ADME of durg

1. ADME Nabaiie 🦋 Alpha arts and science college,porur.

2. INTRODUCTION What Is pharmacokinetic? How the human body act on the drugs? • Pharmacokinetics is the quantitative study of drug movement in, through and out of the body. • Intensity of effect is related to concentration of the drug at the site of action, which depends on its pharmacokinetic properties. • Pharmacokinetic properties of particular drug is important to determine dose, the route of administration, onset of action, peak action time, duration of action and frequency of dosing. • ADME is the abbreviation for Absorption, Distribution, Metabolism and Excretion. ADME studies are designed to investigate how a chemical (e.g., a drug compound) is processed by a living organism. Toxicology tests are often a part of this process, yielding the acronym ADME.

3. ABSORPTION • Absorption is the transfer of a drug from its site of administration to the blood stream. • Most of drugs are absorbed by the way of passive transport. • Intravenous administration has no absorption. • Fraction of administered dose and rate of absorption are important. Factors affecting drug absorption Aqueous solubility ; Rate of dissolution governs the rate of absorptionA drug given as solution is absorbed faster than when the same is given in solid form.

4. Concentration passive transport (simple diffusion) depends on the concentration gradient. Area of absorbing surface; Larger it is faster is the absorption Vascularity of the absorbing surface; Blood circulation maintains the concentration gradient across the membrane Increased blood flow fastens drug absorption. Bioavailability Bioavailability refers to the rate and extent of absorption of a drug. It is a measure of the fraction (F) of administered dose of a drug that reaches the systemic circulation in the unchanged form.

5. Bioavailability of drug injected is 100%, but is frequently lower after oral ingestion, because: • The drug may be incompletely absorbed • The absorbed drug may undergo first pass metabolism in intestinal wall and/or liver or be excreted in bile. DISTRIBUTION • It is the passage of drug from the circulation to the tissue and site of its action. • The extent of distribution of drug depends on its lipid solubility, ionization at physiological pH (dependent on pKa), extent of binding to plasma and tissue proteins and differences in regional blood flow, disease like CHF, uremia, cirrhosis •Movement of drug - until equilibration between unbound drug in plasma and tissue fluids

6. Volume of Distribution (V) • Definition: Apparent Volume of distribution is defined as the volume that would accommodate all the drugs in the body, if the concentration was the same as in plasma. • Expressed as: in Liters V = Dose administered / Plasma concentration Total drug in body=1000mg Plasma drug concentration=50mg/ml. V=1000/50=20L. factors influencing Vd • Lipid solubility (lipid: water partition coefficient) • pKa of the drug • Affinity for different tissues • Blood flow - Brain Vs Fat

7. Disease states • Plasma protein Binding • Redistribution • Highly lipid soluble drugs administered /inhalation initially get distributed to organs with high blood flow • E.g. brain, heart, kidney • Later, less vascular but more bulky tissues take up the drug. E.g. muscle, fat • Greater the lipid solubility of the drug, faster is its redistribution • Therapeutic importance: if the site of action of a drug is one of high vascular area, the action of the drug will be terminated early at the site due to its redistribution • E.g. Thiopentone

8. METABOLISM: • Chemical alteration of the drug in the body. • Aim: to convert non-polar lipid soluble compounds to polar lipid insoluble compounds to avoid reabsorption in renal tubules. • Most hydrophilic drugs are less bio transformed and excreted unchanged - streptomycin, neostigmine etc. • Biotransformation is required for protection of body from toxic metabolites Results of Biotransformatiom • Active drug and its metabolite to inactive metabolites most drugs (ibuprofen, paracetamol, chlormphenicol etc.) • Active drug to active product (phenacetin - acetminophen or paracetamol, morphine to Morphine-6-glucoronide, digitoxin to digoxin etc.)

9. Inactive drug to active/enhanced activity (prodrug) - levodopa - carbidopa, prednisone - prednisolone and enlpril - enlprilat). • No toxic or less toxic drug to toxic metabolites (Isonizide to Acetyl isoniazide). PHASE -1 • It includes oxidative, reductive and hydrolytic biotransformation. • The main purpose of it, to introduce a functional group into xenobiotic molecule to produce more water soluble compound. • They do not sufficiently produce inactive metabolites but mainely tend to provide functional groups that can go to phase-2 reactions.

10. PAHASE-2 • These are true detoxification reaction and are also known as conjugational reactions. • It involves covalent attachment of small polar endogenous molecule to either unchanged drug or phase-1 product having suitable functional groups resulting in formation of highly water soluble conjugate that are excreted by kidney. • Enzymes involved in these reaction is transferase which is mainly found in liver.

