Drug Metabolism Past Paper PDF

OUTLINE Pharm 304: BIOPHARMACEUTICS & PHARMACOKINETICS I. Concepts influencing drug metabolism Unit 7A II. Exemption to Metabolism...

OUTLINE Pharm 304: BIOPHARMACEUTICS & PHARMACOKINETICS I. Concepts influencing drug metabolism Unit 7A II. Exemption to Metabolism III.Drug biotransformation reactions Drug Metabolism IV.Phases of Drug Metabolism V. Enzyme Inducers and Enzyme Inhibitors VI.Genetic Polymorphism S.Y. 2024-2025 MICKO D. DE GUZMAN 1 2 Exemption to Metabolism Metabolism 1. PRODRUG Aka biotransformation (one of the two An inactive parent drug that has to be metabolized to the elimination) active form Enalapril ---hydrolysis-> Enalaprilat Objective: convert drugs into forms Responsible for the antihypertensive effect which are Clopidogrel, allopurinol less active or inactive less toxic or non-toxic polar or water soluble (to be easily excreted) 3 4  Exemption to Metabolism 2. Active drug with active metabolites Examples of Prodrug Prodrug Active form è N-desmethyldiazepam (nordazepam) active Chloramphenicol palmitate Chloramphenicol è Diazepam active Levodopa Dopamine Heroin Monoacteylmorphine -> Morphine è Oxazepam active Prednisone Prednisolone è Glucuronide inactive Codeine Morphine Enalapril Enalaprilat Peripherally prolongs half life of drug ASA Salicylic acid 5 6 Exemption to Metabolism 3. Nontoxic drug metabolized to a Important metabolizing organs toxic drug Liver - most important GIT (stomach, intestines) Sequence: Blood (plasma: portal, systemic) Acetaminophen (nontoxic) --- Kidneys CYP1A2-> N-acetylparabenzoquinone imine ü Imipenem (dihydropeptidase enzyme in kidney) (NAPQI) hepatotoxic ü Cilastatin dihydropeptidase inhibitor ---conjugation with GSH-> Lungs mercapturic acid form inactive Placenta nontoxic Aqueous humor of eyes 7 8  PHASES OF DRUG First Pass Effect/Metabolism METABOLISM 3 possible chemical PHASE 1 Metabolism reaction: A phenomenon where drugs are metabolized initially following absorption but BEFORE it reaches the systemic circulation. 1. Oxidation Functionalization phase non systemic reaction 2. Reduction significance - FPE can dec. oral bioavailability of a drug 3. Hydrolysis (addition or unmasking of a functional group) 9 10 PHASES OF DRUG METABOLISM Oxidative Reactions: 1. CYP – mediated CYP-mediated - involves cytochrome P-450 mixed oxidase system (several isoenzymes) 2. CYP independent Alcohol and aldehyde dehydrogenase, Mono amine oxidase, etc. 11 12  PHASES OF DRUG PHASES OF DRUG METABOLISM METABOLISM Reduction: Hydrolysis: 1. Nitro reduction 1. Esters Chloramphenicol ASA, ester type local anesthetics, ACE inhibitors 2. Carbonyl reduction 2. Amides Naloxone (antagonist of opioids) Procainamide, lidocaine, amide type local anesthetics 3. Azo dye reduction Protonsil 13 14 PHASES OF DRUG Glucoronidation – major/dominant METABOLISM Enzyme: glucuronosyl acyltransferase [GluCAT] PHASE 2 Conjugation reactions / synthetic phase poorly expressed / few in amount in neonates Involves addition of a POLAR conjugate not more than 28 days Chloramphenicol = inability to metabolized by glucuronidation the chloram. metabolites = GREY BABY SYNDROME 15 16  PHASES OF DRUG METABOLISM OTHER PHASE 2 REACTIONS Acetylation Enzyme: N-acetyltransferase Sulfonamide Hydralazine Isoniazid- undergoes phase II metabolism first before Phase I Procainamide, Phenytoin 17 18 Glycine conjugation Most common endogenous amine for conjugation with organic Sulfate conjugation acids Limited, easily depleted Reduced in infants and the elderly Newborn capable but pathway is easily saturated Glutamine conjugation Methylation Enzymes localized in liver and kidneys Minor pathway Methyl transferase 19 20  Glutathione and mercapturic acid conjugation Added Notes: Reacts with electrophilic oxygen intermediates - the liver function in newborn is reduced Detoxification of reactive O2 intermediates - various metabolism pathways mature at different ages GSH conjugates à Precursors for a group of drug conjugates AGE METABOLISM CAPACITY DEVELOPED – mercapturic acid derivatives BIRTH Sulfation 1ST WEEK Reduction, Oxidation 1 MONTH Acetylation 2 MONTHS Glucoronidation 3 MONTHS Glycine conjugation, Glutathione conjugation, Cysteine conjugation 21 22 ENZYME INDUCERS Stimulate activity or production of enzymes Effects depends on the substrate ENZYME INDUCERS/INHIBITORS 23 24  ENZYME INDUCERS ENZYME INHIBITORS Phenobarbital, Phenytoin Decrease activity or production of metabolizing enzyme Rifampicin Effects depends on the substrate Carbamazepine CHRONIC alcoholism Charcoal broiled food St. John’s worth Griseofulvin, SMOKING 25 26 ENZYME INHIBITORS Genetic Polymorphism M Metronidazole, Macrolide E Erythromycin variability in the expression or production of D Disulfiram, Diazepam enzymes based in genetic characteristics of V Valproic acid, vancomycin individuals I Isoniazid C Clarithromycin, Chlorampenicol Cimetidine K Ketoconazole (fluconazole, miconazole) S Saquinavir Grape