PCL201

Pharmacology (lec 1)

• science of drugs

  • study of drug action (pharmacodynamics) and fate (pharmacokinetics) in the body (desirable effects)

• basic and clinical biomedical science

Important distinctions:

• Pharmacy

• Therapeutics

• Toxicology: a science focusing on chemicals w/ undesirable biological activity

Pharmacology purposes and aims (lec 1)

Specific purposes:

• identify drug targets and understand how drugs work by interacting w/ drug targets

• understand how drugs are handled/modified by the living organism

broad aims:

• gain insight into normal and abnormal function

• improve therapeutic intervention by doctors

Toxicology purpose (lec 1)

• looks at how xenobiotics (drugs, chemicals: externally brought into body) are handled and interact w/ targets to cause deleterious effects and reduce these effects (to improve drug)

• studying organochlorine contaminants (ex: thalidomide) and pesticides

Pharmacology history: Ancient civilizations (lec 1)

• medicinal and toxic plants, preparations from mineral and animal sources

• China: Pen Ts’ao (Great Herbal, 2735 BC)

  • 40 volumes of medicinal and toxic plants, antidotes

• Egypt: Ebers Papyrus (1500 BC)

  • >700 drugs in >800 formulas

Pharmacology history: Greek and Roman empires (lec 1)

• Hippocratic Corpus (5th c. BC - 2nd c. AD)

  • ~400 drugs, primarily from vegetable origin

  • rejected divine/spiritual causes and treatment of disease

  • doctrine of the 4 Humors (blood, phlegm, black bile, and yellow bile)

• De Materia Medica (Pedanius Dioscorides, 50-70 AD)

  • >600 medicinal plants

  • each disease has a unique cause for which there is a specific remedy

  • remained in use until ~1600s

  • considred to be basis of modern medecine

Pharmacology history: Medieval times and islam (lec 1)

• The Canon of Medicine (Avicenna, c. 1025)

  • set the standards for medicine, an authoritative reference as late as the 17th c.

  • translated to many langs.

  • list of 800+ drugs/remedies

  • foundation for experimental testing of drugs

Pharmacology history: late 18th-19th c. (lec 1)

• advances in physiology, pathology, and chemistry provided the foundation for pharmacology

  • focus was on isolating and understanding the effects of natural substances (focus on botanicals)

  • examples:

    • Digitalis

    • Morphine

    • Salicin

Digitalis from purple foxglove (lec 1)

• Digitalis Purpurea = purple foxglove

• used to treat “dropsy” (edema from congestive heart failure) (18th c. England)

• digitalis extract (Digitoxin and Digoxin) contain cardiac glycosides (used to treat cardiac arrhythmias and heart failure)

Morphine from Opium poppy (lec 1)

• Papaver Somniferum = Opium poppy

• Opium (sap of poppy) = painkiller

• morphine = 1st active alkaloid discovered from opium poppy

• morphine used for acute and chronic severe pain

• morphine is a precursor to multiple synthetic and semi-synthetic opiates

Salicin from Willow Bark (lec 1)

• Salix alba = white willow

• willow tree bark and leaves powder used for headache, pain, fever (Hippocrates, 5th c. BC)

• 1828: salicin isolated from willow bark

• 1838: salicylic acid purification (active metabolite of acetylsalicylic acid (Aspirin) (Aspirin becomes salicylic acid)

Pharmacology history: mid 19th c. (lec 1)

• offical birth of pharmacology as a separate science focused on studying the interaction of chemicals w/ living systems (1847)

• fathers of pharmacology: Rudolf Buchheim + Oswald Schmiedeberg

Pharmacology history: Early 20th c.: mech of drug action: receptor theory (lec 1)

• Langley and Ehrlich proposed the concept that receptors mediate drug action (1905-1907)

• Clark introduced the receptor occupancy model describing the relationship btwn drug concentration and effect (1933)

• continued focus on isolating and understanding the effects of natural and endogenous substances, aided by strides in synthetic chem, microbiology, and biochem in the 20th c.

