1-C: Renal and Hepatic Elimination
400 mg of moxifloxacin is administered orally to Mr BB, a
68 yr old male who weighs 75 kg. Blood samples were drawn
following the dose and the plasma concentration determined. It is
known that about 20% of a moxifloxacin dose is excreted in the
urine unchanged. A further 20% is excreted unchanged in the bile
and the rest is metabolised to either M1 (sulpho) or M2 (acyl-glucuronide)
Time
(hr)
0
2
6
12
24
36
Plasma analysis has calculated a K = 0.0694 hr-1,
Plasma Conc T½ = 10 hr, ClT = 10.42 L/hr, ClR of 1.86 L/hr,
71.5 mg of moxi in the urine and a ke of 0.0124 hr-1.
(mg/L)
1. Introduce principles of metabolite profiles.
2. Analysis of Mr. BB’s metabolite [ ].
2.32
3. What will analysis of the metabolite profile
1.76
1.16
yield?
0.5
4. What will we need to know to determine how
0.22
much moxi is metabolised through to M1?
1-C: Renal and Hepatic Elimination
400 mg of moxifloxacin is administered orally to Mr BB, a
68 yr old male who weighs 75 kg. Blood samples were drawn
following the dose and the plasma concentration determined. It is
known that about 20% of a moxifloxacin dose is excreted in the
urine unchanged. A further 20% is excreted unchanged in the bile
and the rest is metabolised to either M1 (sulpho) or M2 (acyl-glucuronide)
K = ke + kH + kNR
ClT = ClR + ClH + ClNR
Plasma analysis has calculated a K = 0.0694 hr-1,
T½ = 10 hr, ClT = 10.42 L/hr, ClR of 1.86 L/hr,
71.5 mg of moxi in the urine and a ke of 0.0124 hr-1.
1. Introduce principles of metabolite profiles.
2. Analysis of Mr. BB’s metabolite [ ].
3. What will analysis of the metabolite profile
yield?
4. What will we need to know to determine how
much moxi is metabolised through to M1?
Models Describing Moxi Elimination
It is known that about 20% of a moxifloxacin dose is excreted in the
urine unchanged. A further 20% is excreted unchanged in the bile
and the rest is metabolised to either M1 (sulpho) or M2 (acyl-glucuronide)
K = ke + kH + kNR
ClT = ClR + ClH + ClNR
K = ke + km1 + km2 + kNR
ClT = ClR + Clm1 + Clm2 + ClNR
Models Describing Moxi Elimination
It is known that about 20% of a moxifloxacin dose is excreted in the
urine unchanged. A further 20% is excreted unchanged in the bile
and the rest is metabolised to either M1 (sulpho) or M2 (acyl-glucuronide)
Focus on one metabolite (M1)
which is reported to account for
~40 - 45% of moxifloxacin clearance.
Although only 5-6% of the dose appears in
the urine as M1 and the balance appears
in feces as M1, for our purpose we will
assume complete excretion of M1 into the urine.
~15% of the dose is metabolised through M2.
The metabolite concentration in the body
is a function of the rates of formation (km)
and metabolite elimination (kme)
Models Describing Moxi Elimination
It is known that about 20% of a moxifloxacin dose is excreted in the
urine unchanged. A further 20% is excreted unchanged in the bile
and the rest is metabolised to either M1 (sulpho) or M2 (acyl-glucuronide)
The metabolite concentration in the body
is a function of the rates of formation (km)
and metabolite elimination (kme)
dM = k Dose - k M
m
me
dt
Which can be solved to produce this equation
CM =
kmDose
t
Kt
(-k
(e
me ) - e(- ) )
VM(K-kme)
Which describes the concentration of metabolite
following IV bolus administration of parent.
Models Describing Moxi Elimination
It is known that about 20% of a moxifloxacin dose is excreted in the
urine unchanged. A further 20% is excreted unchanged in the bile
and the rest is metabolised to either M1 (sulpho) or M2 (acyl-glucuronide)
There are a number of parameters in this
equation which will require some
calculation &/or may
be difficult to estimate.
