Introduction to Biopharmaceutics PDF PHA114 2024

PHA114 Introduction to Biopharmaceutics Dr Paul Carter Slide 1 of 33 MPharm Introduction to Biopharmaceutics  Biopharmaceutics Study of how the physiochemical pr...

PHA114 Introduction to Biopharmaceutics Dr Paul Carter Slide 1 of 33 MPharm Introduction to Biopharmaceutics  Biopharmaceutics Study of how the physiochemical properties of the drug, the dosage form and the route of administration affect the rate and extent of drug absorption Pharmacokinetics is the study and characterization of the time course of drug absorption, distribution, metabolism and elimination Pharmacodynamics is the study of the biochemical and physiological effects of the drug on the body. Absorption Distribution Metabolism Excretion: kidney Polar drugs in urine - if necessary, liver metabolises drug to more polar Distribution governed by affinity for various tissues. Depends on: aqueous or lipid solubility binding to extracellular substances e.g. proteins intracellular uptake Slide 2 of 33 Introduction to Biopharmaceutics  Summary of ADME Slide 3 of 33 Introduction to Biopharmaceutics  Absorption - how? Passive diffusion – Movement via concentration gradient across a membrane separating two body compartments – Does not involve a carrier, is not saturable, and shows a low structural specificity. – Majority of drugs gain access to body Cell membranes of living organisms are composed of a lipid bilayer (also for sub-cellular structures). Barrier that keeps ions, proteins and other molecules from diffusing out or into cells. Impermeable to most water-soluble molecules e.g. ions (cells need to regulate salt concentrations and pH by pumping ions across their membranes using ion pumps). Natural bilayers are usually made mostly of phospholipids, which have a hydrophilic head and two hydrophobic tails Polar molecules have low solubility in the hydrocarbon core of a lipid bilayer and hence have low permeability coefficients across the bilayer. Slide 4 of 33 Introduction to Biopharmaceutics  Lipid-soluble drugs readily move across most biological membranes Slide 5 of 33 Introduction to Biopharmaceutics  Absorption - how? A lipid:aqueous drug partition coefficient describes the ease with which a drug moves between aqueous and lipid environments. The ionisation state of a drug is an important factor in determining how well the drug will move across a lipid membrane: charged drugs diffuse through lipid environments with difficulty. The pH and the drug pKa (determined using the Henderson- Hasselbalch equation) are important in determining the drug’s ionisation state, and will significantly affect transport – Water soluble drugs Penetrate the cell membrane through aqueous channels. Slide 6 of 33 Introduction to Biopharmaceutics  Absorption - how? Facilitated Diffusion (no extra energy needed): – Involves carrier proteins, and it is a saturable process e.g. large water soluble/polar compounds Active Transport: – Requires energy – Transport is probably against the concentration gradient. – Active transport is a particularly important mechanism for passage of larger drug molecules. Carrier involved. e.g. levodopa Endocytosis and exocytosis: – These processes mediate entry into cells by very large substances (for example: movement across intestinal wall into blood of vitamin B12 complexed with its binding protein). E.g. solid particles/oil particles, 1- 100 nm Slide 7 of 33 Introduction to Biopharmaceutics  Bioavailability Therapeutic response on a drug depends on adequate concentration at site of action Adjust plasma concentration – adjust response Be careful – drug may be bound to plasma proteins and not available Bioavailability is a measure of the amount of drug from a formulation that appears in the plasma (systemic circulation) i.e. measure of the rate and extent of absorption Calculated by determining the AUC from a blood plasma drug concentration versus time plot – Non i.v.: ranges from 0 to 100% – I.V.: 100% Slide 8 of 33 Introduction to Biopharmaceutics  Single oral dose Absorption Elimination phase phase MSC Cmax Therapeutic intensity window Blood Plasma Conc (mmol l-1) MEC duration tmax Time (hr) onset Slide 9 of 33 Introduction to Biopharmaceutics  Single oral dose Single oral dose of drug Blood samples withdrawn periodically and concentration of drug analysed Initial rise = absorption phase, drug absorption > drug elimination Peak = Cmax, rate of absorption=rate of elimination Elimination phase, elimination > absorption Eventually, no more absorption, elimination is exponential (first order) MEC = minimum effective concentration – minimum concentration required for desired pharmacological effect MSC = maximum safe concentration – above which toxic effects occur Therapeutic window – desired response with no toxic effects Slide 10 of 33 MPharm Introduction to Biopharmaceutics  Plasma Concentration Single oral dose Slide 11 of 33 Introduction to Biopharmaceutics  Factors influencing bioavailability Destroyed Not Destroyed Destroyed in gut Absorbed by gut wall by liver (eg Solubility) ) to Dose systemic circulation Slide 12 of 33 MPharm Introduction to Biopharmaceutics  Drug absorption for 3 formulations of same drug (Similar AUC for A & B) A MSC Plasma B Drug Conc (mmol l-1) MEC C Time (hr) Slide 13 of 33 MPharm MPH116 Routes of Administration - Introduction to Biopharmaceutics 1  Bioequivalence Comparing if two dosage forms containing same drug are equivalent in terms of rate and extent of absorption Use AUC, Cmax and tmax Limits 80 - 120 % difference. Depends on safety and therapeutics Slide 14 of 33 MPharm Introduction to