  • Ach (1906), oxytocin (1906), histamine (1907), insulin (1922), penicillin (1928), streptomycin (1943)

What is a drug? (lec 1)

• an external chemical substance (other than those essential for normal function) that can exert a biochem/physiological effect in a living org, whether therapeutic or not

• can be natural (morphine), semi-synthetic (hydromorphone) or synthetic (fetanyl)

Official definition by FDA:

• drugs defined by their intended use

  • “intended for use in the diagnosis, cure, mitigation, treatment, or prevention of disease”

  • “intended to affect the structure or any function of the body of man or other animals”

• drugs regulated by:

  • FDA in US

  • Therapeutic products directorate (TPD) of Health Canada

Things that might be considered drugs (lec 1)

• dietary components and/or essential nutrients when given in a high dose used for treatment of disease

• endogenous molecules when administered or in high doses

Drug origins (lec 1)

• drugs can be classified by origin:

  1. natural compounds (in crude preparations/pure)

  2. semi-synthetic

  3. synthetic

  4. biologics

Natural preparations (crude/galenicals: extract by hot water) (lec 1)

• Plant sources:

  • Opium

  • Digitalis

  • Atropa Belladonna tincture (evening nightshade)

  • Klamath Weed (St. Johns Wort)

  • Coffee

• Animal sources:

  • Puffer fish venom (contains Tetrodotoxin)

  • Desiccated thyroid (contains thyroid hormone)

  • Extract from pancreatic islet cells (contains insulin)

Pure compounds from natural sources (lec 1)

• ex: Paclitaxel (Taxol) from bark Pacific Yew Tree in late 1960s

  • has anti-cancer activity

  • b4 1990s: almost all paclitaxel was harvested from bark

    • later discovered to be produced by endophytic fungi in bark

  • Early 1990s: semi-synthetic prod. from another compound found in Yew tree needles emerged

  • today: Paclitaxel is directly purified from a plant cell line propagated in fermentation tanks w/ fungi

Semi-synthetic compounds (lec 1)

• produced by chem modification of pure compounds

  • improvement of the parent compound w/ respect to potency, specificity, side effects, PK parameters

  • ex: Hydromorphone (Dilaudid) from morphine

    • increased potency and lipophilicity

    • more rapid onset of action, altered adverse effect profile

    • hydrogenation of ketones

Synthetic compounds (lec 1)

• most drugs

• range from serendipitous discoveries (ex: barbital) to deliberate synthesis based on predicted chem properties/known molecular features necessary for drug action

• improve drug and/or customize design

• reduce cost

Biologics (lec 1)

• monoclonal antibodies, vaccines, recombinant proteins

  • created by biological processes

  • may be extracted from human/animal tissues, tissue cultures or produced by recombinant DNA tech

  • more complex than small-molecule drugs

  • can be expensive to make

Drug action mechs (lec 1)

• drugs can act as/by:

  • agonists

  • antagonists

  • allosteric modulators

  • enzyme inhibitors

  • affecting lvls of endogenous compounds

Drug generations (lec 1)

• Research + Development continues to improve drug by customizing design

• ex: H1 antagonists (antihistamines for allergy)

  • Loratidine less lipophilic so can’t pass BBB

Clinical drug development (lec 1)

• cost increases as process moves on (most in clinical trials)

Drug nomenclature (lec 1)

• chemical name (chem structure)

• drug company code

• generic name (non marketed name and consistent across countries and companies)

• trade name (trademark)

• street name

Patent law (lec 1)

• way for companies to make money off drug development

• country specific

• no other company can market chemical compound for 20 yrs

Bioequivalence (lec 1)

• 2 diff drug preparations w/ equal dosage form produce similar pharmacokinetic measures

• ex: Loestrin and Microgestin

  • pharmacokinetics curve must be 80-120% similar

Overview of Pharmacokinetics and pharmacodynamics (lec 2)

What is Pharmacokinetics (PK) (lec 2)

• “what the body does to the drug”

• a study of the kinetics (time course) of drug conc and the process involved

  • mathematical relationsips btwn drug dosing + resulting drug [ ]

• Quantitatively describe the various steps of drug disposition in the body: ADME

• affected by:

  • physiochem properties of drug

  • anatomy and physiology of individual

• linked to PD by plasma conc

Pharmacokinetics: ADME (lec 2)

Absorption:

