Ex 2. L5: Metabolite Kinetics Flashcards

1
Q

Overview of metabolite Pk

A

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)

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2
Q

Importance of metabolite pk

A

We want to know the percentage of things that happen to metabolites (high or low concentration)

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3
Q

Contribution of metabolites to drug response

A

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

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4
Q

Acetaminophen and metabolite

A

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

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5
Q

Aspirin metabolite

A

Salicylic acid

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6
Q

Amitriptyline metabolite

A

Nortriptyline

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7
Q

Codeine metabolite

A

Morphine

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8
Q

Diazepam metabolite

A

Desmethyldiazepan

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9
Q

Fluoxetine metabolite

A

Norfluoxetine

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10
Q

Isosorbide dinitrate metabolite

A

Isoorbide-5-mononitrate

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11
Q

Meperidine metabolite

A

Noremeperidine

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12
Q

Primidone metabolite

A

Phenobarbital

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13
Q

Propranolol metabolite

A

4-hydroxypropranolol

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14
Q

Verapamil metabolite

A

Norverapamil

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15
Q

Zidovudine metabolite

A

Zidovudine triphosphate

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16
Q

Zidovudine and Zidovudine triphosphate are

A

Prodrug: Molecules with little/no pharmacological activity that are converted to the active drug in vivo by enzymatic or chemical reactions

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17
Q

Prodrug example

A

Irinotecan (inactive prodrug) (parent)
Carboxyesterase->
SN-38 (active drug) (metabolite)
UGT ->
SN-38 glucuronide (inactive)
(metabolite of metabolite)

18
Q

Rate-limiting step

A

Most effects of metabolites are concentration-dependent
Need to understand the formation and elimination kinetics of metabolites

19
Q

Rate-limiting equation

A

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)

20
Q

Formation rate constant

A

Kf - metabolism

21
Q

___ (the slowest step) defines PK profile of metabolite

A

Rate limiting step

22
Q

True rate

A

Higher number - untouched number of formation

23
Q

Apparent rate

A

Number accounted for in summation (slower rate)

24
Q

Apple picking scenario sister

A

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

25
When apparent rate is the slower rate
Metabolite formation rate is slower than metabolite elimination rate
26
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**
27
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**
28
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**
29
If metabolite and parent drug half life are the same, we know
Metabolite pK is governed by formation
30
If metabolite and parent drug half life are NOT the same, (parent drug much slower), we know
Metabolite pk is governed by elimination
31
Rate-limiting step: IV Bolus - **K << K(m)**
Metabolite elimination is **formation rate-limited** **K << 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
32
Rate-limiting step: IV Bolus: **K >> 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**
33
Metabolite PK: Formation-limited: Tolbutamide and Hydroxytolbutamide
Formation-limited Tolbutamide CYP2C9 ----> Hydroxytolbutamide (metabolite)
34
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**
35
Metabolite PK: elimination limited - Methylprednisolone and methylprednisolone hemisuccinate
Parent: Methylprednisolone hemisuccinate Metabolite: Methylprednisolone Metabolite has **much longer half life** stays in the body longer
36
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
37
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 **
38
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**
39
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**
40
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)
41
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
42
Low bioavailability of prodrug means therapeutic efficacy will be
high after oral admin **(large generation of metabolites)**