fruit juice Allopurinol, Acute Alcoholism 27 28  3 groups based on quantity of enzymes produced or expressed: NAT2 Polymorphism EM = extensive metabolizers (produce normal N-acetyl transferase 2 enzyme - catalyzes acetylation (3 or adequate amount of enzymes) - Median group substrates) - Hydralazine UM = ultra metabolizers - Isoniazid (produce excessive amounts of enzyme) - Procainamide PM = poor metabolizers (produce inadequate amount of enzyme) 29 30 NAT2 Polymorphism Pharm 304: BIOPHARMACEUTICS & PHARMACOKINETICS EM - rapid acetylators (asians) PM - slow acetylators (>50% of caucasian) Consequence: Unit 7B Drug Elimination and Clearance - poorly metabolize INH, hydralazine, procainamide- most assoc. - With SLE-like Sx in caucasians [thus higher risk for SLE-like SE (Excretion) with substrates] S.Y. 2024-2025 MICKO D. DE GUZMAN 31 32  L A D TOXICOLOGY Excretion Final LOSS of drug from the body ME R General requirement: water soluble 33 34 ROUTE or MECHANISM RENAL Requirement: Renal (1) polar Biliary (2) small MW 85 mL/min [98 - 0.8 x (age - 20)] x BSA Mild impairment: 60-85 mL/min [1.73 x Serum Creatinine] Moderate impairment: 30-59 mL/min Severe impairment: < 30 mL/min GFR for female: GFR(females) = GFR(males) x 0.9 where, BSA= Body Surface Area 46 47 Application PRACTICE #3 Dose adjustment of renaly excreted drugs among Px with Renal A 20 – year old man weighing 50 kg has a CrSr of 1.50 mg/dL. insufficiency Compute for the creatinine clearance (CLcr). If the regular dose Normal: 80-120 mL/min or 100 mL/min (ave) is 500 mg what is the adjusted dose for the patient Dose adjusted = [(CLcr Px) x Regular dose (CLcr normal)] (100mL/min)] 48 49  RENAL EXCRETION BILIARY EXCRETION Note Requirement: Weak acids + basic urine = ionized Polar Weak base + acidic urine = ionized MW >400-600 (bigger than renal) E.g. Amphetamine: weak base Reabsorbed if urine pH is alkaline More lipid-soluble, nonionized species are formed 50 51 BILIARY EXCRETION MAMMARY EXCRETION if a drug is excreted through the bile, there is a possibility of Many drugs pass into breast milk and may attain a higher drug reabsorption concentration in milk than in plasma o Nursing mothers should avoid taking drugs (biliary recycling / enterohepatic recirculation) o Antithyroid, lithium, chloramphenicol, anticancer drugs à DO NOT NURSE Extremely narrow therapeutic index gentamicin, kanamycin à bile is excreted in duodenum so drug can still be reabsorbed in TAKE SPECIAL CARE duodenum, jejunum and ileum Prolong the duration of the drug 52 53  DRUG EXCRETION INTO SWEAT DRUG EXCRETION INTO EXPIRED AIR Passive diffusion of the non-ionized moiety Less soluble anesthetics Non-ionized compounds: alcohol, antipyrine, urea Soluble gases Weak acids: sulfonamides, salicylic acid Other volatile compounds: alcohol, ethereal oils Weak bases: thiamine Metals: I, Br, Hg, Pb 54 55 GENITAL EXCRETION Pharm 304: BIOPHARMACEUTICS & PHARMACOKINETICS Prostate secretions Unit 7C Seminal fluid: anticancer drugs à malformations Biopharmaceutic Considerations of Drug Design S.Y. 2024-2025 MICKO D. DE GUZMAN 56 57  Biopharmaceutics is the study of the in vitro impact of the Basis of Biopharmaceutics physicochemical properties of drugs and drug products on drug delivery to the body under normal or pathologic conditions. 1. The physical and chemical properties of the drug substance; Aim of Biopharmaceutics: To adjust the delivery of drug from the 2. the route of drug administration, including the anatomic and physiologic drug product in such a manner as to provide optimal therapeutic nature of the application site (ex: oral, topical, injectable, implant, activity and safety for the patient transdermal patch, etc.); 3. desired pharmacodynamic effect (ex: immediate or prolonged activity); A primary concern in biopharmaceutics is the bioavailability of drugs. 4. toxicologic properties of the drug; 5. safety of excipients; 6. effect of excipients and dosage form on drug delivery; and Bioavailability refers to the measurement of the rate and extent of active drug that becomes available at the site of action. 7. manufacturing process 58 59 Biopharmaceutic Considerations Each route of drug administration presents specific biopharmaceutic considerations in drug product design. 1. the type of drug product (ex: solution, suspension, suppository), 2. the nature of the excipients in the drug product, Ex. An eye medication may require special biopharmaceutic 3. the physicochemical properties of the drug molecule, and considerations, including appropriate pH, isotonicity, sterility, 4. the route of drug administration. local irritation to the cornea, draining by tears, and concern for systemic drug absorption. 60 61  RATE-LIMITING STEPS IN DRUG ABSORPTION DISINTEGRATION Complete disintegration is defined by the USP as "that state in which any residue of the tablet, except fragments of insoluble coating, remaining on the screen of the test apparatus in the soft mass have no palpably firm core.