W10 Pharmacokinetics 1 (Mayers-Aymes) - Lecture Notes PDF

Pharmacokinetics I Dr. Mayers-Aymes, PharmD [email protected] Office hours: https://calendly.com/nmayers-aymes/office-hours 1 Reading List Thieme eBook Collection Pharmacology: An essential Textbook Unit 1: General Principles of Pharmacology – Introduction and Pharmacokinetics Pages 2 - 15...

Pharmacokinetics I Dr. Mayers-Aymes, PharmD [email protected] Office hours: https://calendly.com/nmayers-aymes/office-hours 1 Reading List Thieme eBook Collection Pharmacology: An essential Textbook Unit 1: General Principles of Pharmacology – Introduction and Pharmacokinetics Pages 2 - 15 2 2 • Review the Introduction to Pharmacology Lecture • The lecture provided an introduction to Pharmacokinetic principles and we will discuss these principles further in the PK1 and PK2 lectures 3 3 Overview of Pharmacokinetics 1 and 2 lectures • Section A: General Pharmacokinetic principles ➢ Transfer of drugs across cell barriers – how do drugs get to the intended target organ or tissue so that they can exert the pharmacological effect ➢ Drug administration – how drugs are administered, that is, the routes of drug administration • Section B: Specific Pharmacokinetic processes ➢ Drug Absorption, Drug Distribution, Drug Metabolism, Drug Excretion • Section C: Drug Accumulation 4 4 Learning Objectives • There are three main areas for discussion in this lecture: 1. 2. 3. Transfer of drugs across cell barriers Drug Administration Drug Absorption 5 5 Transfer of drugs across membranes 1. 2. 3. 4. 5. 6. List the two main processes of transfer of drugs across cell barriers Describe the main features of lipid diffusion of drugs across membranes. Describe the main features of aqueous diffusion of drugs across membranes. Explain why lipid and water solubility of drugs are related to their and to the pH of the solvent. Calculate the degree of ionization of a drug in cell fluids, using Henderson-Hasselbalch equation. Explain the "ion-trapping mechanism“. cell cell pKa the 6 6 Transfer of drugs across membranes 7. Describe the main features of facilitated diffusion of drugs across cell membranes. 8. Describe the main features of active transport of drugs across cell membranes. 9. Differentiate between the diffusion processes and the carriermediated processes of drug transfer across cell membranes 10. Describe the main features of drug endocytosis and exocytosis 11. Describe the main characteristics of the bulk flow transport of drugs across cell barriers. 7 7 Transfer to Drugs Across Cell Membranes LO 1 • Transcellular movement: drug movement across cell membranes • Paracellular movement: drug movement through gaps or tiny junctions between cells Transcellular transport Paracellular transport Intestinal epithelial cell 8 8 Transfer to Drugs Across Cell Membranes LO 1 Passage of drugs across membranes may occur by: • Passive diffusion • Carrier mediated transport ❖ Facilitated diffusion ❖ Active transport • Endocytosis • Exocytosis • Bulk flow 9 9 Transfer of drugs across membranes: LO 2 Lipid Diffusion of drugs across cell membranes • Cell membranes are composed of a phospholipid bilayer • The lipid membrane is not a barrier to lipophilic drugs (with a small MW) • Drugs diffuse from a region of high concentration to low concentration – passive & non-selective process • Fick’s law: the concentration gradient, membrane surface area and thickness along with lipid-water partition coefficient of the drug will affect the rate of diffusion 10 With regards to lipid diffusion: please note that most drugs have molecular weights between 100 and 1500 D and can therefore cross membranes by lipid diffusion (if they are lipid soluble). 10 Transfer of drugs across membranes: Aqueous Diffusion of drugs across cell membranes LO 3 • Occurs through aquaporin protein channels of cell membranes that cross the lipid bilayer • Passive process and non-selective process • The process is dependent on: ❖ Number of protein channels ❖ Concentration gradient ❖ Water solubility ❖ Molecular size of the drug (the passage of large molecules is restricted) 11 Some drugs utilize aqueous diffusion and need to move through the aquaporin channels – this process depends on the molecular size of the drug. The passage of molecules larger than 100 D is restricted. 