Survey
* Your assessment is very important for improving the workof artificial intelligence, which forms the content of this project
* Your assessment is very important for improving the workof artificial intelligence, which forms the content of this project
CSIM1.4: DRUG METABOLISM 11/02/08 LEARNING OUTCOMES List the major Phase I and II metabolic reactions Metabolism of a drug involves various enzymatic modifications, usually in the liver Drugs tend to be lipophilic and need to be made water-soluble to be excreted Cytochromes P450 mediate oxidation and are crucial in metabolism of most drugs o Some are constitutive (constant), others are synthesised on demand Phase I involves forming a derivative from the drug o Usually oxidation/reduction, hydrolysis o Decrease lipid solubility but may increase pharmacological activity o Activate pro-drugs (e.g. enalapril, codeine morphine) Phase II involves conjugating the derivative with another molecule o Functional groups added or exposed in phase I reactions serve as conjugation points o Large groups are typically conjugated, e.g. glucuronyl, sulphate, acetyl o Further decreases lipid solubility; generally decreases pharmacological activity o Conjugate is then excreted in urine or bile Glucuronidation is the most common phase II reaction producing a usually pharmacologically inactive product that is rapidly excreted Paracetamol is conjugated mainly with glucuronyl and sulphate groups o A minor proportion is metabolised by CYP450 to a highly toxic intermediary o Toxic product normally inactivated by further phase II reactions o In an overdose, conjugation pathways are saturated and the CYP450 pathway produces a build up of the toxic metabolite o Liver proteins are affected causing tissue damage and hepatic necrosis Explain and list the implications of first pass metabolism For some drugs, extensive metabolism occurs before the drug reaches the systemic circulation o The liver and gut wall contain various metabolising enzymes o Larger doses of these drugs are required to produce effects o Considerable variation in metabolism between individuals