“ Exceptions: troches, chewable tablets, and modified-release 1. Disintegration of the drug product and subsequent release of the drug 2. Dissolution of the drug in an aqueous environment drug products 3. Absorption across cell membranes into the systemic circulation 62 63 DISSOLUTION DISSOLUTION process in which a solid drug substance becomes dissolved in a STEPS IN DISSOLUTION: solvent rate at which a solid can get dissolved in a given solvent 1. Drug dissolution at the surface of dynamic property the solid particle an important prior condition for systemic absorption 2. Formation of saturated solution dissolution tests may be used to predict bioavailability and may be around it – stagnant layer used to discriminate formulation factors that affect drug 3. Diffusion of drug to the bulk solvent bioavailability Cs = concentration of drug in the stagnant layer C = concentration of drug in the bulk solvent. 64 65  DISSOLUTION DISSOLUTION NOYES-WHITNEY EQUATION FACTORS THAT AFFECT DRUG DISSOLUTION: 1. the physical and chemical nature of the active drug substance, dC /dt = rate of drug dissolution at time t 2. the nature of the excipients, and D = diffusion rate constant, A = surface area of the particle, CS = concentration of drug (equal to solubility of drug) in the stagnant layer, 3. the method of manufacture C = concentration of drug in the bulk solvent h = thickness of the stagnant layer 66 67 ABSORPTION ABSORPTION Permeation of drug across the gut wall (a model lipid membrane) An increase in temperature will increase the kinetic energy of the is affected by the ability of the drug to diffuse (D) and to partition molecules and increase the diffusion constant, D. between the lipid membrane. Moreover, an increase in agitation of the solvent medium will A favorable partition coefficient (K oil/water) will facilitate drug reduce the thickness, h, of the stagnant layer, allowing for more absorption rapid drug dissolution. 68 69  Particle size and surface area PHYSICOCHEMICAL PROPERTIES FOR CONSIDERATION IN DRUG PRODUCT DESIGN particle size = surface area of particles 1. Particle size and surface area = water penetration = dissolution rate 2. Partition coefficient and extent of ionization 3. Salt formation 4. Polymorphism 5. Chirality 6. Hydrates 7. Complex formation 70 71 Particle size and surface area Partition coefficient and extent of ionization Griseofulvin, nitrofurantoin, and many steroids Henderson-Hasselbalch equation - low aqueous solubility; The ionized species of the drug contains a charge and is more - reduction of the particle size by milling to a micronized form water soluble than the nonionized species of the drug, which is has improved the oral absorption more lipid soluble Hydrophobic drugs – excessive particle size reduction à reaggregate into larger particles à decreased dissolution rate PEG, PVP (polyvinylpyrrolidone), dextrose à prevent reaggregation à enhance dissolution 72 73  Partition coefficient and extent of ionization Salt formation Acid liberates hydrogen ions (H+) Depends on the physical, chemical or pharmacologic properties Base can bind H+ Strong acids, strong bases, strong electrolytes (completely ionized) Basic drug more soluble in stomach forms soluble salt Weak acids and weak bases (partially ionized) Acid drug more soluble in intestine form soluble salt = undissociated compound and ions Nonionized form – lipid-soluble and diffusible Ionized form – lipid-insoluble and non-diffusible 74 75 Salt formation Salt formation 1. Some soluble salt forms are less stable (eg: sodium aspirin) 4. Weakly acidic drugs – K and Na salts are more soluble ex: Voltaren, Cataflam, Fern-C 2. Free acid form + Buffering Agents Buffering agent forms alkaline medium 5. Weak bases Dissolved salt form diffuses into the bulk fluid of the GI - Common water-soluble salts – HCl, Sulfate, Citrate, tract à fine precipitate that redissolves rapidly à available Gluconate for absorption - Less Water Soluble – Estolate, Napsylate, Stearate ex: Lidocaine HCl, Erythromycin estolate 3. Effervescent Granules or Tablets – Acid Drug with NaHCO3, Tartaric Acid, Citric Acid or other ingredients 76 77  Polymorphism Polymorphism The ability of a drug to exist in more than one crystalline form In general, the crystalline form of drugs are more rigid and arrangement of a drug substance in various crystal forms or thermodynamically more stable than the amorphous form. polymorphs The crystal form with the lowest free energy is the most stable Same chemical structure with different physical properties (ex. polymorph. melting point, dissolution rate) A change in crystal form may cause problems in manufacturing the Amorphous forms are non-crystalline forms product. For example, a change in crystal structure of the drug may Solvates are forms that contain a solvent (solvate) or water (hydrate) cause cracking in a tablet or even inability for a granulation to be compressed to form a tablet Desolvated