11 LO 2 Whalen, K. (2018). Lippincott Illustrated Reviews: Pharmacology. [VitalSource Bookshelf]. Retrieved from https://bookshelf.vitalsource.com/#/books/9781496386113/ 12 12 Transfer of drugs across membranes: Facilitated Diffusion • Mediated by a protein carrier • Does not require energy because drug moves along a concentration gradient (high conc -> low conc) • It is carrier mediated so it is saturable and structurally selective for the drug and shows competition for drugs of similar structure. LO 7 13 13 Transfer of drugs across membranes: Active Transport LO 8 • Energy dependent (driven by the hydrolysis of ATP): drug moves against a concentration gradient. • A specialized process requiring a carrier; the carrier molecule may be highly selective for the drug molecule. • Competitive: drugs of similar structure may compete for sites of absorption on the carrier. • Saturation may occur because only a fixed number of carrier molecules are available 14 Active transport can be: a) Primary, when the energy for transport is derived directly from the breakdown of some high-energy phosphate compound (i.e. ATP). b) Secondary, when the energy for transport is derived from energy that has been stored in the form of ionic concentration differences between the two sides of the membrane. 14 LO 7, 8 Whalen, K. (2018). Lippincott Illustrated Reviews: Pharmacology. [VitalSource Bookshelf]. Retrieved 15 from https://bookshelf.vitalsource.com/#/books/9781496386113/ 15 LO 9 Transfer of drugs across membranes: Diffusion processes versus the carrier-mediated processes • Drugs and other molecules can therefore go through epithelial cells by either simple diffusion or a carrier-mediated mechanism. • Carrier mediated processes: active transport and facilitated diffusion • Various carrier-mediated systems (transporters) are present at the intestinal brush border and basolateral membrane: ❖ Influx transporters (increase drug absorption) – move drug molecules into the blood and increase plasma drug concentration ❖ Efflux transporters (decrease drug absorption) – move drug molecules back into the gut lumen and reduce systemic drug absorption 16 16 Transfer of drugs across membranes: Endocytosis and Exocytosis LO 10 • Active transport processes - used to transport drugs of exceptionally large size across the cell membrane. • Endocytosis involves engulfment of a drug by the cell membrane and transport into the cell by pinching off the drug-filled vesicle. ❖ May be receptor mediated: specific cell surface receptors bind the molecule which must be engulfed • Many cells use exocytosis to secrete substances out of the cell through a similar process of vesicle formation. 17 Some drugs are too large to pass through the plasma cell membrane or to move through a transport protein. Very large molecules up to MW 100 000 D can enter cells by endocytosis. 17 LO 10 Exocytosis example: the transport of a protein such as insulin from insulin-producing cells of the pancreas into the extracellular space. The insulin molecules are first packaged into intracellular vesicles, which then fuse with the plasma membrane to release the insulin outside the cell. Endocytosis examples: hormones, growth factors, transport proteins that carry cholesterol (low-density lipoprotein) or iron (transferrin), antibodies etc. 18 18 Transfer of drugs across membranes: Bulk flow transport LO 11 • It is the movement of drug molecules across the membrane by pores between capillaries endothelial cells (intercellular pores) • Used for drugs with a high molecular weight • A passive and non-selective process (depending only on molecular size) 19 Drugs with a MW <15 000 – 16 000 can reach the systemic circulation by bulk flow transport through capillary pores. Drugs with a higher molecular weight enter the systemic circulation by bulk flow transport through lymphatic vessels. 