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
When apparent rate is the slower rate
Metabolite formation rate is slower than metabolite elimination rate
The apparent elimination rate of metabolite is determined by
Metabolite formation rate
(=parent drug disappearance rate, if fe=0)
Curves are parallel to each other meaning half life of parent drug and half life of metabolite are the same
Apple picking scenario: brother
You pick five apples/hr
Your brother can only eat one apple/hr
He can only eat 1 apple/hr because it is his capacity
The apparent rate of his eating apples is determined by his true capability to eat apples
Metabolite formation rate is larger than metabolite elimination rate
The apparent elimination of metabolite is determined by true metabolite elimination rate
Parent drug fast -> metabolite slow
Rapid elimination of parent drug, so parent drug half life is much shorter than metabolite half-life
Contribution of metabolites to drug response
For accurate estimation of metabolite elimination rate (K(m) or CL(m)), metabolites should be administered to figure out pK profile -> does not happen much
In many cases, information on metabolite kinetics is obtained after admin of parent drug
If metabolite and parent drug half life are the same, we know
Metabolite pK is governed by formation
If metabolite and parent drug half life are NOT the same, (parent drug much slower), we know
Metabolite pk is governed by elimination
Rate-limiting step: IV Bolus - K «_space;K(m)
Metabolite elimination is formation rate-limited
K «_space;K(m)
True t1/2 of metabolite (i.e. t1/2 obtained after administration of metabolite) is in fact shorter than t1/2 of parent drug
However, apparent t1/2 of metabolite (i.e., t1/2 obtained after admin of parent drug) is similar to t1/2 of parent drug
Typical pattern for most drugs
Rate-limiting step: IV Bolus: K»_space; K(m)
Apparent metabolite elimination is metabolite elimination rate-limited
Both the apparent and true t1/2 of metabolite is longer than t1/2 of parent drug
Typical pattern for prodrugs
Metabolite PK: Formation-limited: Tolbutamide and Hydroxytolbutamide
Formation-limited
Tolbutamide
CYP2C9
—->
Hydroxytolbutamide (metabolite)
Metabolite PK: formation limited cont.
Plasma concentrations of tolbutamide and hydroxytolbutamide after an I.V. bolus dose of 1g
Note the concentrations of tobutamide and its metabolite decline in parallel
Similar apparent t1/2 between parent drug and metabolite: metabolite elimination is formation rate limited
Metabolite PK: elimination limited - Methylprednisolone and methylprednisolone hemisuccinate
Parent: Methylprednisolone hemisuccinate
Metabolite: Methylprednisolone
Metabolite has much longer half life stays in the body longer
Metabolite PK after infusion; Formation-limited
Time to reach steady state (SS) is determined by t1/2
Time to reach SS for metabolite is the same as that of parent drug
Metabolite PK after oral dosing: First pass effect and active metabolites:
Drugs that experience significant first pass effect (high EH) show high metabolite-to-parent drug concentration ratio after oral administration as compared to IV
To maintain higher systemic circulation, need to give **much higher oral dose **
Metabolite PK after oral dosing: First pass effect and active metabolites: Prodrug
If you have a prodrug, you may not have to give high oral dose (high EH and low bioavailability) because activity comes from metabolite
After oral admin, your parent drug concentration may not be that high, but will get exposure through metabolites
Oral admin:
If you give a drug as oral dose, most of it goes to liver and metabolites
A lot gets converted to metabolites
Oral dose has much greater exposure than IV dose to metabolites
Metabolite PK after oral dosing:
When drugs of high EH are administered and the metabolites are inactive:
-Concentrations of parent drug correspond to pharmacological effect
-IV admin typically leads to faster drug response
-Low F of the drug requires higher oral doses
Example: labetalol -> labetalol glucornide (inactive)
When prodrug of high EH are administered:
A shorter onset and a more intense response may occur after oral admin than IV
Low F of prodrug does not mean a poor therapeutic effect following oral admin
Low bioavailability of prodrug means therapeutic efficacy will be
high after oral admin (large generation of metabolites)