11. Factors affecting Biotransformation • Concurrent use of drugs: Induction and inhibition. • Genetic polymorphism. • Pollutant exposure from environment or industry. • Pathological status. • Age EXCRETION • Excretion is a transport procedure which the prototype drug (or parent drug) or other metabolic products are excreted through excretion organ or secretion organ. • Hydrophilic compounds can be easily excreted.

12. Routes of drug excretion -: • Kidney-Biliary excretion • Sweat • saliva • Milk • Pulmonary Hepatic Excretion • Drugs can be excreted in bile, especially when they are conjugated with - glucuronic Acid • Drug is absorbed → glucuronidated or sulfatated in the liver and secreted through the bile glucuronic acid/sulfate is cleaved off by bacteria in GI tract → drug is reabsorbed (steroid hormones, rifampicin, amoxycillin, contraceptives).

15. ADME database • PACT-F. (Preclinical And Clinical Trials Knowledge Base on Bioavailability). Preclinical And Clinical Trials Knowledge Base on Bioavailability • (PACT-F).TOXNET. Databases on toxicology, hazardous chemicals, environmental health, and toxic releases that can be accessed using a common search interface. provided by the United States NLM. • Leadscope Toxicity Database. Database of 160,000 chemical structures with toxicity data. Distributed by Leadscope. • WOMBAT-PK. Database for Clinical Pharmacokinetics and Drug Target Information. WOMBAT-PK contains 1260 entries (1260 unique SMILES), totaling over 9,450 clinical pharmacokinetic measurements; simplified molecular input line entry system. World of molecular bio active

16. Cloe Knowledge. Open Access ADME/PK Database for a range of marketed drugs. Maintained by Cyprotex. • PHYSPROP. The Physical Properties Database (PHYSPROP) contains chemical structures, names, and physical properties for over 41,000 chemicals. • SIDER. Contains information on marketed medicines and their recorded adverse drug reactions. The information is extracted from public documents and package inserts • SuperTarget Database - Database of about 332828 drug-target relations .DART - (Drug Adverse Reaction Target).

17. DART - (Drug Adverse Reaction Target). A database for facilitating the search for drug adverse reaction target. It contains information about known drug adverse rection targets, • DITOP -(Drug-Induced Toxicity Related Proteins). Database of proteins that mediate toxicities through their interaction with drugs or reactive metabolites.. • ADMEAP -A database for facilitating the search for drug Absorption, Distribution, Metabolism, Excretion associated proteins. It contains information about known drug ADME associated proteins, functions, similarities, substrates/

18. LINKS PHYSPROP- https://guides.library.queensu.ca/c.php?g=560413&p=3855451 PACt- f -https://www.pharmainformatic.com/html/pact-f.html#:~:text=PACT%2DF%3A%20Preclinical%20And%20Clinical%20Trials%20Knowledge%20Base%20on%20Bioavailability&text=PACT%2DF%20contains%20experimental%20bioavailability,manually%20from%20reliable%20scientific%20publications. Toxnet- https://infocus.nlm.nih.gov/2015/11/04/toxnet-the-nlm-toxicology-databases/

19. Some applications of ADME include:  • High-throughput ADME (HT-ADME) screening • An essential part of drug discovery, HT-ADME screening has become more industrialized due to the development of software and automation tools.  • In silico prediction Machine learning is used to predict ADME properties.  • Microphysiological systems • MPS platforms that mimic human physiology can reduce the need for animal models.  • Personalized ADME approaches • These approaches consider factors such as a patient's genome or the time of day when drugs are administered. 

20. CONCLUSION • In drug discovery and development, researchers must examine the activity of a drug in the body to assess safety and toxicity. • Drug metabolism and pharmacokinetics studies, such as ADME and toxicology studies, are a critical step in this process. • The data collected tells researchers if a drug is viable and provides specific targets for future research and development. • Advances in the field have precipitated the rise of personalized ADME approaches, where factors such as a patient's genome or even the time of day during which drugs are administered are considered. • Computational techniques are often used to assist these more precise studies.

21. Induction in ADME is a process that occurs when a series of molecular events increase the production of drug-metabolizing enzymes in the liver. • Biotransformation is a metabolic process that changes the chemical structure of substances that enter the body. • pKa is a physicochemical property that indicates a drug's ionization state at physiological pH. • Conjugation reactions are a type of Phase II reaction in drug metabolism that make compounds water-soluble and pharmacologically inert, allowing the body to easily excrete the • an intrinsic drug property that can impact how a drug is eliminated from the body for polar