Ex 2. L5: Metabolite Kinetics

Question 1

Overview of metabolite Pk

Answer 1

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)

Question 2

Importance of metabolite pk

Answer 2

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

Question 3

Contribution of metabolites to drug response

Answer 3

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

Question 4

Acetaminophen and metabolite

Answer 4

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

Question 5

Aspirin metabolite

Answer 5

Salicylic acid

Question 6

Amitriptyline metabolite

Answer 6

Nortriptyline

Question 7

Codeine metabolite

Answer 7

Morphine

Question 8

Diazepam metabolite

Answer 8

Desmethyldiazepan

Question 9

Fluoxetine metabolite

Answer 9

Norfluoxetine

Question 10

Isosorbide dinitrate metabolite

Answer 10

Isoorbide-5-mononitrate

Question 11

Meperidine metabolite

Answer 11

Noremeperidine

Question 12

Primidone metabolite

Answer 12

Phenobarbital

Question 13

Propranolol metabolite

Answer 13

4-hydroxypropranolol

Question 14

Verapamil metabolite

Answer 14

Norverapamil

Question 15

Zidovudine metabolite

Answer 15

Zidovudine triphosphate

Question 16

Zidovudine and Zidovudine triphosphate are

Answer 16

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

Question 17

Prodrug example

Answer 17

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

Question 18

Rate-limiting step

Answer 18

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

Question 19

Rate-limiting equation

Answer 19

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)

Question 20

Formation rate constant

Answer 20

Kf - metabolism

Question 21

___ (the slowest step) defines PK profile of metabolite

Answer 21

Rate limiting step

Question 22

True rate

Answer 22

Higher number - untouched number of formation

Question 23

Apparent rate

Answer 23

Number accounted for in summation (slower rate)

Question 24

Apple picking scenario sister

Answer 24

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

Question 25

When apparent rate is the slower rate

Answer 25

Metabolite formation rate is slower than metabolite elimination rate

Question 26

The apparent elimination rate of metabolite is determined by

Answer 26

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

Question 27

Apple picking scenario: brother

Answer 27

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

Question 28

Contribution of metabolites to drug response

Answer 28

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

Question 29

If metabolite and parent drug half life are the same, we know

Answer 29

Metabolite pK is governed by formation

Question 30

If metabolite and parent drug half life are NOT the same, (parent drug much slower), we know

Answer 30

Metabolite pk is governed by elimination

Question 31

Rate-limiting step: IV Bolus - K &laquo_space;K(m)

Answer 31

Metabolite elimination is formation rate-limited

K &laquo_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

Question 32

Rate-limiting step: IV Bolus: K&raquo_space; K(m)

Answer 32

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

Question 33

Metabolite PK: Formation-limited: Tolbutamide and Hydroxytolbutamide

Answer 33

Formation-limited
Tolbutamide

CYP2C9
—->

Hydroxytolbutamide (metabolite)

Question 34

Metabolite PK: formation limited cont.

Answer 34

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

Question 35

Metabolite PK: elimination limited - Methylprednisolone and methylprednisolone hemisuccinate

Answer 35

Parent: Methylprednisolone hemisuccinate
Metabolite: Methylprednisolone

Metabolite has much longer half life stays in the body longer

Question 36

Metabolite PK after infusion; Formation-limited

Answer 36

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

Question 37

Metabolite PK after oral dosing: First pass effect and active metabolites:

Answer 37

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 **

Question 38

Metabolite PK after oral dosing: First pass effect and active metabolites: Prodrug

Answer 38

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

Question 39

Oral admin:

Answer 39

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

Question 40

Metabolite PK after oral dosing:

Answer 40

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)

Question 41

When prodrug of high EH are administered:

Answer 41

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

Question 42

Low bioavailability of prodrug means therapeutic efficacy will be

Answer 42

high after oral admin (large generation of metabolites)