CM =
kmDose
(-k
(e
met) - e(-Kt) )
VM(K-kme)
VM volume of metabolite,
kme and km
The case of the Rate-Limiting Exponential
The CM equation is very similar to the bi-exponential oral equation.
The two exponentials are now Kme and K.
Which one of kme or K will appear
in the terminal phase?
CM =
kmDose
(-k
(e
met) - e(-Kt) )
VM(K-kme)
Which one kme or K will be
the smallest … or slowest?
The case of the Rate-Limiting Exponential
The CM equation is very similar to the bi-exponential oral equation.
The two exponentials are now Kme and K.
CM =
kmDose
(-k
(e
met) - e(-Kt) )
VM(K-kme)
In this profile which one is
the smallest … or slowest?
kme or K?
The case of the Rate-Limiting Exponential
The CM equation is very similar to the bi-exponential oral equation.
The two exponentials are now Kme and K.
CM =
kmDose
(-k
(e
met) - e(-Kt) )
VM(K-kme)
Which one is
the smallest … or slowest?
kme or K?
Here, since the parent
compound’s profile following
IV bolus administration
has a faster half-life,
kme appears to rate-limit
elimination of the metabolite.
K > kme
and kme is rate limiting
The case of the Rate-Limiting Exponential
The CM equation is very similar to the bi-exponential oral equation.
The two exponentials are now Kme and K.
Which one will be
the smallest … or slowest?
 K = 0.08
CM =
kmDose
(-k
(e
met) - e(-Kt) )
VM(K-kme)
K > kme
0.08 > 0.04
0.04
The case of the Rate-Limiting Exponential
The CM equation is very similar to the bi-exponential oral equation.
The two exponentials are now Kme and K.
CM =
kmDose
(-k
(e
met) - e(-Kt) )
VM(K-kme)
Which one is
the smallest … or slowest?
kme or K?
Here, since the parent
compound’s profile following
IV bolus administration
has a faster half-life,
kme appears to rate-limit
elimination of the metabolite.
Method of residuals
should generate K
from the metabolite profile
The case of the Rate-Limiting Exponential
The CM equation is very similar to the bi-exponential oral equation.
The two exponentials are now Kme and K.
CM =
kmDose
(-k
(e
met) - e(-Kt) )
VM(K-kme)
What happens when the
metabolite, a very polar
glucuronide, is excreted
rapidly into the urine?
The case of the Rate-Limiting Exponential
The CM equation is very similar to the bi-exponential oral equation.
The two exponentials are now Kme and K.
CM =
kmDose
(-k
(e
met) - e(-Kt) )
VM(K-kme)
What happens when the
metabolite, a very polar
glucuronide, is excreted
rapidly into the urine?
Now, kme >> K, & at some
time (e–kmet) will approach
zero and the equation will
be effectively reduced to:
kmDose
CM  V (K-k ) (e(-Kt))
M
me
The case of the Rate-Limiting Exponential
The CM equation is very similar to the bi-exponential oral equation.
The two exponentials are now Kme and K.
CM =
kmDose
(-k
(e
met) - e(-Kt) )
VM(K-kme)
What happens when the
metabolite, a very polar
glucuronide, is excreted
rapidly into the urine?
Now, kme >> K, then at some
time (e–kmet) will approach
zero and the equation will
be effectively reduced to:
Showing that at later times, the
metabolite concentration-time
profile will be parallel to the
parent [ ]-time profile.
The case of the Rate-Limiting Exponential
The CM equation is very similar to the bi-exponential oral equation.
The two exponentials are now Kme and K.
CM =
kmDose
(-k
(e
met) - e(-Kt) )
VM(K-kme)
Now, which one is
the smallest … or slowest?
kme or K?
