Pharmacokinetics II: Drug Metabolism Lecture Notes (PDF)

PHARMACOKINETICS II: DRUG METABOLISM Block: Foundations Block Director: James Proffitt, PhD Session Date: Tuesday, August 27, 2024 Time: 8:00 - 9:00 am Instructor: Patrick Ronaldson, PhD Department: Pharmacology Email: pronald@ari...

PHARMACOKINETICS II: DRUG METABOLISM Block: Foundations Block Director: James Proffitt, PhD Session Date: Tuesday, August 27, 2024 Time: 8:00 - 9:00 am Instructor: Patrick Ronaldson, PhD Department: Pharmacology Email: [email protected] Instructional Methods Primary Method: IM13: Lecture ☐ Flipped Session Resource Types: RE18: Written or Visual Media (or Digital Equivalent) INSTRUCTIONS Please read lecture objectives and notes prior to attending session. READINGS None LEARNING OBJECTIVES 1. Highlight importance of biotransformation of chemicals. 2. Describe major biotransformation pathways for drugs. 3. Demonstrate competition for biotransformation between drugs. 4. Evaluate factors that influence biotransformation of drugs. 5. Understand the difference between detoxification versus bioactivation. CURRICULAR CONNECTIONS Below are the competencies, educational program objectives (EPOs), block goals, disciplines and threads that most accurately describe the connection of this session to the curriculum. Related Related Competency\EPO Disciplines Threads COs LOs CO-01 LO #1 MK-01: Core of basic sciences Pharmacology EBM: Research Methods CO-01 LO #2 MK-06: The foundations of therapeutic Pharmacology EBM: Research intervention, including concepts of Methods outcomes, treatments, and prevention, and their relationships to specific disease processes CO-02 LO #3 MK-06: The foundations of therapeutic Pharmacology EBM: Research intervention, including concepts of Methods outcomes, treatments, and prevention, and their relationships to specific disease processes Block: Foundations | RONALDSON [1 of 20] PHARMACOKINETICS II: DRUG METABOLISM Related Related Competency\EPO Disciplines Threads COs LOs CO-02 LO #4 MK-06: The foundations of therapeutic Pharmacology EBM: Research intervention, including concepts of Methods outcomes, treatments, and prevention, and their relationships to specific disease processes CO-02 LO #5 MK-01: Core of basic sciences Pharmacology EBM: Research Methods CONTEXT: The processes involved in drug metabolism (i.e., biotransformation) play a major role in determining the duration of the therapeutic effect for an individual drug. In addition to being obviously important for determining dose and frequency of drug administration, understanding the various biotransformation pathways and which pathways specific drugs use is critical in the prediction of drug-drug interactions. 1. BIOTRANSFORMATION - Process by which chemicals (i.e., drugs) are modified by an organism - Usually requires enzymatic activity - Present for endogenous as well as exogenous substrates o Vitamins o Steroids o Hormones o Amino Acids o Drugs 2. PURPOSE OF BIOTRANSFORMATION - Purpose: decrease lipid solubility (increase water solubility) and increase ionization - Event: increase body excretion Block: Foundations | RONALDSON [2 of 20] PHARMACOKINETICS II: DRUG METABOLISM 3. PHARMACOLOGICAL EFFECT CORRELATES TO DRUG CONCENTRATION For most drugs, the therapeutic effect is related to the plasma concentration. Generally, drug effects increase across a range of concentrations until a maximal effect is achieved. Once the maximal effect is achieved, higher concentrations will not lead to an increase in effect,. EXCEPTION: Note that the drug effect has a different time course than the drug concentration in plasma. Why? - 1. Irreversible Binding 2. Active Metabolites Biotransformation is one of the principal biological processes that determine the plasma concentration of a given drug. Block: Foundations | RONALDSON [3 of 20] PHARMACOKINETICS II: DRUG METABOLISM 4. EFFECT OF BIOTRANSFORMATION ON DRUG BODY BURDEN 5. IMPORTANCE OF BIOTRANSFORMATION - Determines therapeutic half-life - May produce an “active metabolite” - Site of drug-drug interactions - May produce toxic metabolites or intermediates 6. BIOTRANSFORMATION PATHWAYS Block: Foundations | RONALDSON [4 of 20] PHARMACOKINETICS II: DRUG METABOLISM 7. BENZENE BIOTRANSFORMATION: AN INTEGRATING EXAMPLE 8. COMMON RESULTS OF BIOTRANSFORMATION 1. Stops pharmacological effect. 