1. The Four Cornerstones of Pharmacokinetics
2011 Updated 1/11
The Four Cornerstones of Pharmacokinetics
Absorption
Distribution
Metabolism
Elimination
Absorption and distribution are influenced by the formulation:
Medicinal Agent --> Formulation --> Medication
Galenic = Science of pharmaceutical formulation
Tinctures of natural products – opium, vegetable drugs
(Galenos of Pergamon, AD)

2. Drug Administration and Absorption
Routes of Drug Administration:
Oral
Topical (Percutaneous)
Rectal or Vaginal
Pulmonal
Parenteral
Route of administration determined by chemical properties and stability of the active substance, desired concentration needed at target tissue, sensitivity of the active agent to degradation (enzymatic) and desired duration of action.

3. Drug Uptake Drug diffusion through phases:
Aqueous phase – passive by concentration gradient*
Lipid phase – passive by both concentration gradient* & lipophilicity of drug
Across barriers:
Carriers
Endocytosis / pinocytosis
Fick’s Law:
Flux = [C1 – C2] X { P } X (Area)
P is Permeability
P = Permeability coefficient
Thickness
Luellmann, 2011

4. Oral Drug Administration
Pills
Antiquated single-dose unit; round, produced by mixing
drug powder with syrup and rolling into shape
Tablets
Oblong or disk-like shape, produced through mechanical pressure; filler
material provides mass; starch or carbonates facilitate disintegration
For details on Eudragit see

5. Oral Drug Administration
Coated Tablets
Tablet covered by a “shell” (wax, highly specialized polymers = Eudragit®) to facilitate swallowing, cover bad taste or protect active ingredient from stomach acid
For details on Eudragit see

6. Oral Drug Administration
Matrix Tablets
Drug is embedded in inert “carrier” meshwork -->
extended or targeted (intestinal) release
Capsules
Oblong casing (Gelatin); contains drug in liquid,
powder or granulated form
Troches or Lozenges; Sublingual Tablets
Intended to be held in the mouth until dissolved

7. Oral Drug Administration

8. Oral Drug Administration
Aequous Solutions (with Sugar=Syrup)
Mostly for pediatric use
20 drops=1g
Alcoholic Solutions (=Tinctures)
Often plant extracts
40 drops=1g
Suspensions
Insoluble drug particles in aequous or lipophilic media

9. Percutaneous Drug Administration
Specific formulation determined by physician/dermatologist:
based on skin type:
Dry vs. Oily
Young vs. Old
Intact vs. Injured
based on drug properties:
Hydrophilic vs. Lipophilic
Soluble vs. Insoluble

10. Percutaneous Drug Administration

11. Percutaneous Drug Administration
Ointment and Lipophilic Cream
Either pure lipophilic base (lanolin=wool fat; paraffin oil; petrolium jelly) or
“water-in-oil” emulsions
Paste
Ointment with >10% pulverized solids (e.g. Zinc- or Titanium-Oxide)
Lotion and Hydrophilic Cream
“oil-in-water” emulsions
Gels
Either alcohol or aequous solution based (Ethanol gels --> Cooling effect)
Increased consistency due to gel-forming agents

12. Percutaneous Drug Administration
Transdermal Drug Delivery Systems =“Patches” (Nicotin, Isosorbid-Nitrate, scopolamine)
Single Layer
Inclusion of the drug directly within the skin-contacting adhesive. In this transdermal system design, the adhesive not only serves to affix the system to the skin, but also serves as the formulation foundation
Multi-Layer
Similar to Single-layer, however, the multi-layer encompasses either the addition of a membrane between two distinct drug-in-adhesive layers or the addition of multiple drug-in-adhesive layers under a single backing film
Reservoir
Inclusion of a liquid compartment containing a drug solution or suspension separated from the release liner by a semi-permeable membrane and adhesive.

13. Other Topical Drug Administration
Eye Drops
Sterile; Isotonic; pH-neutral
Nose Drops/Nasal Sprays
Viscous Solutions
Pulmonary Formulations
Inhalation anesthetics (Hospital use only)
Nebulizers (mostly propellant operated)
dispense defined amount of Aerosol
(= dispersion of liquid or or solid particles in a gas)
Size of aerosol particles determines depth of penetration into the respiratory tract:
>100 mm: Nasopharynx
mm: Trachea, bronchii
<10 mm: Bronchioli, alveoli

