Ex 2. L5: Metabolite Kinetics Flashcards
Overview of metabolite Pk
When you administer a drug, they can be renally excreted as a parent drug or they can undergo hepatic metabolism to become different metabolites
These metabolites can be excreted into urine to finally leave the body
Can also undergo biliary excretion (less common)
Importance of metabolite pk
We want to know the percentage of things that happen to metabolites (high or low concentration)
Contribution of metabolites to drug response
Metabolites can affect PK of parent drugs and alter pharmacologic response to the parent drug
ex: Can inhibit drug metabolizing enzyme, also having similar structure to parent drug, can bind to plasma proteins instead
Acetaminophen and metabolite
Too much = Liver toxicity
too much acetaminophen produces toxic metabolite NAPQI
NAPQI is produced in small doses with regular amount of acetaminophen, but in large doses - attacks and kills liver
Aspirin metabolite
Salicylic acid
Amitriptyline metabolite
Nortriptyline
Codeine metabolite
Morphine
Diazepam metabolite
Desmethyldiazepan
Fluoxetine metabolite
Norfluoxetine
Isosorbide dinitrate metabolite
Isoorbide-5-mononitrate
Meperidine metabolite
Noremeperidine
Primidone metabolite
Phenobarbital
Propranolol metabolite
4-hydroxypropranolol
Verapamil metabolite
Norverapamil
Zidovudine metabolite
Zidovudine triphosphate
Zidovudine and Zidovudine triphosphate are
Prodrug: Molecules with little/no pharmacological activity that are converted to the active drug in vivo by enzymatic or chemical reactions
Prodrug example
Irinotecan (inactive prodrug) (parent)
Carboxyesterase->
SN-38 (active drug) (metabolite)
UGT ->
SN-38 glucuronide (inactive)
(metabolite of metabolite)
Rate-limiting step
Most effects of metabolites are concentration-dependent
Need to understand the formation and elimination kinetics of metabolites
Rate-limiting equation
dA(m)
——– = Kf * A-K(m) *A (m)
dt
A = drug in body
AM = Metabolite in body
Kf = metabolism
Km = elimination
Kf * A - Km*Am (rate of formation minus rate of elimination)
Formation rate constant
Kf - metabolism
___ (the slowest step) defines PK profile of metabolite
Rate limiting step
True rate
Higher number - untouched number of formation
Apparent rate
Number accounted for in summation (slower rate)
Apple picking scenario sister
How fast do you pick apples: 5 apples/hr
How fast can your sister eat apples: 10 apples/hr
She can only eat 5 apples/hr, though she has the capability to eat more if available
The apparent rate of her eating apples is determined by “apple-picking” rate (the slower rate)
Parent drug slow -> metabolite fast