19 As you review think about the following….. • Which of the methods used to transfer drugs across membranes are: – Energy dependent – Passive – Utilize a carrier – Best suited for large molecules – Etc 20 20 LIPID AND WATER SOLUBILITY OF DRUGS IN RELATION TO THEIR PKA AND TO THE PH OF THE SOLVENT 21 21 LO 4 Lipid and water solubility of drugs in relation to their pKa and to the pH of the solvent • Many drugs act as weak electrolytes, such as weak acids and bases • Weak electrolytes are only partially ionized when dissolved in water • The extent of ionization influences the drug’s diffusional permeability ❖ The ionized species of the drug contains a charge and is more water soluble ❖ The un-ionized species of the drug is more lipid soluble. 22 22 LO 4 Lipid and water solubility of drugs in relation to their pKa and to the pH of the solvent • The extent of ionization of a weak electrolyte will depend on both the pKa of the drug and the pH of the medium in which the drug is dissolved. • The lower the pKa of a drug, the more acidic it is (and the higher the pKa, the more basic the drug) 23 23 pH & pKa LO 5 • The Henderson Hasselbalch equation describes the relationship between pKa and pH (for weak acids and bases): HA H+ + A− [A ] Acidic drugs (HA) release a proton (H+), causing a charged anion (A−) to form pH = pKa + log [𝐻𝐴] BH+ H+ + B [𝐵] pH = pKa + log [𝐵𝐻+] Weak bases (BH+) can also release a H+. However, the protonated form of basic drugs is usually charged, and loss of a proton produces the uncharged base (B) 24 24 Question? LO 5 • The un-ionized/uncharged drug diffuses readily across lipid cell membranes: HA H+ + A- For acids: which form of the drug will be un-ionized and will diffuse more readily across the lipid cell membrane? BH+ H+ + For bases: which form of the drug will be un-ionized and will diffuse more readily across the lipid cell membrane? B 25 25 LO 2, 4 Recall that un-ionized drug diffuses readily across lipid cell membranes: For weak acid, the un-ionized HA readily crosses the membrane (diagram A) For weak bases, the un-ionized B readily crosses the membrane (diagram B) Whalen, K. (2018). Lippincott Illustrated Reviews: Pharmacology. [VitalSource Bookshelf]. Retrieved from https://bookshelf.vitalsource.com/#/books/9781496386113/ 26 26 LO 4, 5 Whalen, K. (2018). Lippincott Illustrated Reviews: Pharmacology. [VitalSource Bookshelf]. Retrieved from https://bookshelf.vitalsource.com/#/books/9781496386113/ When pH = pKa: 50% availability of both species (see diagram) pH<pKa: the medium where the drug is dissolved has more protons present than the drug, so the drug gains a proton. [HA] predominates for weak acids and [BH+] for weak bases HA H+ + ABH+ H+ + B 27 27 LO 4,5 Whalen, K. (2018). Lippincott Illustrated Reviews: Pharmacology. [VitalSource Bookshelf]. Retrieved from https://bookshelf.vitalsource.com/#/books/9781496386113/ pH>pKa: the medium where the drug is dissolved has less protons present than the drug so the drug donates a proton. [A-] predominates for weak acids and [B] for weak bases HA H+ + A- BH+ H+ + B 28 28 LO 4 pH & pKa • The amount of water solubility is proportional to the difference between pH and pKa, according to the following table Difference > 2.0 between pH and pKa 2.0 1.0 0.5 0.0 Percentage > 99 99 90 76 50 29 You should aim to memorize this table. There are practice questions available to assist you with understanding how to apply this concept. We will also discuss a related question in the workshop. As an example, consider the following: Drug X is a weak acid with a pKa of 5.4. What percentage of the drug was most likely water soluble in the patient’s plasma (pH of the plasma is 7.4)? To solve this, you should look at the difference between the pH and the pKa for the drug; i.e. 7.4 – 5.4 = 2. In the table this difference (of 2) corresponds to the 99%. This means that the drug was most likely 99 % water soluble in the patient’s plasma. Now let’s twist this question so that it reads as follows: Drug X is a weak acid with a pKa of 5.4. What percentage of the drug was most likely lipid soluble in the patient’s plasma (pH of the plasma is 7.4)? Do you see the difference here? Instead of asking about the water