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Transcript
Assignment 6
Metabolism
A drug is eliminated almost exclusively by
hepatic metabolism via glucuronidation and
subsequent excretion into the bile. The excreted
glucuronide is neither hydrolyzed in nor
reabsorbed from the intestines. The volume of
distribution and half-life of the drug are 100 L
and 9 hrs, respectively.
1. Like this drug, all glucuronides of drugs are inactive
and eliminated via the bile or kidney. Is this statement
true or false? Why?
The statement is false.
Inactive:
• Glucuronides are usually pharmacologically inactive.
• Does not apply to glucuronides of all drugs.
• Examples:
i) Conjugates generated by acyl glucuronidation of
NSAIDs. (toxic metabolite)
ii) Activation of morphine (pharmacologically active
metabolite)
Example 1:
Conjugates generated by acyl glucuronidation of NSAIDs.
UDPglucuronosyltransferase,UGT2B7
(microsomal enzyme)
UDP Glucuronic acid
(endogenic substance)
Prrotein reactive metabolite which may
cause toxicity in some patients.
Example 2:
Activation of morphine
Glucuronidation at the 6-OH
position results in the
formation of an active
metabolite
1. Like this drug, all glucuronides of drugs are inactive
and eliminated via the bile or kidney. Is this statement
true or false? Why?
Eliminated:
• Not 100% of glucuronidated drug excreted in bile will
undergo elimination as some may be hydrolyzed and
reabsorbed in intestines.
• Thus, this will contribute to the distribution of the drug.
• This recycling process is called ‘Enterohepatic Cycle’
Example:
Morphine-3-glucuronide
Deconjugation/hydrolysis
Morphine-3-glucuronide
Morphine
Morphine-3-glucuronide
undergoes
enterohepatic
cycle. This explains the high initial dose of morphine
usually administered, followed by lower maintenance
doses.
1. Like this drug, all glucuronides of drugs are inactive
and eliminated via the bile or kidney. Is this statement
true or false? Why?
Bile or kidney:
• This is true as glucuronide conjugates are generally
hydrophillic
• Excretion of glucuronide conjugates is also promoted by
the carboxylic acid moiety of the glucuronic acid, which
increases the aqueous solubility of the conjugate.
• Specific transporters at the membranes between:
i) liver and bile
ii) renal capillaries and renal tubules
1. Like this drug, all glucuronides of drugs are inactive
and eliminated via the bile or kidney. Is this statement
true or false? Why?
Bile or kidney:
• Increased MW of drug due to glucuronidation.
• As a guideline, drug MW >350g/mol is needed to ensure
high biliary clearance.
• Whereas for kidney, drug MW with anything less than
60000g/mol and not bounded to proteins will be filtered.
2. What is the hepatic extraction of this drug? Hepatic
blood flow is 1.5L/min.
Rate of elimination = CL x C
Since, C = Ab/V
Rearranging, Rate of elimination = (CL/V) x Ab
k is the fractional rate of drug elimination
Thus, k = Rate of elimination/Ab
= CL/V
Also,
Thus,
k
=
0.693/t1/2
t1/2 =
0.693/k
=
(0.693/CL) x V
Thus,
9hrs =
(0.693/CL) x 100L
CL =
7.7L/hr
However, this is CLtotal. But, since it is stated that drug is eliminated almost
exclusively by hepatic metabolism,
CLtotal
=
CLhep
Hepatic CL
Thus,
7.7L/60min
EH
=
=
=
Rate of elimination/CA
QH(CA-CV)/CA
QH x EH
=
=
1.5L/1min x EH
0.086
3. Is the clearance of this drug more likely to be sensitive to a
change in plasma protein binding or a change in hepatic
perfusion?
Known:
• This drug has a low hepatic extraction ratio.
Change in hepatic perfusion:
• Rate of elimination remains unchange with hepatic perfusion
changes.
• Thus, hepatic clearance remains unaltered.
• Therefore, clearance of this drug is not sensitive to changes in
hepatic perfusion.
3. Is the clearance of this drug more likely to be sensitive to a
change in plasma protein binding or a change in hepatic
perfusion?
Change in plasma protein binding:
Rate of elimination = CLu x Cu
Divide equation with C,
CLH = CLu x fu
• An increase in fraction unbound of drug in plasma will cause an
increase in hepatic clearance of this drug, while the intrinsic
clearance of liver remains unchanged.
• Therefore, clearance of this drug is sensitive to changes in plasma
protein binding.