14. Other Topical Drug Administration
Suppositories
Drug incorporated into a fat with a melting point ~35ºC
Rectal: Absorption mostly intended into systemic circulation (e.g. analgesics)
Vaginal: Effects intended to be confined to site of application (e.g. candidiasis)

15. Parenteral Drug Administration
Sterile; iso-osmolar; pyrogen-free; pH=7.4
Ampules
Single use (mostly with fracture ring)
Single and Multi-dose Vials
ml; contain preservatives
Cartridge ampules
Infusions
Solution administered over an extended period of time

16. Parenteral Drug Administration
Advantages:
100% “Absorption”
Drug enters general circulation without hepatic passage -->
No first-pass hepatic elimination
Better bioavailability of hydrophilic drugs
Bioavailability/Speed of Absorption
Intravenous (i.v.): Fastest (infusions; cardio-vascular drugs)
Intramuscular (i.m.): Medium (anti-inflammatory; antibiotics)
Subcutaneous (s.c.): Slowest (vaccines; insulin; depot contraceptives)

17. Drug Distribution

18. Drug Distribution
To be absorbed and distributed, drugs must cross barriers (membranes) to enter and leave the blood stream.
Body contains two type of barriers which are made up of epithelial or endothelial cells:
External (Absorption Barriers): Keratinized epithelium (skin), ciliated epithelium (lung), epithelium with microvilli (intestine), etc.
These epithelial cells are connected via zonulae occludens (tight junctions) to create an unbroken phospholipid bilayer. Therefore, drugs MUST cross the lipophilic membrane to enter the body (except parenteral).

19. Drug Distribution
Internal (Blood-Tissue Barriers): Drug permeation occurs mostly in the capillary bed, which is made up of endothelial cells joined via zonulae occludens.
Blood-Tissue Barrier is developed differently in various capillary beds:
Cardiac muscle: high endo- and transcytotic activity-> drug transport via vesicles
Endocrine glands, gut: Fenestrations of endothelial cells (= pores closed by diaphragms) allow for the passage of small molecules.
Liver: Large fenestration (100 nm) without diaphragms-> drugs exchange freely between blood and interstitium
CNS, placenta: Endothelia lack pores and possess only little trans-cytotic activity-> drugs must diffuse transcellularly, which requires specific physicochemical properties -> Barriers are very restrictive, permeable only to certain types of drugs: “blood-brain barrier”

20. Drug Distribution Membrane Permeation: [solute]oct
Passive Diffusion:
Requires some degree of lipid solubility, which is in part determined by the charge of the molecule
For weak acids or bases (which account for the vast majority of drugs), the charge of the molecule in dependence of the pH of the medium is determined by the Partition coefficient and the Henderson-Hasselbalch Equation:
Log ([H+Drug] / [Drug]) = pKa - pH
Active Transport: Drugs “highjack” cellular transporter (e.g. L-DOPA uptake via L-amino acid carrier)
Receptor-mediated Endocytosis: Clathrin-coated pits form endosomal vesicles; receptor gets “recycled” to the cell surface
[solute]oct
Log P(oct/water)=Log _________
[solute]water
Values negative = more water soluble
Values positive = more octanol soluble
Only the non-protonated form of the drug can move across the lipid membrane to establish an equilibrium. Due to the lower pH of the urine compared to the blood, more of the drug will be converted into the protonated form in the urine. Consequently, the protonated drug can not move back across the membrane and is trapped in the urine --> elimination (this principle is applied when urine acidification is used to detoxify OD victims).

21. WHICH DIRECTION WILL THE DRUG MOVE, BLOOD TO URINE OR URINE TO BLOOD?
Acid : HA  A- + H+ Base : BH+  B + H+
Diffusible Form = HA Diffusible Form = B
Henderson-Hasselbach Equation:
Log [protonated form] = pKa - pH
[unprotonated form]
Consider 2 compartments – with different pH values
blood pH = urine pH = 5.4
WHICH DIRECTION WILL THE DRUG MOVE, BLOOD TO URINE OR URINE TO BLOOD?
Always set X to = nondiffusible form, set the diffusible form concentration = 1.0 uM
Consider weak base: Unprotonated form is readily diffusible. Assume a pKa = 7.0
BLOOD: URINE:
Log {X} = 7.0 – 7.4 = log {X} = 7.0 – 5.4 = 1.6
{1} {1}
X = X = 39.81
Total species = = 1.398uM = = 40.81uM
As the base moves from blood into urine, it gets trapped there
Consider weak acid. Protonated form is readily diffusible; Assume a pKa = 4.4
BLOOD: STOMACH:
Log {1} = 4.4 – 7.4 = log {1} = 4.4 – 1.4 = 3.0
{X} {X}
Log X = 3 X = Log X = -3.0 ; X = 0.001
Total species = = 1001uM = = uM
As the acid moves from stomach into blood, it gets trapped there