solvates are forms that are made by removing the solvent from the solvate. Dissolution rate: amorphous form > crystalline form 78 79 Polymorphism Chirality Polymorphs have the same chemical structure but different Ability of a drug to exist as optically active stereoisomers or physical properties, such as solubility, density, hardness, and enantiomers compression characteristics. Some polymorphic crystals have much lower aqueous solubility Individual enantiomers (S & R) may not have the same than the amorphous forms, causing a product to be pharmacokinetic and pharmacodynamic activity incompletely absorbed Chloramphenicol B polymorph - more soluble and better absorbed 80 81  Chirality Chirality Most chiral drugs are racemic mixtures à results of studies with such mixtures may be misleading because the drug is assumed to behave as a single entity 82 83 Chirality Chirality In a racemic mixture, one enantiomer could have: Ibuprofen exists as the R- and S-(dextrorotatory) enantiomer; only the S-enantiomer is pharmacologically active 1. No activity 2. Some activity When taken orally, R-enantiomer undergoes presystemic inversion in the gut to the S-enantiomer 3. Antagonist activity against the active enantiomer 4. Completely separate beneficial or adverse activity from the active enantiomer Rate and extent of inversion are site specific and formulation dependent, activity may vary considerably 84 85  Chirality Chirality PHARMACODYNAMIC EFFECTS PHARMACODYNAMIC EFFECTS (S)-ibuprofen (dexibuprofen) is over 100-fold more potent an inhibitor of cyclooxygenase I than (R)-ibuprofen cardiotoxicity of bupivacaine is mainly associated with the (R)- enantiomer, the psychomimetic effects of ketamine are more associated with the (R)-enantiomer, and (S)-baclofen (R)-methadone (levomethadone) has a 20-fold higher affinity for the antagonizes the effects of (R)-baclofen µ opioid receptor than (S)-( dextromethadone) methadone (S)-citalopram is over 100-fold more potent an inhibitor of the serotonin reuptake transporter than (R)-citalopram 86 87 Chirality Chirality PHARMACOKINETIC EFFECTS PHARMACOKINETIC EFFECTS the bioavailability of (R)-verapamil is more than double that of the clearance of (R)-fluoxetine is about four times greater than (S)-verapamil due to reduced hepatic first-pass metabolism (S)-fluoxetine due to a higher rate of enzyme metabolism the renal clearance of (R)-pindolol is 25% less than (S)-pindolol the volume of distribution of (R)-methadone is double that of due to reduced renal tubular secretion (S)-methadone due to lower plasma binding and increased enantiomers of warfarin can be metabolized by different tissue binding enzymes 88 89  Hydrates Complex formation Hydrated, solvated or anhydrous Complex – species formed by the reversible or irreversible association of two or more interacting molecules or ions Dissolution rates differ for hydrated and anhydrous form Chelates – complexes that typically involve a ring-like structure formed by the interaction between a partial ring of atoms and a metal Dissolution rate: anhydrous form of ampicillin > hydrated form of ampicillin 90 91 Complex formation Alters the physical and chemical properties of the drug Chelate of tetracycline with Ca is less water soluble and poorly absorbed DRUG PRODUCT AND DRUG Aminophylline (theophylline + ethylenediamine) is more water soluble than theophylline à parenteral and rectal DELIVERY SYSTEMS administration Cyclodextrins + drug = enhance water solubility Drug complexes cannot cross the cell membrane easily 92 93  Design of an appropriate dosage form or Rate-limiting step in bioavailability delivery system Generally, solid dosage forms à rapid disintegration rate Physical & chemical properties of a drug Dose of the drug Controlled- or sustained-release drug product à liberation Route of administration Type of drug delivery desired Desired therapeutic effect Physiologic release of a drug from the delivery system Bioavailability of a drug from the absorption site Pharmacokinetic and pharmacodynamics of a drug 94 95 Solution Solution Homogenous mixtures of one or more solutes dispersed Elixir has a good bioavailability molecularly in a dissolving medium Alcohol aids drug solubility = drug is diluted in the GI tract fluid and other gut contents (ex. food) à form a finely divided precipitate à Most bioavailable and consistent form extensive dispersion & large surface area à redissolution = rapid absorption Reference preparation for solid peroral formulations Viscous drug solution à interfere with dilution & mixing in the GI (ex. relative bioavailability) tract contents Decreases gastric emptying rate = delayed absorption 96 97  Suspension Suspension Dispersion of finely divided solid particles in a liquid medium in which Suspending agents (ex. cellulose derivatives, acacia, xanthan gum) a drug is not readily soluble à increases viscosity, inhibits agglomeration and decrease the rate at which the particles settle Liquid