Drug Metabolism

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What is the main site of drug metabolism in the human body?

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

What is drug metabolism?

Enzymatic conversion of the drug to another chemical entity

What does drug metabolism do to the bioavailability of drugs when administered orally?

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

What is bioavailability?

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. Signup and view all the answers

What is the formula for bioavailability (F)?

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

What are three important equations to calculate bioavailability?

<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

What is the function of drug metabolism in the body?

<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

What is phase 1 metabolism of drugs? What is its purpose?

<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> The overall goal of phase 1 metabolism is to increase the water solubility of these compounds, facilitating their elimination from the body. Signup and view all the answers

What are the protein components involved in phase 1 metabolism?

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

What is the mechanism of the Phase 1 metabolism oxidation cycle?

<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

What is the effect of changed activity of the Phase 1 metabolism?

<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

What is the mechanism of phase 2 metabolism?

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 Signup and view all the answers

What is the purpose of glucuronidation in phase 2 metabolism?

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) Signup and view all the answers

What is glucuronidation? What is the enzyme and cofactor?

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) <ul> <li>Enzyme - uridine disphosphate-glucoronosyltransferases</li> <li>Cofactor - uridine diphosphate glucuronic acid</li> </ul> Signup and view all the answers

What is the role of glucuronidation in paracetamol metabolism?

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. Signup and view all the answers

How is paracetamol metabolised in our body? What is the effect of an overdose?

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. Signup and view all the answers

What is NAPBQI and how is it toxic to the liver?

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. Signup and view all the answers

What is the treatment of paracetamol poisoning?

<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

How does the NAC (n-acetylcysteine) treat paracetamol poisoning?

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. Signup and view all the answers