Flashcards in Metabolism/Pharmacokinetics Deck (33):
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?
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?
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?
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?
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
-hepatic blood flow
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?
-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
What enzymes exhibit genetic variation?
-cytochrome P450 2D6
-cytochrome P450 2C19
Describe metabolism in fetus/premature infants
-drug metabolising enzymes deficient/reduced
-renal function deficient
What is the rate of metabolism in toddlers?
metabolise drugs more rapidly than adults
What is the rate of metabolism by puberty?
metabolise drugs greater than adults
In what way does metabolism differ for men and women?
In response to certain drugs
How does pregnancy affect drug metabolism?
Induction of certain drug metabolising enzymes occurs in second and third trimester
What kind of effect do hormonal changes during development have?
What happens in the elderly?
parameters such as plasma protein, lean body mass and liver weight decrease significantly and so alter drug metabolism