• movement of the drug from its site of administration into the bloodstream

• extent of absorption = bioavailability: fraction of a dose that makes it to systemic circulation in its unchanged form

Distribution:

• spreading of the drug throughout the body once absorbed

• drug distributes from systemic circulation (vasculature) to intracellular and interstitial fluid

Metabolism:

• transformation of the drug to more hydrophilic metabolites (primarily in the liver)

Excretion:

• removal of drug from the body (primarily in urine + feces)

Pharmacokinetic processes ADME (lec 2)

• ADME determines the time course of drug conc in blood and tissues following drug administration

• PK quantitatively describes the various steps of drug disposition and ADME

• used to calculate and understand the relationships btwn drug dosage regimen and resulting drug concs.

Pharmacodynamics (lec 2)

• “what the drug does to the body”

• study of effects and mechs of therapeutic and toxic action of a drug

• Binding: interaction w/ target (receptors, enzymes, molecules)

• Mech of action: changes in signaling (cascades/alteration of pathways)

• effect: physiological/biochemical changes

Drug target interactions (lec 2)

• irreversible drug-receptor interactions (cov/ionic) aren’t common and occur via strong chem bonds (aspirion/anti-tumor drugs)

  • not always desirable

• most drug-receptor interactions are reversible via weak chem bonds (hydrophobic/van der waals)

The “lock and key” (lec 2)

• agonists: mimics natural compound

Nature of the interaction (lec 2)

• receptors are proteins/enzymes that participate in intracellular communication via chem signals

• ligands: signaling molecules, can be endo/exo -genous (neurotransmitter/hormone/drug)

• Effector molecules: those that are activated by the signaling cascade and begin biological response (G-Protein)

Effector activating adenylyl cyclase or extracellular (serotonin) receptor (lec 2)

• increase in cAMP

Nature of Drug-target interaction (lec 2)

1. has an effective conc range (saturation)

2. has desired biological specificity

3. chem specificity (enantiomers)

   • racemic mixtures

     • could lead to higher doses

     • could lead to unintended side effects

     • BUT are cheaper to make

4. can be inhibited/antagonized/blocked

Characterization of D+R binding (lec 2)

• rxn is “on and off” like enzyme kinetics

• an acute response can vary w/ dose (shown w/ picture)

• affinity measures the strength of the D-R interaction

• the Dose-Response curve measures the interaction of D-R

• Classical theory: Response is relative to drug conc and the # of receptors activated

  • increase dose leads to increased response (bc more receptors activated)

Dose response-curve (lec 2)

• semi-logarithmic transformation

• expands conc scale at low [ ] (binding changes rapidly)

• compresses conc scale at high [ ] (binding changes slowly)

• doesn’t change value of Kd (affinity)

Dose-response curve: Efficacy (lec 2)

• Emax: maximal response achieved by an agonist (efficacy)

• EC50: drug conc at 50% of Emax (potency)

  • ED50: 50% of max effective dose

  • affinity (strength of interaction btwn target and drug)

    • Kd

Dose-response curve: potency (lec 2)

• A is more potent because response comes w/ lower drug conc

Efficacy vs. Potency (lec 2)

• looking at multiple drugs interacting w/ target via log dose response curve, we can compare efficacy and potency

  • A more potent

  • B and D highest efficacy

• clinical relevance of a drug depends on the maximal efficacy and ability to activate receptors more than the drug’s potency

Application of D-R curve info (lec 2)

• Y axis: determines the “measurement” (effective vs. lethal vs. toxic response)

Applications of D-R curve (lec 2)

• larger T.I (therapeutic index) = safer drug

• ~833 = very safe

Drug classification (lec 2)

• drugs can be classified by their interaction w/ the target and subsequent “response”

• Agonist:

  • full agonist (100% max efficacy)

  • partial agonist

  • positive allosteric modulator (affects agonist activity)

• Antagonist:

  • competitive

  • noncompetitive: Irreversible or negative allosteric modulator (affects agonist activity)

Agonists (lec 2)

• a drug can mimic (agonist) or enhance (positive allosteric modulator) the action of an endogenous compound at its site of action

Full agonist (lec 2)

