Metabolism/Pharmacokinetics Flashcards
Drug metabolism
biochemical modification of pharmaceutical substances by living organisms usually through specialised enzymatic activity
What is metabolism?
-an essential pharmacokinetic process, which limits the life of a substance in the body, by rendering lipid soluble and non-polar compounds to water soluble and polar compounds so that they can be excreted.
Why does metabolism occur?
only water-soluble substances undergo excretion whereas lipid soluble substances are passively reabsorbed from renal or extra renal excretory sites back into the blood
Where are the important sites of metabolism?
- liver
- gut lining
- kidneys
- lungs
What are the effects of metabolism?
- loss of pharmacological activity
- decrease in activity with metabolites that show some activity
- increase in activity, more active metabolites
- production of toxic metabolites
Describe metabolising enzymes.
- wide substrate specificity
- individual drugs can be metabolised by more than 1
- enzyme activity is regulated at several levels
- some enzymes are expressed constitutively
- others are expressed or induced in the presence of a particular substrate
What are the 3 reactions that phase 1 metabolism can involve?
- hydrolysis
- oxidation
- reduction
What does phase 1 do?
increases the polarity of the compound and provides an active site for phase 2 metabolism
What family of enzymes are the most important metabolising enzymes?
cytochrome P450
How is drug specificity determined?
by the isoform of the cytochrome P450
What is CYP3A4?
- the major constitutive enzyme in human liver and contributes to the metabolism of a wide range of drugs.
- also found in the gut and is responsible for the pre-systemic metabolism of drugs such as diazepam, methadone, simvastatin, CCBs
What is CYP2D6?
- responsible for the metabolism of some antidepressants, antipsychotics and the conversion of codeine to morphine
- induced by cigarette smoke
What is CYP1A2?
- important in the role of metabolism of theophylline
- induced by smoking
What does Phase 2 involve?
-conjugation
What is conjugation?
- Conjugation increases the water solubility and enhances excretion of the metabolised compound.
- Conjugation involves the attachment of glucuronic acid, glutathione, sulphate or acetate to the metabolite generated by phase 1.
- conjugation usually results in inactivation however, a small number of drug metabolites may be active.
What happens during phase 2 metabolism?
a molecule endogenous to the body donates a portion of itself to the foreign molecule
What factors affect metabolism?
- other drugs, herbals, natural substances
- genetics
- hepatic blood flow
- liver disease
- age
- sex
- ethnicity
- pregnancy
What does induction of an enzyme involve?
increased synthesis and therefore increased activity
What can result from genetic variation- pharmacogenetics?
variation in response to drugs can result in therapeutic failure or ADR.
Why are inter-individual differences in gene expression common?
- drug metabolising enzymes are often expressed in multiple forms
- gene mutations can also occur resulting in deficiencies or absence of a particular metabolising enzyme
What does lack or decreased activity of an enzyme often result in?
- drug toxicity
- less commonly, enhanced metabolism, reduced drug effect, drug resistance
What are the 4 phenotype subpopulations of metabolizers known?
- poor metabolisers PM
- intermediate metabolisers IM
- extensive metabolisers EM
- ultrarapid metabolisers UM
What does CYP2C9 do?
metabolises 16 commonly used drugs including warfarin and phenytoin
What is known about CYP2C 19?
there are 8 allelic variants all are non-functional proteins