solubility, the 29 question is asking about the lipid solubility. The table provides the amount of water solubility so to find out the percentage that is lipid soluble it would be 100% - 99 % = 1 %. Therefore, with Drug X, 99% is water soluble and 1 % is lipid soluble. Now it’s your turn! Have a look at the practice questions to apply this concept ☺ 29 LO 4 Question? • If a weak acid has a pKa of 6.4. What percentage of the drug was most likely water soluble in the patient’s plasma (pH of plasma is 7.4)? Difference > 2.0 between pH and pKa 2.0 1.0 0.5 0.0 Percentage > 99 99 90 76 50 30 You should aim to memorize this table. There are practice questions available to assist you with understanding how to apply this concept. We will also discuss a related question in the workshop. As an example, consider the following: Drug X is a weak acid with a pKa of 5.4. What percentage of the drug was most likely water soluble in the patient’s plasma (pH of the plasma is 7.4)? To solve this, you should look at the difference between the pH and the pKa for the drug; i.e. 7.4 – 5.4 = 2. In the table this difference (of 2) corresponds to the 99%. This means that the drug was most likely 99 % water soluble in the patient’s plasma. Now let’s twist this question so that it reads as follows: Drug X is a weak acid with a pKa of 5.4. What percentage of the drug was most likely lipid soluble in the patient’s plasma (pH of the plasma is 7.4)? Do you see the difference here? Instead of asking about the water solubility, the 30 question is asking about the lipid solubility. The table provides the amount of water solubility so to find out the percentage that is lipid soluble it would be 100% - 99 % = 1 %. Therefore, with Drug X, 99% is water soluble and 1 % is lipid soluble. Now it’s your turn! Have a look at the practice questions to apply this concept ☺ 30 ION TRAPPING 31 31 Ion Trapping LO 6 • Drugs become trapped when present in the ionized form so depending on the pH of the medium – drugs can therefore concentrate in specific compartments • The treatment of salicylate poisoning utilizes the ion trapping theory • Both the ionized and unionized molecules are filtered by the glomerulus however only the unionized molecule can be reabsorbed. Alkalinizing the urine (making the pH >7) with sodium bicarbonate is used to treat salicylate poisoning. • Salicylate is a weak acid with a pKa of 3. If the pH > 7, the RCOO- (or A- ) form will predominate – pH > pKa for a weak acid ❖ Therefore the ionized molecules will remain in the urine (trapped) for 32 excretion (and re-absorption is prevented) Aspirin is classified as a nonsteroidal anti-inflammatory drug and toxicity may occur when persons do not take the drug as recommended. We will revisit this concept of changing the pH to manage aspirin overdose/toxicity in the Anti-inflammatory lecture. 32 LO 6 In step 3: there is passive reabsorption of lipid soluble unionized drug molecules In the case of managing salicylate toxicity: alkalinizing the urine will lead to more ionized lipid insoluble molecules which will be easily excreted. Whalen, K. (2018). Lippincott Illustrated Reviews: Pharmacology. [VitalSource Bookshelf]. Retrieved from https://bookshelf.vitalsource.com/#/books/9781496386113/ 33 33 Learning Objectives • There are three main areas for discussion in this lecture: 1. 2. 3. Transfer of drugs across cell barriers Drug Administration Drug Absorption 34 We looked at how drugs are transferred across cell barriers and examined each of the following processes: Passive diffusion, Carrier mediated transport (Facilitated diffusion & Active transport), Endocytosis, Exocytosis and Bulk flow. We will now examine the various routes that are available for drug administration. 34 Drug administration 1. 2. 3. 4. 5. 