• mimics effects of endogenous ligand

• GENERALLY binds at site that endogenous ligand bins

• initiate biological response upon binding R

• produce a full response when all Rs bound

Salbutamol (lec 2)

• selective β2 adrenergic receptor agonist (competes w/ epinephrine)

• for relief of bronchospasm in asthma and COPD

• causes smooth muscle relaxation in bronchi

Partial agonist (lec 2)

• mimics effects of endogenous ligand

• GENERALLY binds at site that endogenous ligand bins

• initiate biological response upon binding R

• will NOT produce a full response even when all Rs bound

• these agents have less efficacy (reduced intrinsic activity)

• ex: Pindolol

Pindolol (lec 2)

• selective β1 adrenergic receptor partial agonist

• used to treat hypertension by “blunting” the β adrenergic signaling at the heart

• reducing strength and speed of cardiac contraction

Positive allosteric modulators (lec 2)

• enhances effect of endogenous ligand

• GENERALLY binds at site distinct from endogenous ligand binding site

• will shift agonist dose-response curve left (less agonist required for response)

• ex: Diazepam

Diazepham (Valium^TM) (lec 2)

• Positive allosteric modulator of GABA_A receptor (an inhibitory channel that decreases neuronal activity)

• used for treatment of anxiety, insomnia, and seizures

• increases frequency of ion channel opening when GABA binds to GABA_A receptor

  • leads to more chloride ions entering the neuron

  • CNS depressant effects

Antagonists, inhibitors and blockers in diff fields (lec 2)

• pharmacological: blocks ability of a D-R interaction by another ligand

  • Cimetidine binds H2 R and blocks ability of histamine to bind therefore lowers gastric acid secretion

• chemical: interaction of 2 compounds in solution such that effect of active drug lost

  • Metal chelator + toxic metal

• Physiological: interaction of 2 drugs w/ opposing physiological actions

  • histamine decreases BP via H1 R and epinephrine increases BP via β-Adr R

Antagonists (lec 2)

• binds R but doesn’t initiate biological activity/signaling cascade

• biological effects from “preventing” natural or endogenous agonist from binding and R activation

• 0 efficacy on its own

Competitive antagonist (lec 2)

• a drug that can block the action of endogenous and other compounds at their site of action

• inhibition can be overcome by increase in [agonist]

• affects Agonist potency (shifts D-R curve right)

  • clinically useful

• ex: Propranolol

Propranolol (lec 2)

• Competitive, non-selective beta antagonist at the beta adrenergic receptor (beta-blocker)

• used for treatment of hypertension (high bp)

  • decreased heart rate, force of contraction and cardiac output

Non-competitive antagonist (lec 2)

• irreversible or negative allosteric modulator

• may not be at same site on R as agonist (neg. allosteric modulator)

• may be covalent bonding (irreversible)

• affects Ag potency and Efficacy (shifts D-R curve right + down)

  • certain amt of receptors are changed so it can’t be used

Neg. allosteric modulator (lec 2)

• impede the action of endogenous and other compounds at diff site of action

• ex: β-carboline

β-carboline (lec 2)

• Alkaloid found in plants and animals

• acts as a negative allosteric modulator of the GABA_A receptor

• induce convulsions and increase anxiety (anxiogenic)

• binds at the benzodiazepine site

  • decreases GABA stimulated chloride movement into cell (less chloride ions entering neuron)

  • less CNS depression and more excitable cells

Antagonists, blockers, and inhibitors (lec 2)

• Antagonists: reserved for drugs acting on receptors

  • bind to agonist site

  • may be “blockers” (block agonists from binding and activating R)

• Blockers and inhibitors: MAY refer to antagonists at Rs (beta blockers) BUT also to drugs that act via other methods to reduce signaling cascades

  • block transporters (Fluoxetine blocks transporter for serotonin)

  • inhibit enzymes (ibuprofen inhibits COX enzyme)

  • act as “sink” for protein (Etanercept is an antibody for TNFα)

  • Allosteric modulators (Diltiazem is a Ca2+ channel blocker)

Ibuprofen (lec 2)

• non-steroidal anti-inflammatory drug (NSAID)

• inhibits the enzyme cyclooxygenase (COX)

