Pharmacokinetics: ADME Processes

Pharmacokinetics Overview

• Pharmacokinetics studies the body's action/effect on a drug
• It examines drug absorption, distribution, metabolism, and excretion (ADME)

ADME Processes

• Absorption: From site of administration into bloodstream.
• Distribution: Drug dispersion throughout the body's fluids and tissues.
• Metabolism: Converts drug into metabolites in the liver and GI tract.
• Excretion: Removes drug and metabolites.

Drug Movement & Barriers

• Drugs encounter membrane barriers that protect physiological compartments during the ADME processes

Qualitative vs. Quantitative Aspects

• Qualitative looks at drug release, membrane crossing, administration route, and influencing factors.
• Quantitative aspects involve bioavailability, first-pass metabolism, volume of distribution, and clearance.

Drug Intake & Systemic Circulation

• Drug administration leads to absorption (input), then the liver (first pass), before entering systemic circulation.
• Reservoirs, such as tissues are involved

Drug Elimination (Output)

• Elimination involves metabolism/biotransformation in the liver
• Then excretion as urine/feces via the kidneys

Drug Administration Routes

• Intravascular administration places drug directly in the blood
• Extravascular administration delivers the drug outside the bloodstream.

Qualitative Absorption Attributes

• The qualitative considerations in drug absorption include:
  • Drug Release
  • Crossing Membranes
  • Administration Route
  • Factors Affecting Absorption

Quantitative Aspects

• Bioavailability is key in quantitative assessment

Drug Release

• Drug release applies to orally administered drugs.
• It involves the release of the drug from a pill, tablet, or capsule and dissolving active drug in GI fluids.

Membrane Characteristics

• Membranes are lipid bilayers
• Therefore, lipid-soluble drugs pass through more easily
• However, being overly lipid-soluble can hinder dissociation and retention in circulation

Passive Transport: The Passage Across Membranes

• It’s also called lipid diffusion and depend on lipid solubility
• It does not involve carriers; thus, the process isn’t saturable

Active Transport Mechanisms: The Passage Across Membranes

• Active transport uses specific proteins spanning membranes.
• This is energy-dependent, using ATP and capable of moving drugs against concentration gradients.

Facilitated Transport Mechanisms: The Passage Across Membranes

• As with Passive Diffusion, the driving force shares the gradient of concentration, but requires specific proteins
• Unlike Active Transport, NO energy is needed
• It’s for polar and ionized drugs that cannot diffuse passively

Additional Transport Processes: The Passage Across Membranes

• Co-absorption: drugs can be absorbed with lipids via micelles
• Channel Filtration, Pinocytosis, and Ions-Paired Diffusion

Drug Properties Affecting Passage

• Molecular weight, charge status, and ionization affect ability to cross membranes.

Drug Ionization & pH

• Acidic drugs will ionize in basic environments
• Basic drugs will ionize in acidic environments
• Oral administration is a commonly suitable and accepted route

pKa and Drug Absorption

• pKa determines the ionization state
• If the pH is higher than the pKa, the drug is more likely to be ionized.
• Oral route is good, unless there is extensive 1st pass metabolism or the drug is unstable in the GI environment

Route Determines Absorption

• Route of administration affects the rate and extent of drug's absorption.
• Enteral (digestive system), parenteral (injection), topical delivery

What is First-Pass Effect?

• It’s where drugs absorbed from the gastrointestinal tract enter the liver before reaching the general circulation.

Oral Route Considerations

• Oral drug administration is the most suitable and accepted route.
• Acidity gastric contents, gastric emptying rate, and intraluminal mucosal all have an effect

Enteral Absorption

• The impact of the pharmaceutical form, pH, transit time, disease, enzymes, bacteria and food must be considered

A Drug's Effect.

• A drug's effect depends on factors including whether the drug is an acid or a base

Intravenous Benefits

• IV avoids first-pass metabolism and allows controlled drug levels, appropriate if PO is not an option.

What are the route disadvantages for IV and Intramuscular drugs?

