Drug Metabolism and Elimination Flashcards
Where are the sites of metabolism in the bdoy?
- gut lumen
- gut wall
- plasma
- lungs
- kidneys
- nerves
- liver
Describe the 2 phases of drug metabolism
Phase I:
- oxidation, reduction or hydrolysis
- introducing/revealing a reactive chemical group
- ‘functionalisation’
- products often more reactive
Phase II:
- synthetic conjugative reactions (adding on a large group)
- hydrophilic inactive compounds usually made
doesn’t always occur in 1 then 2 order
Expand on the possible chemical reactions that occur during Phase I of metabolism
Oxidation involves reactions involving:
- mixed function oxidase system (CYP450)
- alcohol dehydrogenase
- xanthine oxidase
Reduction involves reactions involving:
- ketones
- anaerobic CYP450 metabolism
Hydrolysis involves reactions involving:
- ester hydrolysis
- amide hydrolysis
Where are CYP450 enzymes found in the body, what are they made of and what is needed for metabolism of drugs?
- enzymes found in the liver, kidney, lung, intestine etc.
- made of cytochrome P450, NAPDH-CYP450 reductase and lipid
- needs molecular O2 and NADPH
- expression varies among patients
Describe how the variation of CYP impacts on clinical outcomes of drugs
- African populations more likely to be allele deficient in CYP2B6 which can lead to decreased metabolism of drugs like efavirenz (antiretroviral) leading to increased risk of neurological symptoms
- CYP2C8 deficient alleles more common in European and African populations which can lead to increased drug-induced neuropathies when being treated with paclitaxel (chemo)
- polymorphic overactivity of CYP2D6 more common in African populations which can lead to decreased treatment response to antidepressants (due to increased metabolism)
What factors can affect drug metabolism?
- age (metabolic activity varies)
- genetic variation (range of CYP phenotypes)
- disease (liver function/amino acid supply/kidneys)
- other medications (induce/inhibit metabolic enzymes)
What are the sources of excretion?
- breath
- urine
- saliva
- perspiration
- faeces
- milk
- bile
- hair
What are the main organs of metabolism and excretion?
- metabolism: liver
- excretion: kidneys
What transporters are responsible for taking hydrophilic drugs from the plasma to bile?
- organic cation transporters (OCTs)
- organic anion transporters (AOTs)
- P-glycoproteins (P-GP)
Describe the pathway drugs use to be reabsorbed
- enterohepatic circulation
- from the intestines is transported to the blood
- conjugated in the liver then taken to bile where it is conjugated again
- conjugated in intestines and excreted in faeces or taken up again
Describe the renal excretion of drugs
- glomerulus filters drugs below 20kDa, drug passes if bound to plasma albumin
- secreted in tubules by OATs and OCTs even if bound to plasma albumin
- if tubule freely permeable then 99% reabsorbed
(if polar then stays in lumen)
Describe the excretion of weak acid drugs
- more rapidly excreted if the urine is alkaline due to ion trapping
- makes it less able to be reabsorbed and is eliminated in the urine
Describe zero order kinetics
- few drugs
- constant amount metabolised per unit time
- does not vary with amount of drug present
- can lead to enzyme saturation
Describe first order kinetics
- most drugs
- a constant fraction of drug metabolised per unit time
- increases proportionately to drug concentration (more drug, more metabolised)
