Absorption, Distribution, and Elimination - Spring 2024 Lecture Notes PDF

INTRODUCTION TO PHARMACOKINET ICS: ABSORPTION, DISTRIBUTION AND ELIMINATION Mohammed Sayed, Ph.D. [email protected] DISCLAIMER This session is being recorded. Class recordings are distributed for the exclusive use of students in the LMU DeBusk College of Osteopathic Medicine. Student access...

INTRODUCTION TO PHARMACOKINET ICS: ABSORPTION, DISTRIBUTION AND ELIMINATION Mohammed Sayed, Ph.D. [email protected] DISCLAIMER This session is being recorded. Class recordings are distributed for the exclusive use of students in the LMU DeBusk College of Osteopathic Medicine. Student access to and use of class recordings are conditioned on agreement with the terms and conditions set below. Any student who does not agree to them is prohibited from accessing or making any use of such recordings. 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LECTURE OBJECTIVES Define common pharmacokinetic terms, their dimensional units, and their interrelationships Compare and contrast different routes of medication administration Given the pKa of a drug and given its ability to act as an acid or base, predict how relative ionization impacts passive diffusion Predict impact to pharmacokinetics caused by alterations in protein binding Compare and contrast zero order and first-order elimination kinetics Compare and contrast elimination rate and clearance, including dimensional units associated with each. Given a concentration versus time curve for a single drug dose, identify absorptive, distributive, and elimination portions of the curve; estimate elimination half-life, identify Cmax and Tmax. Given a concentration versus time curve for a single dose of drug, calculate Vd, dose, and/ or Cmax given the other two parameters TERMINOLOGY TO UNDERSTAND FOR EXAM Active transport AUC – area under “concentration vs time” curve Fraction of Bioavailability or “F” Blood-brain barrier “BBB” Cmax, C0, or peak concentration amt of drug per volume (e.g., mg/ml) Fick’s Law of Diffusion (no calculations) Hydrophilic aka lipophobic Ion trapping Lipophilic aka hydrophobic Oil:water partition coefficient (or octanol:water coefficient) pKa Tmax or time to peak Vd = volume of distribution (e.g., L) for single IV dose: Vd = dose/Cmax Clearance = volume of blood cleared per unit of time (e.g., ml/min) Clearance = kel*Vd and kel = 0.7/t1/2 clearance = (Vd)*0.7/(t1/2) First pass metabolism – elimination of orally administered drug as it passes through portal circulation Half life of elimination (t1/2) IMPORTANT ABBREVIATIONS IV = intravenous  CIVI = continuous IV infusion  IVPB = IV piggyback, often administered intermittently IM = intramuscular PO = per os or orally PR = per rectum PV = per vagina SL = sublingually Q = every XL, LA, SR, CC, ER, XR, -Depot, etc. suffixes of drug names that often indicate sustained release form INTRODUCTION TO PHARMACOKINETICS Important to note: we measure drug levels in blood/plasma - drug in tissue does not contribute to measured concentration Effect of the body on the drug Effect of the drug on the body ADME: Absorption → Distribution → Metabolism → Elimination (aka Excretion) Enteral = via the GI tract ROUTES OF ADMINISTRATION Route with no absorptive phase IV= Intravenous  Bolus = rapid injection  Intermittent or piggy-back  Repeated doses (for example every 4 hours)  Continuous IV infusion (talk about infusion rate in ml/min or mg/min) Routes dependent upon absorption         PO = by mouth SL = sublingual PR = per rectum SC= Subcutaneous ID = intradermal Transdermal (patches, ointment, gel, etc) IM=intramuscular INH = inhaled ORAL ROUTE (PO) Oral (PO) (most common)  Drug is exposed to low gastric pH, digestive enzymes, and enters hepatic portal circulation  the liver has a large concentration of drug-altering enzymes – drug is lost on first pass through the liver = “first pass metabolism”  Somewhat less risk of toxicity (can remove drug early post-ingestion via lavage)  Can manipulate drug forms to protect drug or delay onset and prolong duration  