  • stops release of Prostanoids (mediators of pain, inflammation and fever

Fluoxetine (lec 2)

• selective Serotonin reuptake inhibitor (SSRI)

• serotonin is removed from the synapse by reuptake transporters on the presynaptic neuron

  • SSRIs block transporters, allowing it to remain active in the synapse longer

Other mechs of drug action (lec 2)

• create osmotic load (Laxatives like mannitol) (puts H2O into GI tract)

• change pH (ammonium chloride to acidify the urine) (traps drug)

• chelation (EDTA to bind divalent metal cations)

• disruption of membranes (Polymixin antibiotics disrupt bacterial cell membranes)

• damage DNA (chemotherapeutic agents like antimetabolites)

Drug biological action (lec 3)

• for drug to have biological action is MUST be soluble in bodily fluids and able to cross biological membranes

• ability to permeate biological membranes dependent on:

  • drug’s physicochemical properties

  • membrane/tissue physiological and anatomical characteristics

Biological environment: membranes (lec 3)

• phospholipid bilayer:

  • amphipathic lipids (hydrophilic head/lipophilic tails)

  • embedded proteins (some form channels/pores)

Characteristics of biological membranes (lec 3)

• drugs must pass across biological membranes to be absorbed, distribute and reach their site of action, and be eliminated from the body

• BUT drugs must also be able to traverse water (we are mostly made of H2O)

Physicochemical drug properties (lec 3)

• physiochem properties of chem agent affect drug movement in biological environments

  1. molecular size

  2. solubility in water and lipid phases

     • partition coefficient or P_ow

     • total polar surface area (TPSA)

  3. extent of ionization (charge)

Molecular size (lec 3)

• expressed in daltons (Da or kDA)

  • most drugs are 200-500 Da (reasons for drugs = small molecule chemicals)

• proteins are much larger (must be injected, can’t be taken orally)

  • insulin: 6000 Da

  • albumin: 65000 Da

Molecular weight and hydrophilicity (lec 3)

• smaller molecules generally cross membranes and distribute more readily

• more important for hydrophilic drugs (larger size limits passive diffusion, must be transported w/ channels)

Solubility (lec 3)

• ability of a solute to dissolve in a solvent to form a homogenous solution

  • nature of solvent and solute (polarity) (“like dissolves like”)

• hydrophilicity:

  • a drug must be soluble in aq body fluids in order to distribute or reach its site of action

  • polar or ionic compounds (bc of H-bonds)

• lipophilicity:

  • key physical property determining membrane permeability

    • vital for drug to pass through lipid bilayer (A, D, E)

    • potential for bioaccumulation (drug concentrates in adipose and lipid compartments)

  • non polar compounds

Passage across membranes indicates permeability (lec 3)

• more nrg needed for more hydrophilic molecule

Ideal drug (lec 3)

• not only polar/non-polar, best to be amphipathic

• drugs have both polar + non-polar groups, combo of these determine solubility in vivo

Measuring solubility (Lec 3)

• determined through partition coefficient (P_ow or K_ow)

• P_ow can be determined experimentally or in silico

• Log P = log of octanol: water partition coefficient

  • P_ow at equilibrium

  • “drug-like” molecules have log P = 0.5 - 5

  • log P > 5 leads to less permeability bc can’t pass through small water layer on membrane

• high K_ow = high lipid solubility (good permeation across membranes)

• low K_ow = low lipid solubility (poor permeation across membranes)

Fick’s law of diffusion (lec 3)

• a drug will flow from area of high conc to low conc, w/ rate of flow being higher w/ larger conc grads

Lipinski’s rule of 5 (lec 3)

• MOST ORAL drug molecules should have:

  • log P </= 5

  • molecular weight </= 500 g/mol (Da)

  • # of H-bond acceptors </= 10

  • # of H-bond donors </= 5

• molecules violating more than one of these rules “may have probs w/ ORAL bioavailability”

• doesn’t predict drugs biological activity

Role of TPSA: “Topological Polar Surface Area” (lec 3)

• contribution to the outer electron shell “surface area” of the molecule from electronegative atoms/atoms w/ unpaired electrons (ex: N, O) and from groups containing these atoms

