ADME_SUBHAJIT.ppt
- 1. PHARMACOKINETICS - ADME “What the body does to the drug” BY: SUBHAJIT MANDAL REGISTRATION NO. RA1922255010004 M.PHARM (PHARMACOLOGY) SRM COLLEGE OF PHARMACY 2019-2020 DATE: 5th /09/19
- 2. Pharmacokinetics (PK) The study of the disposition of a drug The disposition of a drug includes the processes of ADME Absorption Distribution Metabolism Excretion Elimination
- 3. ADME
- 5. Importance of PK studies •Patients may suffer: Toxic drugs may accumulate Useful drugs may have no benefit because doses are too small to establish therapy A drug can be rapidly metabolized.
- 6. Routes Of Administration Routes Of Drug Administration Enteral Parenteral Oral Injection Rectal Respiratory Topical
- 7. Absorption The process by which drug proceeds from the site of administration to the site of measurement (blood stream) within the body. Necessary for the production of a therapeutic effect. Most drugs undergo gastrointestinal absorption. This is extent to which drug is absorbed from gut lumen into portal circulation Exception: IV drug administration
- 8. IV vs. Oral I.V Drug Oral Drug Immediately Delayed completely incomplete
- 9. The Process • Absorption relies on – Passage through membranes to reach the blood – passive diffusion of lipid soluble species.
- 10. The Rule of Five – LIPINSKI’S RULE Lipinski's rule of five also known as the Pfizer's rule of five or simply the rule of five (RO5) is a rule of thumb to evaluate druglikeness or determine if a chemical compound with a certain pharmacological or biological activity has chemical properties and physical properties that would make it a likely orally active drug in humans. Components of the rule Lipinski's rule states that, in general, an orally active drug has no more than one violation of the following criteria: • No more than 5 hydrogen bond donors (the total number of nitrogen–hydrogen and oxygen–hydrogen bonds) • No more than 10 hydrogen bond acceptors (all nitrogen or oxygen atoms) • A molecular mass less than 500 daltons • An octanol-water partition coefficient (log P) that does not exceed 5
- 11. Absorption & Ionization Non-ionised drug More lipid soluble drug Diffuse across cell membranes more easily
- 13. First Pass Metabolism • Bioavailability: The fraction of the administered dose reaching the systemic circulation Dose Destroyed in gut Not absorbed Destroyed by gut wall Destroyed by liver to systemic circulation
- 14. Determination of bioavailability • A drug given by the intravenous route will have an absolute bioavailability of 1 (F=1 or 100% bioavavailable) • While drugs given by other routes usually have an absolute bioavailability of less than one. • The absolute bioavailability is the area under curve (AUC) non-intravenous divided by AUC intravenous .
- 15. Toxicity • The therapeutic index is the degree of separation between toxic and therapeutic doses. • Relationship Between Dose, Therapeutic Effect and Toxic Effect. The Therapeutic Index is Narrow for Most Cancer Drugs 100× 10×
- 16. DISTRIBUTION • The movement of drug from the blood to and from the tissues
- 17. DISTRIBUTION Which is determined by: • partitioning across various membranes • binding to tissue components • binding to blood components (RBC, plasma protein) • physiological volumes
- 18. DISTRIBUTION • All of the fluid in the body (referred to as the total body water), in which a drug can be dissolved, can be roughly divided into three compartments: intravascular (blood plasma found within blood vessels) interstitial/tissue (fluid surrounding cells) intracellular (fluid within cells, i.e. cytosol) • The distribution of a drug into these compartments is dictated by it's physical and chemical properties
- 19. TOTAL BODY WATER Vascular 3 L 4% BW Extravascular 9 L 13% BW Intracellular 28 L 41% BW
- 20. Distribution • Apparent volume of distribution (Vd) = Amount of drug in body/plasma drug concentration • VOLUME OF DISTRIBUTION FOR SOME DRUGS DRUG Vd (L): cocaine 140 clonazepam 210 amitriptyline 1050 amiodarone ~5000
- 21. Factors affecting drugs Vd Blood flow: rate varies widely as function of tissue Muscle = slow Organs = fast Capillary structure: •Most capillaries are “leaky” and do not impede diffusion of drugs •Blood-brain barrier formed by high level of tight junctions between cells •BBB is impermeable to most water-soluble drugs
- 22. Blood Brain Barrier Disruption by osmotic means: •Use of endogenous transport systems •Blocking of active efflux transporters • Intracerebral implantation
- 23. Plasma Protein Binding • Many drugs bind to plasma proteins in the blood steam • Plasma protein binding limits distribution. • A drug that binds plasma protein diffuses less efficiently, than a drug that doesn’t.