medium comprises a saturated solution of the drug in equilibrium with the solid drug gastric emptying time, drug dissolution and absorption rate Bioavailability similar to a solution à finely divided particles are dispersed Dependent on dissolution rate (ex. good or poor water solubility) 98 99 Capsules Capsules Solid dosage forms with hard or soft gelatin shells that contain a Gelatin softens, swells and begins to dissolve after ingestion drug, usually admixed with excipients Released rapidly & dispersed easily, good bioavailability Coating affects bioavailability Preferred dosage forms for early clinical trials Hard gelatin capsules contain a powder blend Simpler & less compacted than a compressed tablet 100 101  Capsules Capsules Soft gelatin capsules may contain a non-aqueous solution, powder or drug suspension Aging and storage conditions à moisture content of the gelatin component of the capsule shell and bioavailability Vehicle may be water-miscible (ex. PEG) Low moisture levels à brittle and easily ruptures Soft gelatin capsule containing a drug dissolved in a hydrophobic vehicle has a poorer bioavailability than a compressed tablet formulation High moisture levels à moist, soft & distorted à moisture may be transferred to the capsule contents (esp. if hygroscopic) Digoxin dispersed in a water-miscible vehicle (Lanoxicaps) has better bioavailability than compressed tablets (Lanoxin) 102 103 Compressed tablets Solid dosage forms in which high pressure is used to compress a powder blend or granules that contain the drug and other ingredients, or excipients, into a solid mass EXCIPIENTS OF Excipients (diluent, disintegrant, binder, lubricant, glidant, COMPRESSED TABLETS surfactant, dye, flavoring agents) Permit efficient manufacture of compressed tablets Affect the physical & chemical characteristics of the drug Affect bioavailability: higher the ratio of excipient to active drug = greater likelihood that the excipients affect bioavailability 104 105  Disintegrant Lubricants Example: starch, croscarmellose, sodium starch glycolate Usually hydrophobic, water-insoluble substances (ex. stearic acid, magnesium stearate, hydrogenated vegetable oil, talc) Vary in action depending on: 1. Concentration Reduce wetting of the surface of drug particles à 2. Method by which they are mixed with the powder dissolution rate, bioavailability formulation or granulation 3. Degree of tablet compaction Mg stearate – in excess, retard drug dissolution and slow rate of absorption Tablet disintegration is usually faster than dissolution Water-soluble lubricants (ex. L-leucine) do not interfere with Can affect bioavailability if it fails bioavailability & dissolution 106 107 Glidants Surfactants Improve the flow properties of a dry powder blend before it is compressed Reduce interfacial or surface tension between solid drug and liquid Improve the wettability (contact) of solid drug particles by the solvent May reduce tablet-to-tablet variability and improve product efficacy Enhance drug dissolution and bioavailability (at low concentration) High concentration of surfactants à micelle formation à reduced bioavailability 108 109  Coating Enteric coating Sugar coat, film coat, enteric coat Minimize contact between the drug and the gastric contents or gastric mucosa Purpose: 1. Protects the drug from moisture, light & air Insoluble at acidic pHs 2. Improves appearance of the tablet Resist attrition and remain whole long enough for the tablet to leave 3. Masks the taste & odor of the drug the mucosa 4. Affect the release rate of the drug May decrease bioavailability 110 111 Enteric coating Modified-Release Dosage Form Function: Drug products that alter the rate or timing of drug release 1. Minimize irritation of the gastric mucosa by the drug Dose dumping (abrupt release of a large amount of drug) is a 2. Prevent the inactivation or degradation of the drug in the problem stomach Extended-release dosage forms include controlled-release, 3. Delay the release of the drug until the tablet reaches the small sustained-action and long-acting drug delivery systems intestine, where conditions for absorption may be optimal 112 113  Modified-Release Dosage Form Modified-Release Dosage Form 1. Extended-release drug products Extended, slow release of CR drug products produces a relatively flat, sustained plasma drug concentration that avoids Allow at least a two-fold reduction in dosing frequency toxicity (from high drug conc) or lack of efficacy (from low drug conc) compared with conventional immediate-release formulations Sustained releases DF follow – first-order kinetics - Dosage is sustained for prolonged periods of time; drug release is not definite per unit Ex. controlled-release, sustained-release, and long-acting drug products Controlled forms – zero-order kinetics - Drug release is very definite per unit time Diltiazem HCl extended release- Once-a-day dosing 114 115 Modified-Release Dosage Form Transdermal DDS 