22. Easy thought process for direction of drug movement “Ion Trapping”
For weak acid drugs:
if compartment pH is LESS THAN pKa, less ionized, more of drug will pass bilayer membranes – increased flux across bilayer
if compartment pH is MORE THAN pKa, more ionized, less of drug will pass bilayer membranes – decreased flux
For weak base drugs:
if compartment pH is LESS THAN pKa, more ionized, less of drug will pass bilayer membranes – decreased flux
if compartment pH is MORE THAN pKa, less ionized, more of drug will pass bilayer membranes – increased flux

23. Drug Distribution
Drug concentration is a function of absorbtion AND elimination:
Typical plasma drug concentration as function of time after a single oral dose
AUC = Area Under Curve
Plasma curve = rate entering plasma compartment – rate leaving plasma compartment

24. Drug Distribution Bioavailability (F):
the AUC of the (orally) administered drug divided by the AUC of the intravenously administered drug
NOTE: IV yields maximum plasma concentration at time = injection (0 time)

25. Drug Distribution Bioavailability: Intravenous 100% by definition
Intramuscular 75 to <100%
Subcutaneous 75 to <100%
Oral 5 to <100%
Rectal 30 to <100%
Inhalation 5 to <100%
Transdermal 80 to <100%

26. Drug Distribution Volume of Distribution (Vd) [ml or l]:
= Amount of drug in the body [mg] / drug concentrationplasma [mg/ml]
Vd is an apparent volume (volume that the drug must be distributed in to produce measured plasma concentration
Drug with near complete restriction to plasma compartment would have Vd = plasma volume (.04 L/kg) = 2.8 L/70 kg patient
Blood volume is around 5.5L, ECF volume (sans plasma) is ~ 12 L, total body volume ~ 40 L
But: Many drugs are highly tissue bound => large Vd. Where does it go? e.g. Chloroquine: Vd = 13,000 L

27. Drug Distribution Rate of Elimination:
Drug elimination via kidney occurs by filtration => with falling blood concentration the amount of drug filtered per time unit diminishes
Drug elimination via liver occurs by metabolism, where most enzymes operate in the quasi-linear range of their concentration-activity curve => with falling blood concentration the amount of drug metabolized per time unit diminishes
==>Vast majority of drugs follows first-order kinetics (= rate is proportional to drug concentration)
Only three drugs follow linear, zero-order (=concentration-independent) elimination characteristic: Ethanol, Aspirin and Phenytoin

28. Drug Distribution (slide moved up 1)
Half-life (t1/2) [min]:
= ln 2 x Vd [ml] / CL [ml/min] (ln 2 = 0.693) or
= ln 2 / Elimination rate constant (k) [1/min]
Half-life is the time required for the concentration of a drug to fall by 50%
The half-life is constant and related to (k) for drugs that follow first-order kinetics

29. Clearance (New Slide)
How fast a drug is removed (cleared) from the body determines how the drug is used therapeutically!
What will be the dose, how will it be given, what will be the rate of dosing?
“VOLUME PER UNIT TIME”
Low: <500 ml/min; moderate: ml/min; high ml/min
It is the sum of all separate organ clearances:
CL = CLrenal + CLliver + Clother
Clearance is the volume of plasma cleared of all drug per unit of time (a constant for any given drug [ml/min])
The actual quantity of drug [mg] removed per time unit [min] depends on both the clearance [ml/min] and the concentration [mg/ml].
(Hepatic) extraction ratio = EH = 1 – [{Concentration out} / {Concentration in}]
If EH = 0.8, only 20% of drug that enters on portal circulation leaves liver
EH < 0.3: salicylic acid, phenobarbital, diazepam, digitoxin
EH .3-.7: codeine, aspirin, quinidine
EH >0.7: lidocaine, nitroglycerin, morphine, propranolol

30. Drug Distribution Clearance (CL) [ml/min]:
= Rate of Elimination [mg/min] / Drug concentrationplasma (CP) [mg/ml] where
Rate of Elimination [mg/min] = k [1/min] x CP [mg/ml] x Vd [ml] and
Elimination rate constant (k) [1/min] = ln 2 / t1/2 (=half-life) (ln 2 = 0.693)
=> CL [ml/min] = Elimination rate constant (k) [1/min] x Vd [ml] = ln 2 x Vd / t1/2
It is the sum of all separate organ clearances:
CL = CLrenal + CLliver + CLother
Clearance is the volume of plasma cleared of all drug per unit of time (a constant for any given drug [ml/min])
The actual quantity of drug [mg] removed per time unit [min] depends on both the clearance [ml/min] and the concentration [mg/ml].