• polar surface area of >140Ų tend to be poor at permeating cell membranes

  • to access brain (cross BBB), TPSA = <90Ų

Ionization (lec 3)

• many drugs are weak acids/bases containing functional R groups that can be ionized (charged) or unionized (uncharged) depending on pH of the surrounding medium

  • due to protonation/deprotonation of the compound as a result of the drug’s interaction w/ aq medium

• unionized forms of a drug can more readily diffuse across a membrane

• ionized forms of a drug will have lower K_ow and thus a reduced ability to permeate the membrane

  • charged are more hydrophilic due to their ability to interact w/ H2O dipoles through H-bonds

General principles (lec 3)

• drugs in aq solution exist at an equilibrium btwn ionized/non-ionized forms (equilibrium can be shifted by varying the pH of a medium ([H+])

• whether a drug will be mostly ionized/unionized depends on:

  • pH of medium

  • pKa of drug

  • whether drug is an acid/base

• acidic drugs ionize by losing a proton

  • tend to ionize in more basic medium (high pH, low [H+])

  • protonated form = neutral (more lipid soluble)

• basic drugs ionize by accepting a proton

  • tend to ionize in more acidic medium (low pH, high [H+])

  • unprotonated form = neutral (more lipid soluble)

Acids (lec 3)

• proton donors (ionize after losing H+)

• at high pH, reaction is driven right to give more H+, more drug is deprotonated and therefore ionized (less lipid souble)

• at low pH, reaction is driven to the left, more drug is protonated and therefore unionized (more lipid soluble)

Bases (lec 3)

• proton acceptors (ionize after gaining H+)

• at high pH, reaction is driven right to give more H+, more drug is deprotonated and therefore unionized (more lipid soluble)

• at low pH, reaction is driven left, more drug is protonated and therefore ionized (less lipid soluble)

How much drug is ionized at given pH? (lec 3)

• depends on the drug’s pKa

• use Henderson-Hasselbach equation: pH - pKa = log [unprotonated]/[protonated]

• pka < pH = deprotonated

• pka > pH = protonated

pKa (lec 3)

• pKa reflects pH which [protonated] = [deprotonated]

• doesn’t determine whether drug is acid or base

  • depends on functional group

Ionization plays major role in determining… (lec 3)

• solubility and absorption of the compound (bioavailability)

• cell/membrane permeation and distribution to site of action, plasma-protein binding and volume of distribution

• elimination of compound

• binding of a compound at its site of action

• because pH is diff physiological compartments varies

Weakly basic drug w/ pka ~ 9 (lec 3)

Elimination affected by “trapping” drug in compartment due to pH diffs (lec 3)

• diffs in pH of fluid “compartments” can be important in excretion

• BUT can also intentionally alter urinary pH to enhance renal excretion

Barriers to drug movement w/in body (lec 3)

Physical/anatomical barriers:

• cell membranes, which preclude cellular passage

• links formed btwn cells, which preclude intercellular passage of molecules

Functional barriers:

• transport systems that can carry the drug out of cells, thereby lowering drug conc in tissues/compartments w/ those systems

Partition Coefficient (lec 3)

• major factor w/ regards to drug permeation

• higher Pow = more rapidly absorbed

• hydrophilic barrier associated w/ glycocalyx: cut off phenomenon

  • reduced permeability at diff pts depending on nature of membranes

• small intestine has cut off ~20 bc microvilli leads to more of the small water layer on membranes

Physical barriers: epithelial cells (lec 3)

• epithelial cells of skin, GI, bladder, cornea are joined by tight junctions/occluding zonulae

• intercell spaces are completely blocked

• drugs must pass through cells

Endothelial cells (lec 3)

1. capillaries w/ Maculae

   • most transient holes

   • intercell spaces

   • pinocytic vesicles

2. capillaries w/ fenestrations

   • excretory/secretory organs

   • long lasting

   • those <45kDa may pass through basement membrane

   • non protein bound molecules

3. capillaries w/ occluding zonula (BBB)

Physical barriers: BBB (lec 3)