 K = 0.08
Kme > K = 0.2
The case of the Rate-Limiting Exponential
The CM equation is very similar to the bi-exponential oral equation.
The two exponentials are now Kme and K.
Which one is
kmDose
CM = V (K-k ) (e(-kmet) - e(-Kt) ) the smallest … or slowest?
M
me
kme or K?
Here, since the parent
compound’s profile following
IV bolus administration
has a half-life equal
to metabolite,
K appears to rate-limit
elimination of the metabolite.
Method of residuals
should generate kme
from the metabolite profile
The effect of km on the metabolite profile
km is not one of the exponentials in a metabolite profile
So, how does km affect the metabolite profile?
CM =
kmDose
(-k
(e
met) - e(-Kt) )
VM(K-kme)
The effect of km on the metabolite profile
km is not one of the exponentials in a metabolite profile
So, how does km affect the metabolite profile?
CM =
kmDose
(-k
(e
met) - e(-Kt) )
VM(K-kme)
Since K = ke + km
Then as km approaches K,
less drug could be excreted unchanged
and ke would approach zero.
ClR
ke
ke
Ae0-
----- = ----- = ----- = --------ClT
K
k10
DoseIV
The effect of km on the metabolite profile
km is not one of the exponentials in a metabolite profile
So, how does km affect the metabolite profile?
CM =
kmDose
(-k
(e
met) - e(-Kt) )
VM(K-kme)
Since K = ke + km
Then as km approaches K,
less drug could be excreted unchanged
and ke would approach zero.
ClR
ke
ke
Ae0-
----- = ----- = ----- = --------ClT
K
k10
DoseIV
km/K represents the fraction metabolised
just as ke/K represents the amount
excreted unchanged into the urine
The effect of km on the metabolite profile
km is not one of the exponentials in a metabolite profile
So, how does km affect the metabolite profile?
CM =
kmDose
(-k
(e
met) - e(-Kt) )
VM(K-kme)
Consider the situation where
K = 0.08 hr-1, kme = 0.2 hr-1
and km = 0.02 hr-1.
Questions:
1. The metabolite profile is rate
limited by which exponential?
2. What fraction of the dose is
metabolised?
The effect of km on the metabolite profile
km is not one of the exponentials in a metabolite profile
So, how does km affect the metabolite profile?
CM =
kmDose
(-k
(e
met) - e(-Kt) )
VM(K-kme)
Consider the situation where
K = 0.08 hr-1, kme = 0.2 hr-1
and km = 0.02 hr-1.
0.02
0.20
 K = 0.08
Questions:
1. The metabolite profile is rate
limited by which exponential?
K
2. What fraction of the dose is
metabolised?
The effect of km on the metabolite profile
km is not one of the exponentials in a metabolite profile
So, how does km affect the metabolite profile?
CM =
kmDose
(-k
(e
met) - e(-Kt) )
VM(K-kme)
Consider the situation where
K = 0.08 hr-1, kme = 0.2 hr-1
and km = 0.02 hr-1.
Questions:
1. The metabolite profile is rate
limited by which exponential?
K
2. What fraction of the dose is
metabolised?
km/K = 0.02/0.08 = 25%
The effect of km on the metabolite profile
km is not one of the exponentials in a metabolite profile
So, how does km affect the metabolite profile?
CM =
kmDose
(-k
(e
met) - e(-Kt) )
VM(K-kme)
Consider the situation where
K = 0.08 hr-1, kme = 0.2 hr-1
but km is increased to = 0.07 hr-1.
0.02
 K = 0.08
Questions:
1. The metabolite profile is rate
limited by which exponential?
2. What fraction of the dose is
metabolised?
0.20
The effect of km on the metabolite profile
km is not one of the exponentials in a metabolite profile
So, how does km affect the metabolite profile?
CM =
kmDose
(-k
(e
met) - e(-Kt) )
VM(K-kme)
Consider the situation where
K = 0.08 hr-1, kme = 0.2 hr-1
but km is increased to = 0.07 hr-1.