31. Drug Distribution Dosage Regimens:
With multiple dosing or continuous infusion, a drug will accumulate until the amount administered per time unit equals the amount eliminated per time unit. The plasma concentration at this point is called the steady-state concentration (CSS) [mg/ml]:
CSS = Infusion (dose) rate [mg/min] / Clearance [ml/min]
Typically, 90% of the CSS is reached after 3.3 half-lifes; ~100% after 5 half-lifes

32. Drug Distribution Loading Dose: Maintenance Dose:
For drugs with long t1/2, 3-5 half-lifes is to long to wait for CSS => loading dose is used.
Loading dose must ‘fill’ the Vd to achieve the target CP:
Loading dose [mg] = {Vd [ml] x CP [mg/ml]} / bioavailability
Maintenance Dose:
Must replace the drug that is being eliminated over time:
CSS [mg/ml] = Infusion rate [mg/min] / Clearance [ml/min] =>
Infusion rate [mg/min] = Clearance [ml/min] x CSS [mg/ml] =>
Infusion rate [mg/min] = ln 2 x Vd [ml] / t1/2 [min] x CSS [mg/ml]

33. Drug Distribution Drug Binding to Plasma Proteins:
Primarily albumin (4.6g/100ml), also b-globulins and acidic glycoproteins
Other specialized plasma proteins (transcortin; thyroxin-binding globulin; etc.)
Binding to plasma proteins is instantaneous and reversible.
Of great importance, as the free (=effective) drug concentration determines intensity of response
Drug-protein binding also influences biotransformation and elimination =>
Binding to plasma proteins is equivalent to depot formulations
Possible site for drug interactions:
If two drugs bind to the same site on e.g. the albumin molecule, then drug B has the potential of displacing drug A from its binding site --> effective concentration of drug A is increased --> Toxic concentration or increased elimination
Impaired liver function:
can lead to altered pharmacokinetics of drugs that bind to albumin at high rates due to decreased albumin concentrations in the blood

34. Margin of safety Therapeutic Range Margin of safety TIME BLOOD LEVEL
TOXIC
In this example the treatment would not be effective as a therapeutic concentration in the blood is not maintained
LEVELS
Margin of safety
Margin of safety
BLOOD LEVEL
THERAPEUTIC
RANGE
TIME

35. Margin of safety Therapeutic Range Margin of safety TIME BLOOD LEVEL
TOXIC
In this example severe toxicity would occur as the therapeutic concentration in the blood is exceeded due to accumulation of the drug
LEVELS
Margin of safety
Margin of safety
BLOOD LEVEL
THERAPEUTIC
RANGE
TIME

36. Margin of safety Therapeutic Range Margin of safety TIME BLOOD LEVEL
TOXIC
In this example the treatment would be effective as the therapeutic concentration in the blood is maintained without approaching toxic levels
LEVELS
Margin of safety
Margin of safety
BLOOD LEVEL
THERAPEUTIC
RANGE
TIME

37. Therapeutic Range Therapeutic Index:
= Maximum non-toxic dose / Minimum effective dose
Problem:
Does not take into account variability between individuals
=> “Improved formula”:
= LD50 / ED50
Problems:
LD50 reflects only death, but no other toxic side effects (e.g. Ototoxicity of aminoglycosides)
ED50 depends on condition treated (e.g. Aspirin: Headache vs. rheumatism)
LD50 depends on patients overall condition (e.g. Aspirin: dangerous to asthmatic patients)
==>
Therapeutic Index is not particularly useful to describe the clinical usefulness of a drug!

38. Drug Metabolism and Elimination
Elimination of drugs occurs primarily through renal mechanism
Secretion into bile also possible, but allows for re-absorption in the intestine
Secretion into the urine requires ionized or hydrophilic molecules, but:
Most drugs are not small molecules that are highly ionized at body pH
Most drugs are poorly ionized and lipophilic
=> This decreases renal excretion and facilitates renal tubular reabsorption
Many drugs are highly protein bound, and therefore not efficiently filtered in the kidney
Most drugs would have a long duration of action if termination of their effects depended only on renal excretion
Solution: Drug Metabolism