6. List common routes of drug administration Describe the main features of oral drug administration: List the main factors affecting the absorption of drugs administered by oral route Identify the advantages and disadvantages of oral drug administration Explain why gastric emptying may affect the intestinal absorption of drugs Describe the main features of some of the other routes of drug administration: • • Sublingual Rectal • Topical • Transdermal • Pulmonary • Parenteral (e.g. Subcutaneous, intramuscular, intravenous and other injectable routes) 35 35 Drug administration: Routes of Administration LO 1 • The effective dose of a drug may vary with the dosage form and the route of administration. • Drugs administered IV enter the blood stream directly and completely • Varying rates and degrees of absorption can occur with drug administration via different routes 36 36 Drug administration: Common Routes of Administration • • • • • • • LO 1 Oral Sublingual Rectal Parenteral: e.g. IV, IM, SC Topical Transdermal Inhalation 37 37 Drug administration: Oral route LO 2 • A form enteral administration which involves the oral, sublingual, buccal and rectal routes. • The oral route is the most common route for dose administration • The oral dosage form must be designed to account for: ❖ extreme pH ranges, the presence or absence of food, degradative enzymes, varying drug permeability in the different regions of the intestine, and motility of the gastrointestinal tract. • The process of absorption may be affected by: ❖ Physiochemical, formulation, physiological and clinical factors 38 Enteral administration of a drug involves absorption of the drug via the GI tract. Enteral administration includes oral, gastric or duodenal (e.g., feeding tube), and rectal administration. The oral route is therefore a form of enteral administration and there are many ways that drugs can be administered orally as listed on the slide. 38 Drug administration: Factors affecting oral drug absorption LO 3 39 39 Drug administration: Drug absorption by the oral route LO 3 • The small intestine, particularly the duodenum area, is the most important site for passive drug absorption due to its: ❖ high surface area and high blood flow. • Small intestine transit time ranges from 3 to 4 hours for most healthy persons. • If absorption is not completed by the time a drug leaves the small intestine, absorption may be erratic or incomplete. 40 40 LO 4 Drug administration: Oral route Absorption Pattern Variable (affected by many factors) Advantages • Safest and most common • Convenient and economical Disadvantages • Limited absorption of some drugs • Food may affect absorption • Patient compliance is necessary • Drugs may be metabolized before systemic absorption 41 41 LO 5 Gastric emptying and the effect on the intestinal absorption of drugs • Gastric emptying is the process by which the contents of the stomach are moved into the duodenum • A delay in the gastric emptying will slow the rate and possibly the extent of drug absorption, thereby prolonging the onset time for the drug. 42 If gastric emptying is delayed, this will prolong drug delivery to the intestine and as noted on the previous slide, the intestine is the main site for drug absorption. Additionally, the prolonged exposure of material in the stomach can increase gastric acid secretion. The increase in gastric acid secretion also has the possibility to alter the pH of the stomach and this change in pH can in turn affect the degree of ionization and ultimately the permeation behavior of some drugs. Factors which delay gastric emptying, will case the drug to remain in the stomach for a longer time, this will have a negative impact on drug absorption. Alternatively, factors which increase gastric emptying will increase the rate and extent of drug absorption. 42 LO 6 Drug administration: The sublingual and buccal route of drug administration • Mainly used for systemic effects • The sublingual route involves placement of drug under the tongue. • The buccal route involves placement of drug between the cheek and gum. • Both the sublingual and buccal routes of absorption have several advantages including ease of administration, rapid absorption, bypass of the harsh GI environment and avoidance of the first-pass effect 43 43 LO 6 Drug administration: Sublingual administration Absorption Pattern • Primarily by lipid diffusion • Few drugs (e.g. nitroglycerin) have rapid, direct systemic absorption • Most