2. Delayed-release dosage forms release the active drug at a Controlled-release devices that contain the drug for systemic time other than the immediately after the administration at a absorption after topical application to the skin surface desired site in the GI tract Enteric-coated dosage forms Diclofenac sodium delayed-release - Enteric-coated tablet for drug delivery into small intestine. Mesalamine delayed- release - Coated for drug release in terminal ileum 116 117  Transdermal DDS Transdermal DDS Example: nitroglycerin, nicotine, scopolamine, clonidine, Differ from conventional topical preparations in the following fentanyl, 17-b-estradiol & testosterone 1. Impermeable occlusive backing film that prevents insensible Clonidine TTS is applied every 7 days to intact skin on the water loss from the skin beneath the patch à increased upper arm or chest hydration and skin temperature under the patch à enhanced permeation by the drug 3.5, 7, 10.5 cm2 Amount of drug released is proportional to the area of TDS 118 119 Transdermal DDS Targeted (site-specific) DDS 2. Formulation matrix of the patch maintains the drug conc. Drug carrier systems that place the drug at or near the receptor site/ gradient within the device after application so that the drug intended physiological site of reaction delivery to the interface between the patch & skin is sustained Macromolecular drug carriers (protein drug carriers) Particulate DDS (ex. liposomes, nanoparticles) 3. Kept in place on the skin by an adhesive layer ensuring drug Monoclonal antibodies contact with the skin and continued drug delivery Daunorubicin citrate liposome injection – maximize the selectivity of daunorubicin for solid tumors in situ Mesalamine (5-aminosalicylic acid) is a delayed-release tablet coated with an acrylic-based resin that delays the release of mesalamine until it reaches the terminal ileum and colon. 120 121  Targeted (site-specific) DDS Inserts, Implants, and Devices Drug may be delivered to: Used to control drug delivery for localized or systemic drug effects capillary bed of the active site Drug is impregnated into a biodegradable or nonbiodegradable special type of cell (ex. tumor cells) but not to normal cells material and is released slowly a specific organ or tissue by complexing with a carrier that Inserted into cavities (ex. vaginal, buccal) or tissues (ex. skin) recognizes the target Leuprolide acetate implant (Viadur) Inserted beneath the skin of the upper arm For prostate cancer; 12 months supply 122 123 END OF DISCUSSION J 124  OUTLINE Pharm 304: BIOPHARMACEUTICS & PHARMACOKINETICS Introduction to Bioavailability Unit 8 Determination of Bioavailability BIOAVAILABILITY Determination of Area Under the Curve Relative Bioavailability Absolute Bioavailability S.Y. 2024-2025 MICKO D. DE GUZMAN 1 2 BIOAVAILABILITY BIOAVAILABILITY Availability of drug to the biological system FACTORS WHICH ARE KNOWN TO AFFECT DRUG ABSORPTION The extent to which the active ingredient in a dosage form Physicochemical properties of the drug substance intended for extravascular administration becomes available for Method of manufacture of the dosage form absorption. Manufacturing aides used in the fabrication of the dosage form 3 4  BIOAVAILABILITY BIOAVAILABILITY Drug release Absorption Drug in systemic Drug in Intravenous route: completely available to the biological system and distribution circulation tissues Extravascular routes: may or may not be completely available Elimination Factors: Excretion and Pharmacologic 1. Incomplete absorption of the drug dose Metabolism or Clinical Effect 2. Inactivation of part of the administered dose Result of interaction between drug substance and receptors Unavailability of a portion of the administered drug from the dosage form may 3. Metabolism of part of the dose at the absorption site result in variation in the expected therapeutic response 5 6 BIOAVAILABILITY BIOAVAILABILITY The rate at which and extent to which the active drug ingredient Applications of data gathered from bioavailability studies: 1. Determination of extent of absorption is absorbed from a drug product and becomes available at the 2. Determination of rate of absorption of the drug site of drug action 3. Determination of duration of the presence of drug in the biological fluid Approaches to correlate concentration of drug at the site of action: 4. Correlation between concentration of drug in the plasma and clinical response 5. Comparison of systemic availability of drug from different production batches of the 1. Concentration of drug in the blood or plasma dosage form 2. Excretion rate of drug the urine 7 8  BIOAVAILABILITY Determination of Bioavailability Applications of data gathered from bioavailability studies: Clinical evaluation of therapeutic effectiveness of drug 6. Determination of duration of activity of drug Example: lowering of BP, reducing blood glucose level 7. Comparison of systemic availability of drug from