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LECT-2- Pharmakinetics FV.pdf
- 1. PG502: Pharmacokinetics JOHN A. GALDO, PHARM.D., M.B.A, BCPS, BCGP (JAKE) 2021
- 2. Terminology
- 3. Pharmacokinetics PHARMACOKINETICS (PK) REFERS TO HOW A DRUG MOVES THROUGH AN INDIVIDUAL'S BODY
- 4. Time Course of Drug Concentration
- 8. Volume of Distribution (Vd) Relates dose administered to concentration achieved in the blood stream Affected by changes in blood flow, body composition and protein binding Determines size of initial or loading dose of a drug to achieve a target concentration Lipophilic drugs generally have large Vd
- 9. Clearance (Cl) Volume of blood from which drug is removed over time Represents the intrinsic ability of organs to eliminate drug from blood Determines the size of the daily maintenance dose required to maintain a target concentration
- 10. Half-life • Length of time required for concentration of drug in the blood stream to be reduced to half of the original concentration • Assumes first order elimination-a constant proportion of dose eliminated per unit of time • Determines dosing interval • Approximately five half-lives are required to reach steady- state
- 12. First-Pass Effect Drug is biotransformed by enzymes prior to reaching systemic circulation Reduces bioavailability Sites •GI tract •Liver •usually greatest for drugs which are extensively and efficiently metabolized
- 13. Absorption
- 14. Absorption Factors Physiologic Factors Membrane •Phospholipid bilayer •Hydrophilic surfaces with lipophilic centers •Surface area Transport process •Passive diffusion •Facilitated diffusion •Active transport Physical/Chemical Properties of the Drug Oil/water partition coefficient •Lipophilic vs hydrophilic •Ionization at pH of absorption site vs blood stream •Unionized form absorbed
- 17. GI Absorption
- 18. Properties of the GI tract Stomach Acidic Limited surface area Primary site for oral drug disintegration and dissolution Duodenum Less acidic to neutral pH Large surface area Rich blood supply to maintain concentration gradient Primary site of oral drug absorption
- 19. Distribution
- 20. Distribution Factors Physiologic Factors Blood flow • Cardiac output Body Composition • Lean vs fat Protein Binding • alpha1 acid glycoprotein • Albumin Physical/Chemical Factors of Drug O/W partition coefficient • Lipophilic drugs Degree of ionization • pKa of drug vs pH of body
- 22. Process of Protein Binding
- 23. Effect of Protein Binding on Drug Distribution
- 25. Metabolism
- 26. Metabolism (Biotransformation) Usually enzymatic Purpose to inactivate and eventually eliminate drug not easily cleared through the kidney Liver is most common site Blood flow Enzyme activity Protein binding
- 27. Hepatic Metabolism • Phase I ◦ Usually occur first and introduce or expose a functional group on the drug molecule increasing polarity ◦ Include oxidation, reduction, hydrolysis ◦ Cytochrome P-450 ◦ Inhibition ◦ Induction • Phase II ◦ Conjugating reactions ◦ Glucuronide ◦ Entero-hepatic recycling ◦ Less affected by age, other chemicals
- 28. Excretion
- 29. Excretion Removal of intact drug Non-volatile Water soluble Low molecular weight No or slow biotransformation Primarily accomplished by kidney Blood flow Nephron
- 30. Renal Excretion • Glomerular Filtration ◦ Passive diffusion ◦ Limited by protein binding (large molecule) ◦ Driven by hydrostatic pressure ◦ Tubular Secretion ◦ Increases excretion ◦ Active process ◦ requires energy and carrier ◦ Two carrier systems ◦ Acids, Bases ◦ Reabsorption ◦ Reduces excretion ◦ Requires ◦ Unionized form ◦ Lipophilic
- 32. Pharmacokinetic Parameters • Bioavailability ◦ Extent of drug absorption ◦ Limited by ◦ Disintegration and dissolution of drug from dosage form ◦ Absorption characteristics of drug ◦ Dosage form ◦ Route of administration ◦ Stability of active ingredient at absorption site ◦ Extent of biotransformation prior to reaching systemic circulation
- 34. Common Pharmacokinetic Pathway • Absorption • Distribution • Protein Binding • Metabolism (Biotransformation) • Excretion • Resources can be exhausted ◦ Transport proteins ◦ Binding proteins ◦ Enzymes ◦ Energy
- 35. Metabolism (Biotransformation) Hepatic Clearance Hepatic Blood Flow Metabolism Protein Binding Protein Binding Enzymatic Activity Inhibition Induction
- 36. Cytochrome P450 System Most important function is its ability to activate molecular oxygen Increases aqueous solubility of the product for its transport and excretion Usually transforms in ways that lead to detoxification some cases may lead to cytotoxic, mutagenic or carcinogenic properties
- 37. Cytochrome P450 Induction Increases metabolism of other drug substrates Reduces serum concentrations of those drugs Reduces effect of parent drug Produces more metabolites • if active or toxic may cause toxicity
- 38. / Cytochrome P450 Inhibition Decreases metabolism of other drug substrates Increases serum concentrations of those drugs Increases effect of parent drug may cause toxicity
- 39. P-glycoprotein Efflux pump in esophagus, stomach, and small intestine that pumps drugs back into the GI lumen Think CYP450 More important factor in drug absorption than intestinal CYP3A4 Most CYP3A4 substrates are also P- glycoprotein substrates Same with inducers/inhibitors
- 40. Pharmacogenetics •CPIC creates freely available, peer-reviewed, evidence-based pharmacogenetic guidelines •HOW available genetic test results should be used to optimize drug therapy Clinical Pharmacogenetics Implementation Consortium (CPIC) •The location pharmacogenetic commentary matters •Most important: Boxed Warning •Important: Dosage and Administration, Contraindications, Warnings and Precautions, Adverse Effects, Drug Interactions •Summary of pharmacogenetic information in drug labels: Pharmacogenomic Biomarkers in Drug Labeling FDA: Drug Label •Collects, curates, and disseminates knowledge about genetic variation on drug responses •PharmGKB publishes evidenced-based pathways •Includes a detailed pathway description •Can be pharmacodynamic or pharmacokinetic PharmGKB
- 42. Clopidogrel, Cont. • Yes CPIC guidelines available • Bioactivates clopidogrel Role of CYP2C19 • Ineffective clopidogrel therapy à myocardial infarction, stroke, or death Risk from this drug-gene association • CYP2C19 poor or intermediate metabolizers Actionable phenotypes • Consider alternative antiplatelet agent (i.e., prasugrel, ticagrelor) Therapeutic options for actionable phenotypes
- 43. CYP2C19 Information Phenotype Frequency Genotypes Examples Ultrarapid Metabolizer ~2-5% Has two increased function alleles *17/*17 Rapid Metabolizer ~2-30% Has one increased function allele and one normal function allele *1/*17 Normal Metabolizer ~35-50% Has two normal function alleles *1/*1 Intermediate Metabolizer ~18-45% Has one decreased function allele and either one normal function allele or increased function allele *1/*2, *1/*3, *2/*17 Poor Metabolizer ~2-15% Has two no function alleles *2/*2, *3/*3, *2/*3
- 44. Clinical Considerations CYP2C19 Phenotype Standard Clopidogrel Dosing Intermediate Metabolizer Poor Metabolizer Normal Metabolizer Consider alternative antiplatelet agent (i.e., prasugrel, ticagrelor) Ultra-rapid Metabolizer Rapid Metabolizer
- 45. PG502: Pharmacokinetics JOHN A. GALDO, PHARM.D., M.B.A, BCPS, BCGP (JAKE) 2021