Video Summary - Biopharmaceutics and Pharmacokinetics Principles and P K Models

Main ideas, concepts, and lessons

Purpose of the lecture (biopharmaceutics + pharmacokinetics)
- Biopharmaceutics: how the body behaves after administering a drug to an individual.
- Focuses on biological parameters affecting:
  - drug stay time
  - elimination
  - absorption
  - and how modifying drug parameters can help manage these effects.
- Goal across lectures: connect biological parameters with pharmaceutical parameters to design a bioavailable, safe, efficacious drug delivery system.
- Learning objectives:
  - Understand principles of biopharmaceutics and pharmacokinetics
  - Review pharmacokinetic (PK) models
  - Understand how drugs are disposed of in different PK models
Definition of biopharmaceutics
- Study of interrelationships among:
  - physicochemical properties
  - physiological properties
  - pharmaceutical properties
  - of the active pharmaceutical ingredient (API) and the dosage form
- Used to predict bioavailability, absorption, distribution, and elimination based on biological performance.

Key factors discussed in biopharmaceutics (what controls drug performance)

1) API (active pharmaceutical ingredient) properties

Solubility
Particle size
Porosity
Density
Volume
Impurities
Tendency to form complexes

2) Drug product / formulation considerations

Choose the type of drug product appropriate to the route of delivery:
- Examples mentioned for achieving maximum bioavailability:
  - capsule
  - tablet
  - solution
Choose and optimize:
- Immediate or modified release design
- manufacturing variables
- excipients

3) Physiological factors

Route of administration
Permeability across cell membranes
Binding to proteins
Blood flow
Surface area
Biotransformation (metabolism)
Pharmacokinetics

4) Pharmacodynamic and pharmacokinetic considerations

Bioavailability
Therapeutic objective
Side effects
Dose-related side effects
Toxic effects

5) Manufacturing and quality control

Decide production methodology and quality control
Evaluate formulation aspects tied to biopharmaceutical properties
- Example: particle size to support good solubility
- Better solubility → expected higher absorption vs poor aqueous solubility
Consider:
- raw material quality/specifications
- processing
- cost
- stability (important for shelf life)

6) Patient considerations and patient compliance

Compliance with taking the drug
- Example: injectables described as less patient-compliant
- Alternative suggested: oral or liquid dosage forms (self-administrable)

7) Labeling and product info

Label should provide necessary steps/precautions
Include:
- how to take the drug
- cost of dosage form (mentioned as a consideration)

LADMER framework (biopharmaceutical + PK sequence)

LADMER stands for:
- Liberation
- Absorption
- Distribution
- Metabolism (biotransformation)
- Excretion
Then R = assessment of therapeutic response
Core concept:
- The drug must be liberated first from the dosage form at the desired site,
- then it proceeds through absorption → distribution → metabolism → excretion.

Detailed absorption concepts and mechanisms

Dissolution and release factors (before absorption)

Stability in the drug product
Rate of drug release
Rate of dissolution inside the body
- impacts absorption rate
- determines availability at the site of action

Solid oral dosage form stages (example: tablets)

For tablets, the drug must progress through stages:

tablet → disintegrates into granules
granules → disintegrate into fine powders
dissolution occurs during these stages

Dissolution produces a solubilized form of drug:

can be micellar or simple solution

Key takeaway: only unionized (non-ionized) drug is absorbed Ionized drugs may have higher solubility but are not absorbed effectively.

Absorption occurs through barriers such as:

GI barrier
mucosal lining

Mechanisms of absorption

Passive diffusion (non-ionic diffusion)
- Driven by:
  - concentration gradient / electrochemical gradient
- No energy required
- Governed by a diffusion-gradient relationship (conceptually proportional to drug concentration gradient between GI and plasma)
Carrier-mediated transport
- Requires membrane carriers
- Carrier must bind drug reversibly
- Capacity-limited (depends on number of carriers)
- Site-specific and structure-specific
- Transported for hydrophilic drugs/ions/nutrients