different dosage forms of the same drug manufactured by the same manufacturer May be difficult if therapeutic efficacy is difficult to quantify; if subjective 8. Comparison of systemic availability of drug from the same dosage form produced Blood or plasma, urine by different manufacturers Less costly and more time-saving 9. Determination of plasma concentration of drug at which toxicity occurs Can provide a quantifiable and highly reliable evaluation of 10. Determination of the design of the proper dosage regimen for the patient pharmacokinetic parameters of the drug product 9 10 Blood or Plasma Blood or Plasma Most commonly used body fluid to correlate concentration of Blood samples are collected at predetermined time intervals after drug at the receptor site extravascular administration of the drug dose Most drugs reach site of action through systemic circulation Drug concentration in each blood sample is determined using Also referred to as systemic availability suitable assay method and these concentrations are plotted as a function of time on a suitable graph paper The venous and arterial blood is considered systemic circulation (blood in the portal vein is excluded) 11 12  Blood or Plasma Urine Advantage: if the study is well designed and executed properly, Since the rate of excretion of drug in the urine depends on the it can provide a quantifiable and highly reliable evaluation of concentration of drug in blood, it follows that: pharmacokinetic parameters of the drug product —the rate of urinary excretion of drug is representative of the rate of absorption; and Disadvantage: subjects participating in the study have to be —cumulative amount of drug excreted in the urine is under medical supervision and blood samples must be representative of the extent of drug absorption withdrawn by qualified individuals 13 14 Urine Urine The drug dose is administered by an extravascular route and the Advantage: simpler, less troublesome, and least painful to patient is asked to void their bladder at frequent time intervals. patients Volume of urine and concentration of drug in each urine sample is Disadvantages: Collection of urine samples is limited due to an calculated 𝐴𝑚𝑜𝑢𝑛𝑡 𝑜𝑓 𝑑𝑟𝑢𝑔 𝑒𝑥𝑐𝑟𝑒𝑡𝑒𝑑 individual’s ability to void bladder at frequent intervals. This = (Volume of urine collected) 𝑥 (Concentration of drug in urine) approach is generally limited to only those drugs with at least 𝐴𝑚𝑜𝑢𝑛𝑡 𝑜𝑓 𝑑𝑟𝑢𝑔 𝑒𝑥𝑐𝑟𝑒𝑡𝑒𝑑 10% of the drug is excreted unchanged in the urine 𝐸𝑥𝑐𝑟𝑒𝑡𝑖𝑜𝑛 𝑟𝑎𝑡𝑒 = 𝑡𝑖𝑚𝑒 15 16  Bioavailability Studies Parameters of Bioavailability The rate at which and extent to which the active drug ingredient is absorbed from a drug product and becomes available at the site of drug action Data derived from: Plasma concentration Urine A Typical Plot of Concentration of Drug in Plasma as a Function of Time 17 18 Parameters of Bioavailability Rate of Absorption When plasma concentration data are used to estimate The __________ the Cmax, bioavailability, the parameters are: The ___________ the rate of drug absorption 1. Peak plasma concentration (Cmax) The ____________ the drug attains Tmax, 2. Time of peak plasma concentration (Tmax) The _____________ the rate of drug 3. Area under the plasma concentration absorption versus time curve (AUC) Plasma concentration of three different formulations 19 20  Extent of Drug Absorption DETERMINATION OF AREA UNDER THE CURVE Signifies the fraction of administered 1. Planimeter dose that is actually absorbed and 2. Counting squares appears in the systemic circulation Applies only to extravascular drug 3. Cutting and weighing administration 4. Trapezoidal rule If IV, the extent of absorption is 100% Plasma concentration versus time plot (shaded part is AUC) 21 22 Planimeter Counting Squares Instrument that mechanically measures area of plane figures The total number of squares enclosed by the plasma concentration Consists of an arm attached to a rotating wheel, which moves a dial versus time curve are counted with the movement of the arm 1. Plot plasma concentration as a function of time on a rectilinear graphing paper The dial is equipped with Vernier calipers to ensure accurate reading 2. Draw a smooth curve to join data points The reading on the dial is then converted to AUC by using a factor obtained by tracing the arm over a square or circle of known area 3. Draw a straight line to connect last concentration data point with the corresponding time point on the x-axis Considered as the simplest and most reliable but not in common use 4. Count the squares enclosed within the bounded curve 23 24  Counting Squares Counting Squares The total number of squares enclosed by the plasma concentration The total number of squares enclosed by the plasma concentration versus time curve are counted versus time curve are counted 5. Determine area of each square using: Only the whole squares and squares that are covered 50% or more than 50% are counted Area = (height in units of conc.)