2. Restricts distribution. 3. Facilitates excretion. 9. KEY ORGANS INVOLVED IN BIOTRANSFORMATION CAPACITY ORGAN High Liver Medium Lung, Kidney, Intestine Low Skin, Testis, Placenta, Adrenals 10. PHASE I BIOTRANSFORMATION – CYP450 (USUALLY) - Variety of substrates - Variety of reactions – oxidation, hydroxylation - Reactive oxygen - Adds a functional group to a drug molecule Block: Foundations | RONALDSON [5 of 20] PHARMACOKINETICS II: DRUG METABOLISM Hydroxyl Group added to parent compound = INCREASES HYDROPHILICITY 11. CYTOCHROME P450 - Family of enzymes - Unique hemoprotein - Highest concentration = liver - Induction: increase activity/concentration - Inhibition: decrease activity/concentration - Common site of drug-drug interactions 12. CYTOCHROME P450 FAMILY - 17 subgroups (CYP1, CYP2,... ) - Classed by biochemical characteristics - CYP3A o Predominant in humans o Site of metabolism for corticosteroids, antifungals, etc. - CYP2E, CYP1A o Other drugs and toxicants o Analgesics, ethanol, etc. Block: Foundations | RONALDSON [6 of 20] PHARMACOKINETICS II: DRUG METABOLISM Figure 1: Major hepatic P450 enzymes involved in drug metabolism. Circles are intended to reflect the mean size of the pool of each of the main P450s (CYPs) in human liver. The exact pattern will vary among individuals. A few commonly recognized substrates, inhibitors, and induces of these CYPs are indicated. From: Rendic. Drug Metabolism Rev. 34: 83-448, 2002. 13. PHASE I – HYDROLYSIS: AMIDES, ESTERS - Add water across a covalent bond - Exposes functional group(s) - Esterases, amidases - Most tissues and plasma express esterases Block: Foundations | RONALDSON [7 of 20] PHARMACOKINETICS II: DRUG METABOLISM 14. INTEGRATION OF PHASE I BIOTRANSFORMATION KEY CONCEPT: The same drug molecule can have multiple phase I metabolites. 15. PHASE II BIOTRANSFORMATION a. Conjugation: coupling of an endogenous group to a drug or metabolite b. Increase water solubility and ionization = enhanced renal/biliary excretion c. Pharmacologically inactive d. Present for endogenous substrates. Block: Foundations | RONALDSON [8 of 20] PHARMACOKINETICS II: DRUG METABOLISM 16.MAJOR CONJUGATION REACTIONS Block: Foundations | RONALDSON [9 of 20] PHARMACOKINETICS II: DRUG METABOLISM 17. PHASE II CONJUGATION 18. Key GLUTATHIONE CONJUGATION Concept: A single drug molecule can have multiple conjugated (phase II) drug metabolites. 19. VARIABLES AFFECTING DRUG METABOLISM Dose Diet GI Flora Enzyme Induction Age Genetics Enzyme Inhibition Disease Gender Block: Foundations | RONALDSON [10 of 20] PHARMACOKINETICS II: DRUG METABOLISM 20. INDUCTION - Increased rate of biotransformation - Increase in biotransformation enzymes Result: - Decreased half-life - Decreased pharmacological effect 21. INDUCTION IN MAN 22. EFFECT OF PHENYTOIN ON THEOPHYLLINE PK Block: Foundations | RONALDSON [11 of 20] PHARMACOKINETICS II: DRUG METABOLISM 23. PERSISTENCE OF INDUCTION 24. EXAMPLES OF DRUG-DRUG INTERACTIONS DUE TO INDUCTION OF DRUG METABOLIZING ENYMES – ST. JOHN’S WORT 25. INHIBITION - Decreased rate of biotransformation - Drug-drug interactions Result: - Increased half-life - Increased potential for exacerbated pharmacological effect Block: Foundations | RONALDSON [12 of 20] PHARMACOKINETICS II: DRUG METABOLISM 25. DRUG-DRUG INTERACTIONS - BIOTRANSFORMATION - Competing for same enzymes - Case reports o Delayed – only after complications - Primarily two-drug combinations 26. WARFARIN CLEARANCE AND COAGULATION TIME: INHIBITORY EFFECT OF CIMETIDINE 27. DRUG-DRUG INTERACTIONS - Numerous o Polypharmacy - Physician Desk Reference (PDR) o CYP isozyme – drug versus other drugs using CYP - Drug Inserts o Much like PDR - Drug Reports o After complications - Several drug withdrawals o Drug-drug interactions Block: Foundations | RONALDSON [13 of 20] PHARMACOKINETICS II: DRUG METABOLISM 28. PREVENTING DRUG-DRUG INTERACTIONS a. Profile patient for biotransformation capacity o Phenotyping strategies o “Cocktail” of markers o Ideal – not practical b. Pre-screen drugs for specific isozymes involved o Specific human isozyme screening systems o Grouping of drugs to isozymes o Predict potential interactions c. Drug interaction tables The tables at http://medicine.iupui.edu/flockhart/ list drug substrates for CYP isoforms as well as inhibitors and inducers and genetic considerations. (Tables created and updated by: David Flockhart, MD, PhD) 29. DIET INHIBITING BIOTRANSFORMATION a. 1991 – Citrus Juices affected pharmacological activity of certain drugs i. Increased blood concentrations ii. Increased half-life of nifedipine b. Grapefruit Juice – MOST EFFECTIVE i. Increased half-life of: 1. Immunosuppressive drugs (Cyclosporine A) 2. Benzodiazepines (Midazolam) 3. H1-inhibitors (Terfenadine) 4. Others c. Grapefruit Juice inhibits biotransformation i. Inhibits CYP3A isozymes in the liver and intestine ii. Drug affected = primarily those metabolized by CYP3A iii. Inhibitory component of grapefruit juice = Bergamottin 30. FIRST PASS BIOTRANSFORMATION a. Oral drugs removed: GI and liver b. Less drug reaches systemic circulation i. Larger dose required ii. Marked individual variation c. Liver – primarily d. GI – some effect i. Intestinal wall ii. Bacteria – gut microflora iii. Enterohepatic circulation Absorption ➔ Liver ➔ Bile (i.e., conjugate) ➔ Degrade ➔ Reabsorb Block: Foundations | RONALDSON [14 of 20] PHARMACOKINETICS II: DRUG METABOLISM 31. HUMAN VARIATION IN BIOTRANSFORMATION a. Reasonably consistent b. But 3X variations are possible and higher c. Twins d. Sex e. Age i. Neonates ii. Elderly 32. GENETICS Block: Foundations | RONALDSON [15 of 20] PHARMACOKINETICS II: DRUG METABOLISM Block: Foundations | RONALDSON [16 of 20] PHARMACOKINETICS II: DRUG METABOLISM 33. GENDER-BASED DIFFERENCES 34. DEVELOPMENT OF DRUG METABOLISM a. Can be deficient at birth b. Glucuronyl transferases c. Phase I present – but lower activity d. Reaches adult activity (1-3 months) 35. AGING INCREASES HALF-LIFE OF DIAZEPAM Block: Foundations | RONALDSON [17 of 20] PHARMACOKINETICS II: DRUG METABOLISM 36. AGING EFFECTS ON PHARMACOTHERAPY 37. DISEASES: EFFECT OF LIVER DISEASE ON BIOTRANSFORMATION 38. BIOACTIVATION Block: Foundations | RONALDSON [18 of 20] PHARMACOKINETICS II: DRUG METABOLISM 39. ACETAMINOPHEN BIOTRANSFORMATION 40. PERCENT OF ACETAMINOPHEN DOSE EXCRETED 41. LIVER MORPHOLOGY AND ACETAMINOPHEN HEPATOTOXICITY Block: Foundations | RONALDSON [19 of 20] PHARMACOKINETICS II: DRUG METABOLISM 42. ACETAMINOPHEN TOXICITY a. Phase II biotransformation i. Sulfation pathway is overwhelmed in presence of high acetaminophen concentrations. ii. High acetaminophen concentrations exceed metabolic capacity of glucuronidation pathway. b. CYP450 biotransformation i. Production of a reactive intermediate ii. Reactive intermediate is produced at a rate faster than can be handled by glutathione conjugation pathway. c. Liver necrosis i. Cerebral edema ii. Lethality d. Therapy? i. Antidote for acetaminophen toxicity is N-acetylcysteine. GI decontamination: Consider decontamination with activated charcoal in any patient that presents within 4 hours of acetaminophen ingestion. Consider gastric lavage if ingestion occurred within 1 hour of evaluation. Oral N-acetylcysteine (Mucomyst): The antidote for acetaminophen toxicity is N-acetylcysteine (NAC), which has several mechanisms to prevent hepatotoxicity. The oral formulation is the drug of choice for the treatment of acute, chronic, or late-presenting acetaminophen ingestion. NAC is converted to cysteine, which replenishes glutathione stores. NAC also directly detoxifies N-acetyl- benzoquinoneimine (NAPQI) to nontoxic metabolites. NAC provides a substrate for sulfation, increasing the capacity for nontoxic metabolism. NAC can directly conjugate to NAPQI to reduce toxicity. Block: Foundations | RONALDSON [20 of 20]