Types within carrier-mediated transport

  - **Facilitated diffusion**
      - **Downhill** transport via passive mechanism
      - **No energy**
      - **Competitive kinetics**
      - Example: **vitamin B12 absorption** via intrinsic factor
  - **Active transport**
      - **Uphill** transport against concentration gradient
      - Requires energy
      - Carrier-drug complex shuttles drug across, releases it, and returns
      - Used for biliary/renal secretion
      - Examples given:
          - **levodopa and methyl dopa** via **L-amino acid transporter**
          - **enalapril** via **peptide transporter**
          - **5-fluorouracil** via **pyrimidine transporter**
      - Also **capacity-limited and saturable**

Intestinal transporter / efflux & influx
- Transporters in intestinal brush border and basolateral membrane:
  - P-glycoprotein (P-gp)
  - amino acid transporters
- Can reduce permeability for many lipophilic/cytotoxic drugs
- Example:
  - oral cephalosporins via amino acid transporters
- P-gp efflux
  - beneficial: helps avoid toxic drug retention
  - harmful: reduces bioavailability for drugs that need absorption
Vesicular transport (endocytosis)
- Cell engulfs material via:
  - phagocytosis (large particles/macromolecules)
  - pinocytosis (small solutes/fluids)
- Example:
  - polio vaccine transported; large proteins also mentioned

The lecture also references broader categories such as:

transcellular passive
paracellular passive
efflux/influx mechanisms
carrier-mediated transport
endocytosis
transcytosis

Distribution concepts (what happens after absorption)

Distribution = reversible transfer between blood and extravascular fluids/tissues
Purpose: move drug from absorption site to site of action
Depends heavily on drug’s physiological nature and absorption, plus:
- Volume of distribution (Vd):
  - Hypothetical volume representing distribution extent
  - calculated as: dose / plasma concentration
Vd depends on:
- blood flow rate
- lipid solubility
- tissue partition coefficient
- binding to biological materials
Patient factors influencing Vd:
- body weight, obesity, edema

Examples

Hydrophilic drugs: lower Vd in obese patients (less partitioning into fatty tissues)
Edema: affects Vd due to water accumulation

Special distribution limitations

Blood flow is rate-limiting
CNS distribution limited by blood-brain barrier (BBB)
- depends on:
  - ionization in plasma
  - lipid solubility
- lipid-soluble drugs cross readily (example: thiopental)
- polar compounds may have poor brain bioavailability (example: barbital)
Placental distribution
- interest increased due to teratogenic risks (example context: thalidomide)
Protein binding
- drug binds plasma proteins reversibly
- only unbound drug is available for action
- high protein binding can complicate bioavailability and dosing
- examples of acid/base interactions:
  - basic amino acids (arginine, histidine, lysine) bind acidic drugs
  - acidic amino acids (aspartic, glutamic, tyrosine) bind basic drugs

Biotransformation (metabolism) concepts

Biotransformation = chemical conversion of drug into other compounds
Usually mediated by enzymes in tissues/biofluids:
- non-enzymatic or mixed pathways also occur
Types of transformation:
- catabolic: hydrolysis, reduction, oxidation
- anabolic (conjugation): glucuronic acid, glycine, sulfate
Results:
- formation of new chemical entities
- their distribution/excretion can differ from the parent compound
Two phases:
- Phase 1: oxidative/reductive/hydrolytic reactions
- Phase 2: conjugation reactions (glucuronidation, sulfation, methylation, acetylation)
Mentioned sites of metabolism:
- microsomes, cytosol, blood, lysosomes, microflora, mitochondria

First-pass effect

First-pass metabolism (pre-systemic clearance):
- drug is metabolized before reaching systemic circulation
- primarily via liver first-pass metabolism
Result:
- reduced availability of parent drug
- therefore poor bioavailability for some drugs

Excretion and elimination concepts

Routes of excretion

Excretion = final loss from the body
Routes mentioned:
- urine, bile, intestine, saliva, alveolar air, sweat, milk
Prominent pathways:
- kidney → urine
- liver → feces

Renal excretion mechanisms

Glomerular filtration
Tubular reabsorption
Tubular secretion
Governing processes can be:
- passive diffusion
- carrier-mediated mechanisms
Key quantitative ideas:
- glomerular filtration rate (GFR) dependence on:
  - unbound drug concentration
  - GFR
Renal clearance affects:
- plasma half-life
- elimination rate constant
- fractions metabolized/renally eliminated

Enterohepatic circulation

Includes:
- biliary excretion and hepatic metabolism
Biliary recycling:
- drug secreted into bile
- stored in gallbladder
- released into duodenum
- may be metabolized, reabsorbed, and re-secreted
“Entrohepatic cycle” described as a complete liver + bile pathway cycle.

