Drug Metabolism

The main organ of drug metabolism is the liver, but the GI tract, lungs, and plasma also have activity.

Enzymatic conversion of the drug to another chemical entity

Metabolism of the drugs in the liver or gut reduces the bioavailability of drugs when administered orally.

<p>The amount of drug that eventually reaches systemic circulation and hence is available for drug action on the target of an administered dose of the drug is the drug's bioavailability for that route of administration.</p> Signup and view all the answers

<p>F= (quantity of drug reaching systemic circulation)/ quantity of drug administered (dose)</p> Signup and view all the answers

<ol> <li>Vd = total amount of drug in the body ÷ plasma drug concentration</li> <li>F = mass of the drug delivered to the plasma ÷ total mass of the drug administered</li> <li>F = AUC for X route of administration ÷ AUC for IV administration. In this one, F is expressed as a percentage because F of IV is the benchmark for the bioavailability.</li> </ol> Signup and view all the answers

<ol> <li>Convert parent drugs to more polar metabolites that are not readily reabsorbed by the kidney (from the renal tubules), facilitating excretion</li> <li>Convert drugs to metabolites that are usually pharmacologically less active than the parent compound</li> <li>Less frequently, metabolites may: <ul> <li>Be converted from inactive prodrugs to active compounds or gain activity</li> <li>Have unchanged activity</li> <li>Possess a different type, or spectrum, of action</li> </ul> </li> </ol> Signup and view all the answers

<ol> <li>Use of enzymes (oxidases) to unmask or introduce polar groups (e.g. -OH, -O) on the drug.</li> <li>Mainly uses the cytochrome P450 enzymes</li> </ol> <p>The overall goal of phase 1 metabolism is to increase the water solubility of these compounds, facilitating their elimination from the body.</p> Signup and view all the answers

<p>Haem proteins located in the endoplasmic reticulum of liver hepatocytes mediating oxidation reactions (phase 1) of many lipid soluble drugs.</p> Signup and view all the answers

<ol> <li>Drug enters cycle as drug substrate, RH</li> <li>Molecular oxygen (O2) provides two atoms of oxygen</li> <li>One atom of oxygen is added to the drug to yield the hydroxyl product, ROH, which leaves the cycle, the second oxygen combines with protons to form H2O</li> </ol> Signup and view all the answers

<ol> <li>Activity is genetically determined <ul> <li>Some people lack activity - higher drug plasma levels (adverse actions)</li> </ul> </li> <li>High levels of activity = reduced drug action</li> <li>Other drugs can interact with P450 system – increase or decrease activity</li> </ol> Signup and view all the answers

<p>Phase II metabolism: involve the combination of the drug with one of several polar molecules to form a water-soluble metabolite - conjugation - Usually involves the reactive group produced by phase I - Usually terminates all biological activity - Largely occurs in the liver - Products can be readily excreted via kidneys</p> Signup and view all the answers

<p>Glucuronidation is a crucial process in phase 2 metabolism, which involves the conjugation of drugs and endogenous substances with glucuronic acid. This conjugation reaction is catalyzed by enzymes known as UDP-glucuronosyltransferases (UGTs)</p> Signup and view all the answers

<p>Glucuronidation is a common reaction involving the transfer of glucuronic acid to electron-rich atoms of the substrate - Many endogenous substances are subject to glucuronidation (e.g. bilirubin, adrenal corticosteroids)</p> <ul> <li>Enzyme - uridine disphosphate-glucoronosyltransferases</li> <li>Cofactor - uridine diphosphate glucuronic acid</li> </ul> Signup and view all the answers

<p>Acetaminophen (Paracetamol) Metabolism: Acetaminophen is primarily metabolized through glucuronidation. In the liver, acetaminophen is conjugated with glucuronic acid by UGT enzymes, forming the glucuronide metabolite. The glucuronide is then excreted in the urine.</p> Signup and view all the answers

<p>In normal doses paracetamol is metabolised to a glucuonate and a sulphate (phase 2 reactions), but in overdose these processes are saturated and P450 mixed function oxidases (phase 1 reaction) produce a toxic metabolite - NAPBQI.</p> Signup and view all the answers

<p>NAPBQI can be inactivated by conjugation with glutathione (GSH) but if toxic dose depletes GSH (glutathione) stores, NAPBQI interacts with cellular proteins causing hepatocellular necrosis and more rarely renal tubular necrosis.</p> Signup and view all the answers

<ol> <li>Within 1 hour, use activated charcoal</li> <li>After 4 hours, check plasma concentration level. If it is above normal treatment levels, administer the antidote N-acetylcysteine (NAC) by IV infusion.</li> </ol> <ul> <li>Most effective in protecting the liver if given within 8 hours of paracetamol ingestion, but also of benefit over longer time period.</li> </ul> Signup and view all the answers

<p>NAC increases the synthesis of GSH permitting increased conjugation and elimination of NAPBQI. This protects the liver from the adverse effects of the toxic metabolite NAPBQI.</p> Signup and view all the answers