drugs erratically or incompletely absorbed Advantages Disadvantages • Bypasses first pass • Limited to certain types effect of drugs • Bypasses destruction • Limited to drugs that by stomach acid can be taken in small • Drug stability doses maintained because • May lose part of the the pH of saliva is drug dose if swallowed relatively neutral • May cause immediate pharmacological effects 44 44 Drug administration: Rectal drug administration LO 6 • May be used for systemic or local effects Absorption Pattern Advantages Disadvantages • Primarily by lipid diffusion • Erratic and variable • Partially by passes first pass effect • By passes destruction by stomach acid • Ideal if drug causes vomiting • Ideal in patients who are vomiting or comatose • Drugs may irritate rectal mucosa • Not a well accepted route 45 45 LO 6 Drug administration: Topical application • Topical: drug applied for action on the skin - used when a local effect is desired Absorption Pattern Advantages Disadvantages • Primarily by lipid • Suitable when local • Some systemic diffusion effect of drug is desired absorption can occur • Variable: affected • May be used for skin, • Unsuitable for drugs by the condition eye, intravaginal and with high molecular of the skin, area intranasal products weight or poor lipid of application • Easy for patient solubility along with other factors 46 46 Drug administration: Transdermal administration LO 6 • Transdermal: drug applied and ‘goes through the skin’ – used when a systemic effect is desired Absorption Pattern • Primarily by lipid diffusion • Slow and sustained Advantages • Bypasses the first-pass effect • Convenient and painless • Ideal for drugs that are lipophilic and have poor oral bioavailability • Ideal for drugs that are quickly eliminated from the body Disadvantages • Some patients are allergic to patches, which can cause irritation • Drugs must be highly lipophilic • May cause delayed delivery of drug to pharmacological site of action • Limited to drugs than can be taken in small daily doses 47 47 Drug administration: Pulmonary administration (gases) LO 6 • To achieve systemic effects Absorption Pattern • Primarily by lipid diffusion through the alveolar membrane • Rapid Advantages • Consciousness is not required • The dosage is tightly controlled Disadvantages • Drug must be a gas or a volatile liquid • Sophisticated equipment usually needed Nitrous oxide is an example of a medication delivered as a gas 48 48 Drug administration: Pulmonary administration (aerosols) LO 6 • To achieve local effect Absorption Pattern • Primarily by lipid diffusion through the alveolar membrane Advantages Disadvantages • Drug concentration is • Specific equipment locally high required • Systemic absorption is delayed and limited; adverse effects minimized Albuterol is an example of a medication delivered as an aerosol 49 49 Drug administration: Intravenous (IV) LO 6 • To achieve systemic effects – drugs injected directly into the general circulation Absorption Pattern Advantages • Drug is immediately available in the systemic circulation • Can have immediate effects • Ideal if dosed in large volumes • Suitable for irritating substances (to GI) • Valuable in emergency situations • Dosage titrations permissible • Ideal for high molecular weight proteins and peptide drugs Disadvantages • Unsuitable for oily substances • Bolus injection may result in adverse effects • Most substances must be slowly injected • Strict aseptic techniques needed 50 50 LO 6 Drug administration: Intramuscular (IM) • Generally used to achieve systemic effects Absorption Pattern Advantages • Depends on drug • Suitable if drug volume is diluents: moderate • Aqueous solution • Suitable for oily vehicles and – prompt certain irritating substances • Depot preparations slow and sustained Disadvantages • Affects certain lab tests (creatine kinase) • Can be painful N.B. A depot preparation allows for the slow release of a medication over time; this allows for less frequent dosing 51 51 LO 6 Drug administration: Subcutaneous (SC) • Generally used to achieve systemic effects Absorption Pattern • Depends on