(width in units of time) 6. Calculate AUC using: Accuracy depends on: —The number of squares per linear inch on graphing paper AUC = (# of squares)(area of one square) (smaller squares will provide more accurate AUC) —The investigator counting the squares 25 26 Cutting and Weighing Involves plotting the plasma profile on a graph paper and then cutting and weighing the plasma profile Involves the use of two graphs: one contains plotted data, other is used as a reference Same AUC, different Cmax and Tmax Frequently used to compare AUC of two or more formulations Same extent of absorption, different rates of absorption 27 28  Trapezoidal Rule Trapezoidal Rule Estimation of the AUC by Trapezoidal Rule The total area under the curve from the time the drug appears in 7 systemic circulation to the time that the drug is virtually Plasma concentration (mcg/L) 6 c 𝑪 𝟎 + 𝑪𝟏 eliminated from the systemic circulation 5 𝑨𝑼𝑪 = 𝟐 𝒕𝟏 − 𝒕𝟎 4 3 a b 2 1 h 0 0 d 10 20 30 40 50 60 Time (h) 29 30 Trapezoidal Rule Trapezoidal Rule 𝑪 𝟎 + 𝑪𝟏 𝑪 𝟏 + 𝑪𝟐 𝑪 𝟐 + 𝑪𝟑 𝑪 𝟎 + 𝑪𝟏 𝑪 𝟏 + 𝑪𝟐 𝑪 𝟐 + 𝑪𝟑 𝑨𝑼𝑪 𝟎 → 𝒕 = 𝒕𝟏 − 𝒕 𝟎 + 𝒕𝟐 − 𝒕 𝟏 + 𝒕𝟑 − 𝒕 𝟐 + … 𝑨𝑼𝑪 𝟎 → 𝒕 = 𝒕𝟏 − 𝒕 𝟎 + 𝒕𝟐 − 𝒕 𝟏 + 𝒕𝟑 − 𝒕 𝟐 + … 𝟐 𝟐 𝟐 𝟐 𝟐 𝟐 𝑪𝒍𝒂𝒔𝒕 𝑪𝒍𝒂𝒔𝒕 𝑨𝑼𝑪 𝒕 → ∞ = 𝑨𝑼𝑪 𝒕 → ∞ = 𝒌𝒆𝒍 𝒌𝒆𝒍 𝑨𝑼𝑪 𝟎 → ∞ = 𝑨𝑼𝑪 𝟎 → 𝒕 + 𝑨𝑼𝑪𝒕 →∞ 𝑨𝑼𝑪 𝟎 → ∞ = 𝑨𝑼𝑪 𝟎 → 𝒕 + 𝑨𝑼𝑪𝒕 →∞ Where: Where: C 0 = concentration of drug in plasma at t0 𝑨𝑼𝑪 𝟎 → ∞ = Since most drug are absorbed almost immediately after t0 = time when plasma concentration of drug reached C0 administration of the drug dose, the appearance of drug in plasma is kel = apparent first-order elimination rate constant considered to have taken place at time zero 31 32  Trapezoidal Rule Trapezoidal Rule 𝑪 𝟎 + 𝑪𝟏 𝑪 𝟏 + 𝑪𝟐 𝑪 𝟐 + 𝑪𝟑 Estimation of the AUC by Trapezoidal Rule 𝑨𝑼𝑪 𝟎 → 𝒕 = 𝒕𝟏 − 𝒕 𝟎 + 𝒕𝟐 − 𝒕 𝟏 + 𝒕𝟑 − 𝒕 𝟐 + … 𝟐 𝟐 𝟐 7 𝑪𝒍𝒂𝒔𝒕 Plasma concentration (mcg/L) 6 𝑨𝑼𝑪 𝒕 → ∞ = c 𝒌𝒆𝒍 5 𝑨𝑼𝑪 = 𝑪 𝟎 + 𝑪𝟏 𝒕𝟏 − 𝒕𝟎 𝟐 𝑨𝑼𝑪 𝟎 → ∞ = 𝑨𝑼𝑪 𝟎 → 𝒕 + 𝑨𝑼𝑪𝒕 →∞ 4 Where: 3 𝑨𝑼𝑪𝟎 → ∞ = 𝑨𝑼𝑪𝟎 → 𝒕 + 𝑨𝑼𝑪𝒕 → ∞ a b 𝑨𝑼𝑪𝟎 → ∞ 2 𝑪𝒍𝒂𝒔𝒕 o Pharmacokinetic studies are seldom carried out long enough to allow the drug to be almost completely 𝑨𝑼𝑪𝒕 → ∞ = eliminated from the body. 1 h 𝒌𝒆𝒍 o The entire drug concentration versus time curve is usually not available for estimating the total AUC 0 o Early termination of pharmacokinetic study is partly due to time constraints 0 d 10 20 30 40 50 60 o Very low concentrations of drug in the plasma samples are very difficult to determine accurately Time (h) 33 34 Sample Problems: Sample Problems: 1. Given the data below, compute for the total AUC using the trapezoidal rule. 1. Given the data below, compute for the total AUC using the trapezoidal rule. Time (h) Conc. (mcg/L) 𝑪𝟎 + 𝑪𝟏 Time (h) Conc. (mcg/L) 𝑨𝑼𝑪 𝟎 → 𝟗 = 𝑻 𝟏 + 𝑻 𝟐 + … + 𝑻𝟗 0 0 𝑻𝟏 = 𝒕𝟏 − 𝒕𝟎 0 0 1 3.13 𝟐 1 3.13 2 4.93 2 4.93 5 6.28 5 6.28 7 5.81 7 5.81 10 4.66 10 4.66 18 2.19 18 2.19 24 1.20 24 1.20 32 0.54 32 0.54 48 0.10 48 0.10 35 37  Sample Problems: INTRAVENOUS ADMINISTRATION 1. Given the data below, compute for the total AUC using the trapezoidal rule. When the drug is administered intravenously, Time (h) Conc. (mcg/L) 𝑨𝑼𝑪𝟎 → ∞ = 𝑨𝑼𝑪𝟎 → 𝒕 + 𝑨𝑼𝑪𝒕 →∞ 0 0 the entire drug dose is placed into the 1 3.13 2 4.93 systemic circulation 𝑙𝑛𝐶1 − 𝑙𝑛𝐶2 𝐶9 5 6.28 𝑘𝑒𝑙 = 𝐴𝑈𝐶 9 → ∞ = 7 5.81 𝑡2 − 𝑡1 𝑘𝑒𝑙 The amount of drug absorbed from an IV dose 10 4.66 18 2.19 is considered to be equal to the amount of 24 1.20 drug administered 32 0.54 48 0.10 38 40 INTRAVENOUS ADMINISTRATION Sample Problems: 1. The plasma concentration as a function of time following a single bolus IV 10 mg dose 𝑪𝟎 of a drug is shown below. Calculate total area under the curve. 𝑨𝑼𝑪 𝟎 → ∞ = 𝒌𝒆𝒍 Time (h) 1 2 3 4 6 7 Concentration (mcg/L) 16 13 10 8 5 4 𝑙𝑛𝐶 𝑡 = 𝑙𝑛𝐶0 − 𝑘1𝑡 Where: 𝑪𝟎 C0 = concentration of drug in the post-absorptive phase 𝑨𝑼𝑪𝟎 → ∞ = 𝒌𝒆𝒍 Kel = first-order rate constant 𝑙𝑛𝐶 1 − 𝑙𝑛𝐶 2 𝑘1 = 𝑡2 − 𝑡1 41 42  Sample Problems: RELATIVE BIOAVAILABILITY Bioavailability in relation to a given standard 1. The AUC from a 325-mg dose of a drug administered as an oral suspension was found to be 105 mcg∙h/mL and AUC from a similar dose = 1 or 100% administered orally, as a tablet, was found to be 130 mcg∙h/mL. Same drug bioavailability Calculate the relative bioavailability of the drug from the suspension Does not indicated completeness of systemic drug absorption formulation. May exceed the value of 1 or 100% as compared to a reference drug product Important in generic drug studies 44 45 ABSOLUTE BIOAVAILABILITY Sample Problems: Systemic availability after extravascular administration, 2. The AUC from a 325-mg bolus dose of a drug administered compared to IV dosing intravenously as an aqueous solution was found to be 185 mcg∙h/mL and the AUC from a similar dose administered orally as a tablet was Measure of the extent of drug absorption found to be 153 mcg∙h/mL. What is the extent of absorption from the May not exceed 100% tablet formulation? F = fraction of the dose that is bioavailable Expressed as fraction or percent (F x 100) 47 48