Sometimes drugs are given by mouth to produce local effect in GI tract (as opposed to systemic effects) OTHER ENTERAL ROUTES Sublingual, Buccal, Rectal  Drug bypasses harsh GI environment and bypasses first pass through liver (50% of PR will bypass)  Fairly rapid onset  Absorption for most drugs is erratic INTRAVENOUS ROUTE (IV)  Rapid onset (no liberation or absorption)  100% bioavailability (all drug is initially available – no “F” fraction of bioavailability)  Advantages:  Continuous infusion for drugs with short duration in body  Maximum control over blood levels  Good for unconscious/vomiting patients  Disadvantages:  Not generally for self-administration  Irritating drugs may cause thrombosis  Most IV drugs are in solution (though a few are emulsions) – more feasible for non-oily drugs  Chemical compatibility an issue (forming precipitate in blood, not so good…) OTHER PARENTERAL ROUTES (SC, ID AND IM) Pros  Bypass harsh gut (good for acid-labile, proteins)  Can increase availability of poorly absorbed drugs  Chemical manipulation may prolong duration by delaying liberation (Depot injections, formation of insulin hexamers, precipitation of insulin subcut.)  Subcutaneous continuous infusion may also prolong duration (e.g., insulin pump)  Subcutaneous injection may be used for local effect (e.g., local anesthetic) Cons  Invasive; fear of needles, infection risk  Once the drug in in, it can’t readily be washed out  Need for sterility = $$$$$  Absorptive phase delays onset, may limit bioavailability  Irritants may cause tissue damage BIOAVAILABILITY Bioavailability: The fraction of an administered drug that reaches the systemic circulation. The only route of administration that has 100% bioavailability is the intravenous route (IV). For all other routes, a portion of the drug is lost before it reaches the circulation, depending on absorption. ABSORPTION From: Introduction: The Nature of Drugs &Drug Development &Regulation Basic &Clinical Pharmacology, 13e, 2015 Drug permeation is important! Legend: figure 1-4 Mechanisms of drug permeation. Drugs may diffuse passively through aqueous channels in the intercellular junctions (eg, tight junctions, A), or through lipid cell membranes (B). Drugs with the appropriate characteristics may be transported by carriers into or out of cells (C). Very impermeant drugs may also bind to cell surface receptors (dark binding sites), be engulfed by the cell membrane (endocytosis), and then released inside the cell or expelled via the membrane-limited vesicles out of the cell into the extracellular space (exocytosis, D). Copyright © 2016 McGraw-Hill Education. All rights reserved. FICK’S (1ST) LAW OF DIFFUSION The flux (amount of material flowing through a membrane) is directly proportional to the diffusivity and concentration gradient, and inversely proportional to the membrane thickness. J=-D ΔC/X J= flux D= diffusivity (mol/area) ΔC= concentration gradient X = membrane thickness Constant temperature is assumed FICK’S (1ST) LAW OF DIFFUSION Diffusivity depends upon  Surface area of membrane (Cannot control it)  Molecular size (smaller is better) (Can control it, to a degree)  Lipophilicity/Ionization (Can control it)  Ionized/hydrophilic drugs (molecules carrying a charge) do not readily pass into tissues whose cells have tight junctions (e.g., CNS, testes, placenta) = low diffusivity Concentration gradient may be maintained by blood flow.     Rubbing site of IM injection increases rate of absorption (increased flow) Pulmonary vasculature = rapid blood flow to maintain gradient Occlusive dressings increase blood flow Shock can decrease blood flow IONIZATION Charged molecules don’t diffuse readily through lipid bilayer; uncharged molecules do so more readily Can potentially affect:      Liberation Absorption Distribution Metabolism Elimination The ionized form is “trapped” on one side of the membrane pH = pKa + log[A-]/[HA] Influence of pH on the distribution of a weak acid (pKa = 4.4) between plasma and gastric juice separated by a lipid barrier. A weak acid dissociates to different