• Brain capillaries

• endothelial cells joined by tight junctions/occluding zonulae

• NO intercellular spaces

• few transient fenestrae

• major issue in drug targeting

  • even w/ exceptions to occluding zonulae of capillaries w/in brain, it is IMPERATIVE to note that MANY COMPOUNDS are excluded from CNS via BBB

  • drugs w/ desired CNS action should be lipophilic/utilize “help”

Physical barriers: Placenta (lec 3)

• assume all drugs cross placenta

  • limited maternal blood flow into placenta therefore equilibration of drug btnw mom and fetus takes at least 10-15 mins

• but physiochem properties of the drug will determine its relative ability to cross placenta (bio membrane)

  • degree of lipophilicity

  • drug size

  • extent of ionization

  • extent of plasma protein binding

• drug transporters/efflux pumps

Functional barriers: the Transporters (lec 3)

• transport systems that can carry the drug out of cells, thereby lowering drug conc in tissues/compartments w/ those systems

Sites of drug transport (lec 3)

• some are located throughout the body (ubiquitous) and others have specific tissue expression

• commonly found in enterocytes, hepatocytes, renal tubular cells and BBB epithelial cells

• small intestine: absorption

• liver: hepatobiliary transport

• Kidney: tubular secretion

• Brain capillaries: brain function

Polarization terminology (lec 3)

• enterocytes (intestine): basolateral (blood), apical (gut lumen)

• Hepatocytes (liver): sinusoidal (blood), Canalicular (bile)

• Renal tubular cells (kidney): basolateral, apical (kidney lumen, urine)

• Brain capillary endothelial cells (BBB): abluminal (brain), luminal (blood capillary)

• location of transporters can affect time course of drug in body (absorption vs elimination)

Solute Carrier (SLC) transporters (lec 3)

• distinct from primary active transporters and ion channels, both structurally and functionally

• localized to cellular membranes as well as organelle membranes (ex: SLC25 fam of mitochondrial transporters)

• most are transport specific molecules, but some are broad-range (ex: SLC21 and SLC22 fams)

• important drug targets (ex: SLC 6 + 12 fams)

ATP binding cassette (ABC) transporters (lec 3)

• substrates undergo primary active transport

  • hydrolysis of bound ATP powers unidirectional transport of substrates against their conc grad (usually out of cells)

• important for limiting cellular exposure to drugs and toxins

  • beneficial when preventing unwanted exposure to environment toxins

  • can limit therapeutic efficacy of cytotoxic drugs such as chemotherapeutics and antibiotics

P-gp structure and binding (lec 3)

• substrate spans membrane and becomes locked in a p-gp drug-binding pocket near the intracell leaf of membrane

• 2 ATP molecules bind to the intracellular ATP-binding sites

  • hydrolysis of ATP to ADP promotes conformational change in p-gp

• substrate is released into extracell environment

P-gp localization and direction of efflux (lec 3)

• P-gp localization favours preferential transport of substrates out of tissues and into blood, feces, mucus or urine

Multidrug resistance (lec 3)

• ABC transporters w/ broad substrate specificity can affect therapeutic actions of various chemotherapeutics and antibiotics when expressed in tumor/bacterial cells

• these transporters contribute to multidrug resistance: ability of microorgs/tumor cells to resist the action of a wide variety of chems

• main multidrug resistance transporters are p-gp, MRPs, and BCRP

  • inhibiting these transporters is common practice alongside standard chemotherapy

Transporters can lead to… (lec 3)

1. therapeutic failure

   • significant in infectious disease and cancer drug therapy

   • anti-infectious disease agents: several genetic polymorphisms P-glycoprotein, anionic + cationic and other transporters

   • multiple cancers: ABC transports (P-gp, MRP1, and BCRP) up-regulated in diff tumors + over-expressed in various cancer cells

   • increased AE

2. improve efficacy and safety

   • remove drugs from “locations” (placental transfer)

     • digoxin, glyberide

   • increase distribution (deliver drugs to targets)

     • statins

Ex: BBB (lec 3)

• Epithelial occluding zonulae (tight junctions) and luminal expression of p-gp, BCRP and MRP efflux transporters all heavily limit drug transport to the brain (protects brain)

• OATP1A2 is one of the few luminal influx transporters at the blood brain barrier, and substrates of this transporter can achieve significant brain concentrations