- 24. Physiochemical properties- Po/w • The Partition coefficient (Po/w) and can be used to determine where a drug likes to go in the body • Any drug with a Po/w greater than 1(diffuse through cell membranes easily) is likely be found throughout all three fluid compartments • Drugs with low Po/w values (meaning that they are fairly water-soluble) are often unable to cross and require more time to distribute throughout the rest of the body
- 25. Physiochemical Properties- Size of drug •The size of a drug also dictates where it can go in the body. •Most drugs : 250 and 450 Da MW •Tiny drugs (150-200 Da) with low Po/w values like caffeine can passively diffuse through cell membranes •Antibodies and other drugs range into the thousands of daltons •Drugs >200 Da with low Po/w values cannot passively cross membranes- require specialized protein-based transmembrane transport systems- slower distribution •Drugs < thousand daltons with high Po/w values-simply diffuse between the lipid molecules that make up membranes, while anything larger requires specialized transport.
- 26. Elimination • The irreversible removal of the parent drugs from the body Elimination Drug Metabolism (Biotransformation) Excretion
- 27. Drug Metabolism The chemical modification of drugs with the overall goal of getting rid of the drug Enzymes are typically involved in metabolism
- 28. Phases of Drug Metabolism • Phase I Reactions • Convert parent compound into a more polar (=hydrophilic) metabolite by adding or unmasking functional groups (-OH, -SH, -NH2, -COOH, etc.) eg. oxidation • Often these metabolites are inactive • May be sufficiently polar to be excreted readily
- 29. Phases of metabolism – Phase II Reactions • Conjugation with endogenous substrate to further increase aqueous solubility • Conjugation with glucoronide, sulfate, acetate, amino acid
- 30. Mostly occurs in the liver because all of the blood in the body passes through the liver
- 31. The Most Important Enzymes • Microsomal cytochrome P450 monooxygenase family of enzymes, which oxidize drugs • Act on structurally unrelated drugs • Metabolize the widest range of drugs.
- 32. • Found in liver, small intestine, lungs, kidneys, placenta • Consists of > 50 isoforms • Major source of catalytic activity for drug oxidation • It’s been estimated that 90% or more of human drug oxidation can be attributed to 6 main enzymes: • CYP1A2 • CYP2D6 • CYP2C9 • CYP2E1 • CYP2C19 • CYP3A4 •In different people and different populations, activity of CYP oxidases differs. CYP family of enzymes
- 33. Phase I (Drug Metabolism) • Phase I biotransformation reactions introduce or expose functional groups on the drug with the goal of increasing the polarity of the compound. • Although Phase I drug metabolism occurs in most tissues, the primary and first pass site of metabolism occurs during hepatic circulation.
- 34. Phase II (Conjugation) • Main function of phase I reactions is to prepare chemicals for phase II metabolism and subsequent excretion • Phase II is the true “detoxification” step in the metabolism process.
- 35. Phase II reactions • Conjugation reactions – Glucuronidation (on -OH, -COOH, -NH2, -SH groups) – Sulfation (on -NH2, -SO2NH2, -OH groups) – Acetylation (on -NH2, -SO2NH2, -OH groups) – Amino acid conjugation (on -COOH groups) – Glutathione conjugation (to epoxides or organic halides) – Fatty acid conjugation (on -OH groups) – Condensation reactions
- 36. Phase I and II - Summary • Products are generally more water soluble • These reactions products are ready for (renal) excretion • There are many complementary, sequential and competing pathways • Phase I and Phase II metabolism are a coupled interactive system interfacing with endogenous metabolic pathways
- 37. Excretion The main process that body eliminates "unwanted" substances. Most common route - biliary or renal Other routes - lung (through exhalation), skin (through perspiration) etc. Lipophilic drugs may require several metabolism steps before they are excreted
- 39. ADME - Summary