extents in plasma (pH 7.4) and gastric acid (pH 1.4): The higher pH facilitates dissociation; the lower pH reduces dissociation. The uncharged form, HA, equilibrates across the membrane. Blue numbers in brackets show relative equilibrium concentrations of HA and A−, as calculated from Equation 2–1. Source: Pharmacokinetics: The Dynamics of Drug Absorption, Distribution, Metabolism, and Elimination, Goodman & Gilman's: The Pharmacological Basis of Therapeutics, 13e Citation: Brunton LL, Hilal-Dandan R, Knollmann BC. Goodman & Gilman's: The Pharmacological Basis of Therapeutics, 13e; 2017 Available at: http://accessmedicine.mhmedical.com/content.aspx?bookid=2189&sectionid=166182905 Accessed: March 20, 2018 Copyright © 2018 McGraw-Hill Education. All rights reserved IONIZATION MADE EASY Environment pH < pKa a relatively acidic environment pH= pKa (neutral environment) pH>pKa a relatively alkaline environment Acidic drugs – have a proton to donate (protonated form is unionized) Un-ionized > ionized (free to leave) Ionized = un-ionized Ionized > un-ionized (trapped) Basic drugs – have a pair of electrons to accept a proton (protonated form is ionized) Ionized > un-ionized (trapped) Ionized = un-ionized Un-ionized > ionized (free to leave) Type of drug IONIZATION SUMMARY Un-ionized drugs generally pass more readily through non-fenestrated membranes (either on the way into the body, on the way around the body, or on the way out of the body)  Acid drugs will be un-ionized in an acidic medium (pHpKa) because there aren’t any protons around (free to leave)  Acid drugs will be ionized in alkaline environment (pH>pKa) because they can readily donate their proton (trapped) ACTIVE TRANSPORT AND FACILITATED DIFFUSION In general, active transport (through pumps) and facilitated diffusion (through transport proteins) does not care about Fick’s laws or ionization. Active transport proteins can be used for uptake into the cell, or efflux out of the cell. ACTIVE TRANSPORT PROTEINS: INTERACTIONS AND VARIATIONS One xenobiotic may compete with another for a ride on the transporter or may inhibit noncompetitively To illustrate, , the black pump is inhibited by the drug CNS (shown as a circule) Transport expression may be INDUCED (increased genetic expression = increased protein synthesis) To illustrate, the brain at the right has induction of red transporters) Individuals may have phenotypic variation in transporter expression For a more complete listing, see http://www.fda.gov/Drugs/DevelopmentApprovalProcess/DevelopmentResources/ DrugInteractionsLabeling/ucm081177.htm#major MEMBRANE “BARRIERS” AND ACCESS TO ORGANS A. Hepatic blood vessels. Capillaries are lined with a basement membrane broken by slit junctions (fenestrations) B. Blood-brain barrier. Cells have very tight junctions effectively eliminating transcellular movement of drugs/toxins. Active efflux mechanisms further limit penetration of polar compounds. Smaller lipophilic molecules can easily enter the brain across the cellular membrane. C. Blood capillaries and renal glomerular membranes. Quite porous allow non-polar and polar molecules (up to albumin, M.Wt 69,000) to pass through D. Renal tubules. Membranes are relatively non-porous and as such only drugs which are lipophilic or non-ionized (i.e., dependent on pH and pKa) can be passively reabsorbed. THE BLOODBRAIN BARRIER Pathophysiology of Blood–Brain Barrier Permeability Throughout the Different Stages of Ischemic Stroke and Its Implication on Hemorrhagic Transformation and Recovery. (Bernardo-Castro et al. Frontiers in Neurology 2020) DISTRIBUTION Drug Administration (non-IV) Liberation from solid dosage form Absorption into circulation IV administration Distribution: tissue storage Unbound drug (plasma) Protein-bound drug (plasma) (not all drugs bind to protein) Distribution: sites of Action (desired or not) Distribution: sites of metabolism (biotransformation) Only unbound drug in plasma is free to distribute Only unbound drug is free to interact with receptor Labs generally measure both bound and unbound Distribution: