4 - Elementary Drug Metabolism Flashcards
drugs need to be made more ___ for exctretion
polar - some drugs are already highly charged but others need to be metabolised by the liver first
what are the main routes of excretion?
kidneys
what is another route of excretion?
through bile- excretion in faeces
minor contributions via sweat or milk
examples of a drug that is converted from prodrug to active compound by metabolism
enalapril to enalaprilat
example of a drug having unchanged activity on metabolism
diazepam to nordiazepam
phase 1 metabolism in liver involves which three processes?
oxidation, reduction, hydrolysis
phase 2 metabolism in liver involves what process?
conjugation
phase 1 makes a drug ___ ___
more polar
phase 2 ___ an ____ compound
adds an endogenous compound
what compounds can be added in phase 2? 6
glucoronyl, sulphate, methyl, acetyl, glycyl or glutathione
CYP 450 - ___ proteins located in the ___ ___ of the liver _____ (and elsewhere) mediating ____ reactions (phase__) of many lipid soluble drugs
haem,
endoplasmic reticulum
hepatocytes
oxidation
phase 1
CYP 3A4
what does the 3 denote?
gene family
CYP 3A4
what does the A denote?
gene subfamily
CYP 3A4
what does the 4 denote?
individual gene
what are the main cytochrome p450 monoxygenase gene families in the liver?
CYP1, CYP2, CYP3
the monoxygenase CYP cyles:
what you need to know
- drug enters as a drug ____
- molecular ___ provides __ atoms
- one atom is added to the drug to yield ___ ____ , which ___ the cycle
- The second atom combines with ____ to form ___
- drug enters as a drug substrate
- molecular oxygen provides 2 atoms
- one atom is added to the drug to yield the hydroxyl product , which leaves the cycle
- The second atom combines with protons to form water
phase 2 involves the conjugation of ___ ___ groups (e.g. ____, ___ (SH) or ___ (__) )with ______, ____, ___ or ___ groups
chemically reactive groups (e.g. hydroxyl, thiol (SH) or amino (NH2) with glucoronyl, methyl, sulphate or acetyl groups
____ is a common phase 2 reatcion
glucuronidation
what is the molecule that transfers a glucuronyl group in glucuronidation?
UDP - alpha - glucuronide
what enzyme causes the glucuronyl transfer?
UDP- glucuronyl trasferase
give two examples of endogenous sustances that are suject to glucuronidation
bilirubin, adrenal corticosteroids
what are the three basic processes of renal excretion
- glumerular filtration (glomerulous)
- active tubular secretion (proximal convoluted tubule)
- passive reabsorption by diffusion across the tubular epithelium
ultrafiltration occurs only with ___ drugs
free/ unbound
clearance by filtration = ___ x ___
glomerular filtration rate x fraction of drug unbound in plasma
up to ___ % of renal plasma flow is filtered through the glomerulus . the rest is delivered to the peritubular capillaries of the proximal tubule
20%
epithelial cells of the proximal tubule contain __ , independent transporter systems that ____ secrete drugs into the lumen of the nephron
2, actively
what are the two transporter systems actively secreting drugs in the proximal tubule
organic anion transporter (OAT) and organic cation transporter (OCT)
OATs handle ___ drugs and OCTs handle ___ drugs
acidis, basic
active tubular secretion is a ___ process , each carrier ha a transport maximum
saturable
what factors promote tubular reabsorption ?
lipid solbility, low polarity, low blow rate, (pH will depend on the direction of movement)
having an alkaline urinary pH promotes the excretion of ___ and the reverse is tru for acids
acids,
uriniary ____ can be used to accelerate the excretion of aspirin (weak acid) in overdose
alkalisation