drug diluents: • Aqueous solution – prompt • Depot preparations slow and sustained Advantages • Suitable for slow-release drugs • Ideal for some poorly soluble suspensions Disadvantages • Pain if drug is irritating • Unsuitable for drugs administered in large volumes 52 52 Drug administration: Special parenteral routes LO 6 • Intrathecal: The blood brain barrier typically delays or prevents the absorption of drugs into the CNS. It may be necessary to introduce drugs directly into the cerebrospinal fluid • Intraarterial: used to localize the effects of drugs in a particular tissue or organ by delaying their systemic distribution • Intracardiac: sometimes used in cardiac emergencies • Intrapleural, intraperitoneal - used to localize the effect of a drug at a specific site by reducing the systemic absorption 53 53 Learning Objectives • There are three main areas for discussion in this lecture: 1. 2. 3. Transfer of drugs across cell barriers Drug Administration Drug Absorption 54 54 Drug absorption 1. 2. 3. 4. 5. 6. 7. Define the term "drug absorption" List the main factors affecting drug absorption Define bioavailability Relate the routes of administration to the bioavailability of a drug. Relate the routes of administration to the speed and magnitude of drug effect. Explain the meaning of the “area under the curve (AUC)” of a drug. Calculate the bioavailability of a drug, given sufficient data. 55 55 LO 1,3 Drug absorption • Unless a drug is given IV or is absorbed cutaneously, it must be absorbed into the systemic circulation to exert its effect. • Absorption is the process by which the unchanged drug proceeds from the site of administration into the systemic circulation • Bioavailability (F) provides a quantitative measure of absorption – it is the fraction of a given drug dose that reaches the systemic circulation 56 Consider Drug A: Drug A is available as two different products containing the same dose of the drug, but the two products do not yield similar concentrations of the drug in the blood (when given to the same subject). This means that the two products differ in their bioavailability. For example, Drug A could be administered orally and intravenously. You should note that the bioavailability of a drug is constant and therefore does not depend on the administered dose. For example, if the bioavailability of Drug A when given orally is 40%, this will remain 40% if you administer 100 mg or a 200 mg dose of the drug. Similarly, the bioavailability of the IV form of Drug A will be 100 % regardless of the dose given IV. 56 Drug absorption LO 2 FACTORS AFFECTING ABSORPTION 1. 2. 3. 4. 5. 6. 7. pH changes Membrane thickness & surface area Hepatic and GI metabolism (e.g. first pass effect) Drug Formulation (e.g. dosage form, particle size etc.) Destruction by stomach acid (acid resistant enteric coating prevents this) Gastric transit time Digestive enzymes (e.g. pepsin) which may break down drugs 57 57 LO 3 Drug absorption: Bioavailability • Bioavailability is the extent to which an administered drug reaches the systemic circulation. • Bioavailability most commonly refers to the comparison of the amount of drug absorbed from a dosage form to the amount delivered in an intravenous dose. • Calculating (absolute) bioavailability: 𝑨𝑼𝑪 𝒙 𝑫𝒐𝒔𝒆 𝑰𝑽 𝒐𝒓𝒂𝒍 𝒙 𝑨𝑼𝑪𝑰𝑽 F = 𝑫𝒐𝒔𝒆𝒐𝒓𝒂𝒍 If you wanted to calculate the bioavailability of one dosage form versus any other, the formula above can be manipulated. For example, intramuscular bioavailability is calculated by: (AUC IM ) / (AUC IV) ** If the doses are not the same this needs to be taken into consideration in the equation. 58 Drug absorption: Bioavailability LO 3, 7 • Example 1: A drug given IV results in an AUC of (400 mg/L) x h. If the same dose of drug is given orally and the resulting AUC is 300(mg/L) x h, what percentage of the oral dose reaches the systemic circulation? 