sites of elimination DRUG DISTRIBUTION – WHO LEAVES THE BLOOD AND WHO STAYS? (ANSWERS IN NOTES VIEW) Drug leaves the blood stream (reversibly) and enters extracellular fluid, cells, and tissues. Which of the following tends to stay in the plasma and which gets distributed? Lipophilic: Small Molecular Weight: High Protein Binding: Hydrophilic: Large Molecular Weight: If a drug leaves the blood, what happens to its concentration in the blood? After dosing, how/where do we sample to get an estimate of how much drug is in the body? DIFFUSION AND TRANSPORT The curve depicts brain penetration (Y axis) and lipid solubility (Oil:Water) on X axis. The curve shows the best fit for the relationship, a function of molecular size and lipid solubility Highly lipophilic drugs (those furthest to right) can diffuse more readily (higher penetration on Y axis) Why are glucose and L-dopa to left of curve (higher penetration despite low O:W) Why are phenobarbital and phenytoin to right of curve? (low penetration despite high O:W) Golan. Principles of Pharmacology (2017) p107 VOLUME OF DISTRIBUTION (VD) Concentration = Dose/Volume The apparent volume of distribution is the theoretic volume that a drug occupies in the body.  It is a theoretic volume, NOT an actual volume  As drug leaves the bloodstream (where we sample) the concentration falls because the “volume” increases VD = Dose/Cmax Vd for drugs are often published in the literature based upon the mean Vd in large population samples. We can use these population estimates to calculate the dose needed to “load” the body to achieve a target Cmax – this is the “loading dose” – used when we want to hit a target concentration quickly – for example to get the drug concentration above the (minimum effective concentration) to treat infection. APPARENT VOLUME OF DISTRIBUTION (VD) When we measure drug levels in the body, we only sample the blood, but the drug distributes throughout the body. We calculate the apparent volume of distribution after a single IV dose: Vd = dose/Cmax (notice there is one objective that says “calculate”) (volume = amount of drug/ (amount of drug/volume)) We wait until the distributive phase is complete before sample draw! CLEARANCE AND ELIMINATION (EXCRETION) ELIMINATION Once drug has entered the body, the body tries to eliminate the drug via:     Hepatic biotransformation (metabolism) Biliary excretion (elimination) Renal excretion (elimination) Other routes of elimination (enzyme catalyzed metabolism outside of the liver, elimination through saliva, exhalation, etc.) We measure the rate of elimination of drug as amount of drug removed/unit of time. FIRST ORDER ELIMINATION The rate of elimination is the tangent at each point of the curve – as the concentration decreases, the rate of elimination also decreases – first order – first order rates are dependent on the concentration of one of the reactants – in other words we have -dC/dt. This is because the rate limiting step for eliminating the drug is usually delivery of the drug by the bloodstream to the organ that’s eliminating the drug. As the concentration falls, the rate of delivery falls, so the elimination rate falls. ZERO ORDER ELIMINATION Less commonly, a drug is eliminated by a saturated enzyme system – the concentration of the drug is approaching/ exceeding Vmax (maximum reaction velocity) In this case, the elimination rate does not change with concentration – the reaction is going as fast as it can, so it doesn’t matter how fast the drug is delivered At toxic blood concentrations, drugs often undergo zero order kinetics (drug delivery to organ of elimination > Vmax) Some drugs are at or above Vmax at normal levels:     Aspirin Ethanol Phenytoin Theophylline ORDER OF ELIMINATION ZERO (BLUE) VS FIRST (ORANGE) ORDER ELIMINATION 100 Zero order First order Zero-order drugs have a greater potential to accumulate with repeated dosing If you double the daily dose of a zeroorder drug, you more than double the steady state drug level ml in bucket 75 50 25 0 0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 Hours Zero order Set amount cleared/time Rate of elimination constant Elimination is linear No true t1/2 First order Fraction cleared per time Rate changes with concentration Elimination is proportional T½ elim = amt of time it takes to reduce by 0.5 IMPORTANT TERMS Elimination half-life (T1/2 elim) = amount of time it takes to eliminate 50% of a drug from the body. For a drug that undergoes first-order elimination, the mg/hr eliminated changes, but the half-life will remain constant.  