Download Drug Metabolism

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