Biopharmaceutics  Regular drug dosing (computer simulation) Slide 15 of 33 MPharm Introduction to Biopharmaceutics  The steady state (computer simulation) Slide 16 of 33 MPharm Introduction to Biopharmaceutics  The steady state Slide 17 of 33 MPharm Introduction to Biopharmaceutics  Importance of protein binding Slide 18 of 33 MPharm Introduction to Biopharmaceutics WEEK 2 Oral vs intravenous Slide 19 of 33 MPharm MPH116 Routes of Administration - Introduction to Biopharmaceutics 1  Plasma Concentration mmol l -1 i.v. administration Slide 20 of 33 MPharm MPH116 Routes of Administration - Introduction to Biopharmaceutics 1  Absolute bioavailability Fraction of administered dose absorbed into the systemic circulation (accounting for different oral/i.v. doses) = (AUC)abs/(AUC)i.v. abs = via absorption site i.v. via intravenous bolus injection (100% bioavailable) Slide 21 of 33 MPharm Introduction to Biopharmaceutics  Drug distribution Drugs may distribute into any or all of the following compartments: – Plasma Plasma (3 litres) – Interstitial Fluid – Intracellular Fluid Interstitial Fluid (10 litres) Factors: Aqueous or lipid solubility Only the un-ionised form will diffuse across Intracellular Fluid membrane (28 litres) Blood flow Parts of the body which receive the most blood flow gets the most drug Slide 22 of 33 MPharm Introduction to Biopharmaceutics  Volume of distribution (V) If put dose of drug in flask, dose = vol x conc e.g. if 2 L flask and conc is 10 mg L-1 , the dose would be 2 x 10 = 20 mg. Example: Two drugs, A and B, given 100 mg i.v. (intravenously) and then plasma conc determined, (plasma is fluid part of blood containing proteins (mainly albumin) i.e suspended cells removed. About 3 litres). A = 10 mg L-1 B = 1 mg L-1 What is the volume of distribution? Slide 23 of 33 MPharm Introduction to Biopharmaceutics  Volume of distribution (V) A has V= 10 L and B has V = 100 L. Why? Water sol drugs or protein bound drugs will be present in high concs in plasma therefore low V. Lipid sol drugs or those bound to tissues will be present in low concs in plasma therefore high V. Warfarin, 99% bound to protein, low lipid solubility - low V ( 0.14 L/kg) Chloroquine, 61% protein bound, high lipid solubility - high V (115.00 L/kg) Slide 24 of 33 MPharm Introduction to Biopharmaceutics  Metabolism Metabolism = biotransformation – any process which results in a chemical change in a drug in the body May go in stages, and generally goes from more lipophilic to increasingly hydrophilic A drug may have several metabolites (by products or waste products) – Metabolites may be inactive or active Slide 25 of 33 MPharm Introduction to Biopharmaceutics  Metabolic processes can occur in any tissue, but are most likely to occur in liver, kidneys, lungs, & GI tract Cleavage – Splitting of the molecule into 2 or more simpler molecules Oxidation – combining the molecule with oxygen, or increasing the electropositive charge by the loss of hydrogen or of one or more electrons Conjugation – The combining of the molecule with glucuronic or sulfuric acid Reduction – The molecule gains 1 or more electrons and becomes more negatively charged Slide 25 of 33 MPharm MPH116 Routes of Administration - Introduction to Biopharmaceutics 1  Elimination M A J Kidney Liver O Filtration Metabolism R Secretion Secretion M I N Others Lungs O Mother’s milk, Exhalation R sweat, saliva Slide 27 of 33 MPharm Introduction to Biopharmaceutics  Elimination Kidney: Glomerular filtration - drug crosses the glomerular filter to be excreted Liver: Change a lipid soluble to more water soluble molecule to be excreted in kidney. Possibility of active metabolites with same or different properties as parent molecule Mediated via CYP450 enzyme Slide 28 of 33 MPharm Introduction to Biopharmaceutics  Half life – time taken for concentration to decrease to half its value Conc drops from 10 to 5 mmol l-1 12 i.e. conc halved in t1/2 Plasma drug conc mmol l-1 8 4 t1/2 t1 time t2 Slide 29 of 33 MPharm Introduction to Biopharmaceutics  Half life t1/2 important in determining the frequency of dosing Drugs with short t1/2 , give more frequently e.g. every four or six hourly Drugs with long t1/2, may give once a day Linear kinetics, elimination rate α concentration i.e. first order kinetics (most drugs) 1 t1/2 50% eliminated 2 t1/2 75% eliminated 3 t1/2 87.5% eliminated 4 t1/2 93.75 eliminated Therefore after 5 t1/2 there is over 95% of drug eliminated Slide 30 of 33 MPharm Introduction to Biopharmaceutics  Half life Exponential decay C = Coe-kt If take natural logs, lnC = lnCo + lne-kt Therefore lnC = lnCo – kt (y=mx + c) Or logC = logCo – kt/2.303 Plot of logC or lnC versus t will give straight line with slope -k/2.303 or -k respectively Slide 31 of 33 MPharm Introduction to Biopharmaceutics  Half life calculation 30 lnCo 25 20 Slope = -k ln C 15 10 5 0 0 5 10 15 20 T ime (hours ) Slide 31 of 33 MPharm Introduction to Biopharmaceutics  Half life calculation lnC = lnCo – kt Therefore kt = lnCo - lnC = ln Co/C If t = t1/2, C = Co/2 i.e. kt1/2 = ln 2Co/Co = ln2 = 0.693 Therefore t1/2 = 0.693/k Slide 31 of 33 MPharm Introduction to Biopharmaceutics  Summary Biopharmaceutics is the study (qualitative) of the relationships between physical and chemical properties of the drug and its dosage forms and the biological effects observed following the administration of the drug in its various dosage forms Pharmacokinetics is the quantitative study of the kinetics of drug absorption, distribution, metabolism and excretion (ADME) Aulton’s Pharmaceutics 6th Ed, online Slide 32 of 33 MPharm Introduction to Biopharmaceutics