For first-order elimination drugs, we often speak of “clearance” – which is the volume of blood cleared of drug per unit time. Since a fraction of the blood is presented to the organ of elimination with each pass through the organ, the fraction of blood cleared per unit of time is constant – our clearance (e.g., ml/hr) is constant and determined by perfusion For drugs that undergo zero order elimination, the mg/hr eliminated stays the same, so there is no true elimination half-life  Our rate of elimination is constant, but the theoretical volume of blood cleared changes FIRST ORDER ELIMINATION Conc. (mg/L) 7.5 Concentration = mass/ volume; if dose is 100mg and Cmax (from graph) is 10mg/L, the Vd is 100mg/10mg/L = 10L. Dose=100 mg, Vd=10 L, C0=Dose/Vd = 10 mg/L 10 5 5 Looking at the graph, what is the half-life of this drug? 2.5 2.5 1.25 0.625 0 0 2 4 6 time (h) 8 10 It takes 4 half-lives to clear 94% of a drug with first-order clearance, and about 5 half-lives to clear 97% of the drug It will take 10 hours to clear 97% of drug Notice that the only objective that contains the verb “calculate” relates to Vd=dose/Cmax - – this means I will not ask you to perform any other calculation from this session!! END OF SESSION Questions? (Practice questions with answers follow this slide) COMPREHENSION QUESTIONS Phenobarbital is a weak acid with pKa 7.3. Which will increase the amount of phenobarbital in the urine: changing pH to 8 or changing pH to 6? Aspirin is a weak acid with pKa 3.5. In the GI tract, where will aspirin be most greatly absorbed – in the stomach (pH appx 2) or duodenum (pH 5)? Propranolol is a substrate of p-glycoprotein, which transports propranolol back into the lumen of the gut. If a patient drinks a large quantity of grapefruit juice (p-glycoprotein inhibitor), will propranolol blood levels go up or down? Induction of transporters requires increased transcription and translation of the protein. Will this happen rapidly (with first dose) or over time with repeated dosing? COMPREHENSION ANSWERS Phenobarbital is a weak acid with pKa 7.3. Which will increase the amount of phenobarbital in the urine: changing pH to 8 or changing pH to 6?  Increasing pH to 8 will allow phenobarbital to donate its proton to become ionized Aspirin is a weak acid with pKa 3.5. In the GI tract, where will aspirin be most greatly absorbed via diffusion – in the stomach (pH appx 2) or duodenum (pH 5)?  Aspirin as an acid will be less ionized in an acidic medium, so absorption will be higher from the stomach Propranolol is a substrate of p-glycoprotein, which transports propranolol back into the lumen of the gut. If a patient drinks a large quantity of grapefruit juice, will propranolol blood levels go up or down?  Grapefruit inhibits the transporter, so propranolol levels will go up (there’s more to the grapefruit story, but this is to illustrate the transport interaction) Induction of transporters requires increased transcription and translation of the protein. Will this happen rapidly (with first dose) or over time with repeated dosing?  It often happens over the course of days to weeks; Allosteric activation may occur (and occur rapidly), but it’s less common. COMPREHENSION QUESTIONS What route of administration most likely? What t1/2 elimination? What Vd? FYI (not tested) What clearance? COMPREHENSION QUESTIONS ANSWERS What route of administration most likely? IV – no absorptive phase What t1/2 elimination? 5 hours (from 8ng to 4mg = 5hr, from 4mg to 2mg = 5 hours) What Vd? 100mg / 8mg/L = 12.5 L What clearance? 12.5L (0.7/5 hr) = 1.75 L/ hr