Other excretion mechanisms

Lung: volatile/gaseous substances (breath analysis example for alcohol)
Salivary recycling:
- pH-dependent; influenced by protein binding
Mammary excretion (milk):
- important to avoid drug exposure to infant
- depends on passive diffusion and ionization
- pH: milk ~ 6.6, plasma ~ 7.4
- milk-plasma ratio higher for weak bases, lower for weak acids

Pharmacokinetic (PK) modeling concepts

What pharmacokinetics is

Pharmacon = drug
Kinesis = motion/rate change
Defines the time course of drug/metabolite concentration

Types of PK models mentioned

Compartment modeling
Non-compartment modeling
Physiological modeling

Compartment models (structure and use)

A PK model is a hypothetical structure to categorize reproducibility of drug fate/behavior given route and dosage form.
Compartment counts:
- one-compartment
- two-compartment
- multi-compartment
Fit data using:
- blood concentration vs time
- urinary cumulative excretion vs time

Model arrangement types

Mammillary model
- central compartment (plasma; highly perfused tissues like lung/liver/kidney)
- peripheral compartments (low vascularity/poor perfusion)
Catenary model
- compartments connected in series
- described as rarely used because organs aren’t truly parallel/sequential; many connect to a central blood compartment

One-compartment open model

Drug rapidly distributes throughout the body
Plasma concentration reflects tissue concentration proportionally
Example scenarios:
- IV bolus
- IV infusion
- first-order absorption
- zero-order absorption

IV bolus in one-compartment model (first-order kinetics)

Elimination rate determined by elimination rate constant (Ke)
From semilog plot concepts:
- slope → elimination rate constant
- half-life from elimination rate constant
- clearance from elimination rate / plasma concentration
Clearance meaning:
- theoretical volume/time for complete removal (volume per time)
Relationship noted:
- elimination half-life relates to Vd and clearance

IV infusion (one-compartment model)

Uses zero-order infusion rate
Benefits mentioned:
- easier control of infusion rate
- prevents fluctuating plasma levels
Steady-state concentration (Css):
- reached after multiple half-lives
- accumulation described:
  - ~50% at 1 half-life
  - ~75% at 2 half-lives
  - ~90% of Css after 3.3 half-lives
  - ~99% after 6.6 half-lives

Extravascular absorption modeling (oral/IM/SC/transdermal)

Includes absorption influenced by:
- solubility
- permeability
- GI motility
- first-pass metabolism
Uses a conceptual drug concentration vs time equation (details not fully provided).

Two-compartment models

Drug does not instantly equilibrate between blood/plasma and tissues
One compartment = blood/central
Other compartment(s) = peripheral tissues
Governed by transfer rate constants; elimination constant (K) used
IV bolus can show biexponential decline (distribution + elimination).

Non-compartmental modeling

Does not assume explicit compartments
Uses:
- area under the curve (AUC)
- clearance metrics
Used for estimating non-compartmental parameters

Physiological models

Series of lumped compartments representing organs/tissue spaces
Drug concentrations assumed uniform within regions
Movement depends on organ blood flow rates
Described as perfusion rate-limited

Conclusion

Biopharmaceutics + pharmacokinetics are critical in drug development
PK models help interpret LADME:
- absorption, distribution, metabolism, elimination, and response
Improved PK understanding can:
- improve efficacy
- minimize toxicity
- improve patient outcomes

Speakers / sources featured

No specific speaker name or external source is identified in the provided subtitles (the narrator/lecturer is not named).

Biopharmaceutics and Pharmacokinetics Principles and P K Models

Key takeaways