The Four Cornerstones of Pharmacokinetics

1. 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, 129-199 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

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

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 • 10-100 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 • 10-100 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: • 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

21. 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 = 7.4 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 = - 0.4 log {X} = 7.0 – 5.4 = 1.6 {1} {1} X = .398 X = 39.81 Total species = 1 + .398 = 1.398uM = 1 + 39.81 = 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 = - 3.0 log {1} = 4.4 – 1.4 = 3.0 {X} {X} Log X = 3 X = 1000 Log X = -3.0 ; X = 0.001 Total species = 1 + 1000 = 1001uM = 1 + 0.001 = 1.001uM 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 2x 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: 500-1000 ml/min; high 1000-1500 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 2x 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: 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]xCP [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 2x 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. Therapeutic Range TOXIC In this example the treatment would not be effective as a therapeutic concentration in the blood is not maintained LEVELS Margin ofsafety Margin of safety BLOOD LEVEL THERAPEUTIC RANGE TIME

35. Therapeutic Range 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 ofsafety Margin of safety BLOOD LEVEL THERAPEUTIC RANGE TIME

36. Therapeutic Range TOXIC In this example the treatment would be effective as the therapeutic concentration in the blood is maintained without approaching toxic levels LEVELS Margin ofsafety 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