300 F = 400 = 0.75 That is, 75 % of the oral dose reaches the systemic circulation 59 Let’s have a look at another example: If a dose of a drug given orally yields an AUC of (35 mcg/ml)x min while the same dose given IV yields an AUC of 100 (mcg/ml) x min Oral bioavailability = 35/100 = .35 or 35% This means that the patient only gets 35% as much drug if they are given the drug orally instead of IV 59 Drug absorption : Area under the curve LO 6 • The area under the plasma drug concentration-time curve (AUC) reflects the actual body exposure to drug after administration of a dose • AUC is related to the total amount of drug that reaches the systemic circulation 60 Drug absorption : Area under the curve Le, Tao, et al. First Aid for the USMLE Step 1 2022, Thirty Second Edition. Available from: VitalSource Bookshelf, (32nd Edition). McGraw-Hill Professional, 2022. 61 61 LO 3 Time concentration Curve • Parameters used to compare the bioavailability of preparations: – Peak height concentration (Cmax) – Time of peak concentration (Tmax) – Area under the blood concentration time curve (AUC) • Other useful parameters: – Minimum effective concentration (MEC) – Minimum toxic concentration (MTC) 62 Cmax: the maximum drug concentration reached in the plasma after administration of a given dose. Tmax: the time of maximum drug concentration in the plasma. When giving a drug, it would be advisable to achieve a concentration which is ‘above; the minimum effective concentration (MEC) but below the minimum toxic concentration (MTC). 62 Time concentration curve 63 63 Comparing drug absorption by different routes LO 4 • For the same drug given in different dosage forms, the rate and extent of drug absorption may vary Available from: https://www.researchgate.net/figure/First-order-kinetics-of-absorption-and-elimination-by-oral-administrationand-injections_fig6_281734573 64 64 Learning Objectives • 1. 2. 3. The learning objectives are posted in a separate document on Canvas. There are three main areas for discussion: Transfer of drugs across cell membranes Drug Absorption Drug administration 65 65 QUESTION 1 Different methods of drug administration were showed to students during a lab experiment. Which method of drug administration may be painful and lead to alterations in creatinine kinase? 66 66 QUESTION 2 The transmembrane transport of a new drug was studied in a lab experiment. It was found that the transport exhibited selectivity, competition, saturability and required metabolic energy by the cell. Which of the following transport systems was most likely involved? • A. Aqueous diffusion B. Lipid diffusion C. Facilitated diffusion D. Active transport E. Endocytosis 67 67 QUESTION 3 A 38-year-old man received treatment with a weak acid with a pKa of 6.5. What percentage of the drug was most likely lipid soluble in the patient’s duodenal lumen (assuming pH = 7 in the lumen)? A. B. C. D. E. 1% 24% 50% 76% 99% 68 68 QUESTION 3 A 38-year-old man received treatment with a weak acid with a pKa of 6.5. What percentage of the drug was most likely lipid soluble in the patient’s duodenal lumen (assuming pH = 7 in the lumen)? A. B. C. D. E. 1% 24% 50% 76% 99% The amount of water solubility is proportional to the difference between pH and pKa, according to the following table Difference between pH and pKa > 2.0 2.0 1.0 0.5 0.0 Percentage > 99 99 90 76 50 69 69 QUESTION 4 The pharmacokinetics properties of two new drugs A and B were studied in healthy volunteers. The same dose of each drug was administered IV and orally to the same subject on two separate occasions. The results were the following: Drug AUC Oral (mg/L hour) AUC IV (mg/L hour) Which drug has the lower bioavailability? A. Drug A B. Drug B A 30 100 B 200 220 70 70 QUESTION 5 • Acetyl salicylic acid (aspirin) has a pka of 3.5 and it is easily absorbed from the stomach (pH 1.2) whereas quinidine (pka 8.6) is not. • With reference to the pH of the stomach and the pka of the drugs, explain why there is a difference in absorption. 71 This question requires you to apply the Henderson Hassle batch equation and the related concepts. 71 QUESTION 5 • Drug X is a polar drug with a small molecular weight Which permeation process will mediate the intestinal absorption of Drug X? 72 72 QUESTION 6 • If 400 mg of a drug is given orally and 200 mg is absorbed into the systemic circulation, what is F? 73 73