lipid membranes (lipophilic, non-ionized).
• Drug absorption depends on its ionization degree, characterized by its pKa.
• Partition coefficient relates to solubility in ionized form.
• Passive diffusion is primary absorption.

Absorption Factors

• PH of the environment
• Pka of the active ingredient
• Liposolubility
• Galenic form

Key Digestive Tract Areas for Absorption

• Buccal cavity and esophagus aren't optimal because of insufficient time, but sublingual administration can bypass first-pass liver metabolism, giving quick effects, with limits tied to compliance and irritation.
• Stomach is unfavorable due to low surface area, thick mucosa, low vascularization, variable emptying time, and acidic pH.
• The stomach does degrade some compounds, but it's suited for weak acids and PA transformation
• Small Intestine (Duodenum/Jejunum) offers a favorable environment due to large surface area and bile presence
• Ileum is highly favorable due to surface size, high vascularization, and active transport mechanisms
• Colon targets sustained-release formulations

Mechanisms of Passage

• Diffusion can be enhanced via transporters or permeases.
• Active transport, which requires energy against concentration gradients, is rare, primarily in the brain and intestines.

Administration Routes

• Oral, transcutaneous, rectal, intramuscular, and subcutaneous, each affecting absorption and drug availability
• Intravenous route bypasses the need for resorption entirely.
• Variations of the routes affect the rate

What can affect a poor oral absorption

• Membrane passage leads to potential medication loss
• Absorption hurdles require simpler oral formulations
• If resorption's low, the galenic formulation needs more complexity to protect PA from enzyme/hydrolysis degradation
• The goal is to control biopharmaceutical phase
• If no galenic solution exists, consider a pro-drug approach or parenteral route (IV).
• Dissolution helps with absorption
• Equilibrium between ionized and non-ionized forms is necessary for cell entry.
• Gastric Emptying impacts absorption, slowed by high-fat meals, exercise, ulcers and sped up by drinking water, standing
• Intestinal Blood Flow affects absorption rates

First-Pass Effect

• Drug modification, often inactivation, occurs during initial passage through an organ before general circulation.
• The coefficient of extraction varies by organ (Ein, Eh, Ep, Ec).
• Oral route involves intestinal and hepatic first-pass effects, plus pulmonary passage.
• Mechanisms include enzymatic degradation
• Some drugs are inactive until metabolized.
• Activity varies based on enzyme activity, age, blood flow, health.

Clinical Implications

• Decreased therapeutic effect when drug is lost
• Heightened effect if active metabolites are formed
• Some drugs become active once metabolized

Bioavailability

• Measures medicine percentage reaching general circulation after administration.
• Route dependent, intravenous route at 100% bioavailability
• Bioavailability Formula:
  • F = f (1 – E)
  • Where f -> resorption coefficent and E -> is the organ extraction coefficent
• The area under the curve (AUC) in IV administration serves as a reference.
• Reflects effectiveness in a single dose
• Requires reference and may not reflect loss of biotransformation

Factors Modulating Bioavailability

• Diet
• Age
• Health
• Drug Interactions

Relative Bioavailability

• Compares drug availability from a new form against a reference
• Focuses on different pharmaceutical forms

Drug Distribution in Circulation

• Distribution is the second step where drugs circulate generally after administration.

After passage general circulation involves

• Fixation to blood components, tissue binding, and distribution into tissues impacts volume of drug distribution

Distribution factors

• Sanguine: Concentration differences between plasma and whole blood. \(!) concentration in blood is not the same as concentration sanguine in plasma.
• The ratio between medicine in the sanguine and plasma: $rato Sang Plasma = \rac{concentration sanguine}{concentration plasmatique}$
• Fractions:
  • Protein
  • Albumin
  • Lipoproteins
• Protein binding depends on protein concentration and drug affinity.
  • Drug molecule [M] + Protein [P] <=> [MP]
• The van der Waals forces contribute to drug-protein interactions.
• Factors like drug type specificity, site saturation, and bond reversibility influence interactions.