• Limited for certain drugs by the size of arterial damage
• Depots are unsustainable

Pulmonary Administration

• Inhalation is the rapid delivery through surface area of the respiratory tract.
• The particular drug is particularly effective, convenient, fast-acting, but requires patient compliance

Intranasel Administration

• Nasal route is use for admin like hormones, like desmopressin
• Drugs like cocaine, however, are sniffed

Factors Affecting Drug Absorption

Factors include: the administration route, lipid solubility, and blood flow

Bioavailability Definition

• The FRACTION of the drug that is absorbed and available to the target of the system
• Also refers to how fast the drug is available and absorbed

How can you Measure Bioavailabilty?

• By measuring the amount of the drug present, divided by the total dose of the drug

Absolute and Relative Bioavailability Measurements

• Absolute bioavailability can be measured for IV drugs as well. It is the fraction compared to relative.
• Relative bioavailability compares two non-IVs, as fraction absorbed

Why should you study bioequivalence?

• Bioequivalence assesses the expected in vivo equivalence
• Must be within FDA standards to be equivalent

What are the methods for calculation of bioavailabilty?

• The trapezoidal rule
• the method of residuals

What is drug DISTRIBUTION?

• The transit of drugs, usually REVERSIBLY, from one location
• Distribution involves reaching equilibrium, uptake of cells

What is first, Initial phase?

• It is defined by blood flow, like liver/heart
• More specifically, redistribution of drugs

What characteristics affect extent depends distribution?

• Molecular size, lipid solubility, protein binding and tissue binding

What is the relationship between distribution of the following?

• High protein capacity = low rate
• High blood flow = high rate
• Affinity = high rate

Why is the drug stored? Is storage good or bad?

• Drug reservoirs retain while also releasing slowly
• Can be good to prolong use

What type of cells are in the drug

• Accumlation of drugs
• They are often FAT

What special consideration should you take for drug distribution?

• Need consideration if blood-brain involved or placental involvement

What are the important of protein

• What affect affinity with a molecule

Blood Flow & Distribution

• High-flow organs like the heart and liver get drugs first, followed by slower uptake in muscles, skin, and fat.

There are 2 methods to estimate volume (Vd)

What is drug METABOLISM?

• Transformation of the drug by different enzymes to eliminated from the body
• Purposes include water-soluability

Enzyme Reactions: Phase-1

• Reactions involve exposing or adding polar groups. (hydrolysis etc)

Enzyme Reactions: Phase-2

• Reactions involve reactions are conjugation
• These occur in

What is Cyt P450

• The best-researched enzyme family that catalyzes various biotransformations.

What are TYPES of Cyt P450, or Cytochrome?

• N-Oxidation
• Hydroxylation

Factors Affecting p450 System

• Enzyme system, multiple pathways, and enzyme terminology

What is the role of drug elimination?

• Is the REMOVAL of drug from body Fluids

What parts of the body are considered when considering drug elimination in pharmacokinetics?

• Mainy the Kidneys

What's the different in tububualr selection vs passive diffusion?

• Depends on contents in tubule

What is DRUB dextoification of the drug?

• Playing to the urinal system
• Alkaline vs acide, and which base to give

What's the process of Heptaic elimination, aka Hepatic clearance?

• Major way using Phases 1/ 2

Do drug interact with each other?

• Some drugs Interact
• Substrate competition

What are Cl and Vd?

• Cl = Rate of elimination/plasma concentration
• Vd is at a Drug dose

Note: The volume at which as substance will be completely cleared

What about CL?

• Depends at renal and non-renal
• Non renal is liver, kidney

What does the CL clearance tell you?

• It is the expression used when measuring elimination rate
• Cl clearance is is how they say the amount has been extracted or eliminated

Define half life?

• (t1/2) Is half life where it measure the body to half, and its relationship with clearance
• Dependent and in independent of dosse

Do enzyme affect these variables mentioned?

• Yes!

Zero vs first order - elimination kinetics!

• First order (rate depends on variable)
• Zero order (rate independent of external) The order affect what can be used etc

Is there drug storage and/or reservoirs?

• Yes fat exists too
• Storage

Define elimination?

• Rate of extraction. Can depend on many external factors.

ONE Compartment Model

• Simplified
• The highly perfused organs (e.g., liver, heart, and kidney) is most importabt

What are the clinical PK and PD studies to remember?

• Is the work