Determining Free and Bound Drug Fractions

• Dialysis separates free and bound forms.

Tissue Distribution

• Only the free fraction of a drug is distributes to the tissue
• Equilibrium: drug concentration in plasma corresponds with the one of the tissue
• This distribution is reversible -> Drug can re-enter the blood.
• Factors influencing distribution involves protein binding and blood flow.
• Distribution depends on drug traits and size/blood flow in organs.
• $V_d = V_{plasma} + \rac{f_u}{f_{ut}} * V_{tissues}$
• VD is large with high tissular concentration, and high non-homogenous distribution. Low levels of VD show minimum plasma concentration

Factors that affect drug Volume Distribution

• Age increases the volume distribution less bound drugs
• Pregnancy increases extracellular volume
• Obesity increases distribution of fat-soluble distributions

Cas Particuliers

• Passage in Central Nervous System, involves blood-brain barrier. The brain has tight junctions and astrocytes, has few proteins, rare transporters and is limited due to liposolubility.
• Placental Transfer determines fetal exposure to drugs. A gradient between mother and fetus where liposoluble molecules transfer freely
• The increase of transfer depends on blood flow

Drug Elimination

• Relates to clearance of drugs.

Clearance

• Volume of plasma cleared of drug per unit time, using organ extraction ratio.
• $Cl_{Organe} = Q * E = Q * \rac{C_a - C_v}{C_a}$
• Cltotal = Clrenal + Clhepatic
• Renal and hepatic clearance, where metabolic and biliary clearance
• Clearance is characterized by rate.

Renal Clearance

• Involves glomerular filtration, tubular secretion and reabsorption
• Excretion = filtration + secretion - reabsorption
• Depends on filtration, active transport and passive reabsoprtion of lipophilic substances
• Age can lower renal clearance

Assessing Renal Function

• Creatinine levels indicate kidney function and glomerular filtration rate (GFR).
  • Direct or indirect estimations of creatinine clearance help assess renal function.
  • GFR is proportional to total muscle mass and highest among young adults and lowered in Caucasian descent
• Urine Collection can evaluate nutrition/albumin
• Cockcroft-Gault equation accuracy gets affected by GFR
• MDRD equation is more accurate to determine GFR
• Hepatic Clearance is the sum of metabolism and biliary clearance.

Physiological Factors affecting Hepatic clearance

• It receives blood flow and relies on enzymatic activity.
• The cytochrome P450 enzyme is the main mechanism responsible for the biotransformation of drug, involves in reduction

Biotransformation

• Body gets energy from endogenous substrates like cholesterol
• With xenobiotics
• Liver is source where activity affects by autoinduction, environmental agents.
• Drug clearance can be affected by specific enzymatic reactions, genetic differences, liver health, or the presence of other drugs.
• The goal is for polar compounds to be assimilated in urinary
• CL = Q *Eh

Specific Properties of Metabolic reactions

• Phase 1 : Polarity gets affected by chemical functions
• Oxidation and reduction
• Phase 2 : conjugation by glucoronic transferase
• Metabolites end up in the urine

Biliary Clearance

• Bile secretion involves active transport
• There are cycles and recirculation Factors that affect this include:
• Liver
• Renal Function
• Blood Flow
• This clearance mainly targets polar drugs. Pharmacokinetics focuses on administration route and concentration effects. For IVs there is mono-exponential decrease
• The concentration plasma described exponential distribution $ C = C_0 * e^{-kt}$

Half Life

• Time for plasma levels to half determined by elimination and volume of distribution
• T1/2 = 0.7 * VD/CL
• It conditions equilibrium when dosage becomes repeated. Time to steady state depends on half life. The accumulation depends of repeated dosages

Influence of other factors

• Dose diminish concentration amplitude
• Modification in rythm does not change the mean concentration
• Can observe exposition concentration

T Value

• Half-life reflects drug elimination and is key in toxicology, but is not in linear relationship
• Factors involves total clearance and constant volume
• VD can be major sign for insufficiency. It is utilized for posology shematics