0.02
0.20
 K = 0.08
Questions:
1. The metabolite profile is rate
limited by which exponential?
K
2. What fraction of the dose is
metabolised?
The effect of km on the metabolite profile
km is not one of the exponentials in a metabolite profile
So, how does km affect the metabolite profile?
CM =
kmDose
(-k
(e
met) - e(-Kt) )
VM(K-kme)
Consider the situation where
K = 0.08 hr-1, kme = 0.2 hr-1
but km is increased to = 0.07 hr-1.
Questions:
1. The metabolite profile is rate
limited by which exponential?
K
2. What fraction of the dose is
metabolised?
km/K = 0.07/0.08 = 87.5%
The effect of km on the metabolite profile
km is not one of the exponentials in a metabolite profile
So, how does km affect the metabolite profile?
km/K = 0.02 / 0.08 = 25%
km/K = 0.07 / 0.08 = 87.5%
Peak = 0.621 mg/L
Peak =
0.177 mg/L
1-C: Renal and Hepatic Elimination
Following a 400 mg of moxifloxacin to Mr BB, the following
concentrations of parent and metabolite are observed. It is known
that about ~18% of the moxi dose in this patient is excreted into the
urine unchanged. How much is metabolised through to M1?
Parent
Time Plasma Conc.
(hr)
(mg/L)
0
1
2
3
4
6
8
12
24
36
2.49
2.32
2.17
2.02
1.76
1.53
1.16
0.5
0.22
M1
Plasma analysis has calculated a
Plasma Conc K = 0.0694 hr-1, T½ = 10 hr,
(mg/L)
ClT = 10.42 L/hr, ClR of 1.86 L/hr,
0.18
0.31
0.41
0.48
0.56
0.58
0.53
0.28
0.13
71.5 mg of moxi in the urine
and a ke of 0.0124 hr-1.
1. Introduce principles of
metabolite profiles.
2. Analysis of metabolite [ ].
3.
What will analysis of the
metabolite profile yield?
4.
What will we need to know
to determine how much moxi
is metabolised through to M1?
1-C: Renal and Hepatic Elimination
Following a 400 mg of moxifloxacin to Mr BB, the following
concentrations of parent and metabolite are observed. It is known
that about ~18% of the moxi dose in this patient is excreted into the
urine unchanged. How much is metabolised through to M1?
Parent
Time Plasma Conc.
(hr)
(mg/L)
0
1
2
3
4
6
8
12
24
36
2.49
2.32
2.17
2.02
1.76
1.53
1.16
0.5
0.22
M1
Plasma analysis has calculated a
Plasma Conc K = 0.0694 hr-1, T½ = 10 hr,
(mg/L)
ClT = 10.42 L/hr, ClR of 1.86 L/hr,
0.18
0.31
0.41
0.48
0.56
0.58
0.53
0.28
0.13
71.5 mg of moxi in the urine
and a ke of 0.0124 hr-1.
1. Introduce principles of
metabolite profiles.
2. Analysis of metabolite [ ].
3. What will analysis of the
metabolite profile yield?
4.
What will we need to know
to determine how much moxi
is metabolised through to M1?
1-C: Renal and Hepatic Elimination
Following a 400 mg of moxifloxacin to Mr BB, the following
concentrations of parent and metabolite are observed. It is known
that about ~18% of the moxi dose in this patient is excreted into the
urine unchanged. How much is metabolised through to M1?
Plasma analysis has calculated a
K = 0.0694 hr-1, T½ = 10 hr,
ClT = 10.42 L/hr, ClR of 1.86 L/hr,
71.5 mg of moxi in the urine
and a ke of 0.0124 hr-1.
1. Introduce principles of
metabolite profiles.
2. Analysis of metabolite [ ].
3.
What will analysis of the
metabolite profile yield?
4.
What will we need to know
to determine how much moxi
is metabolised through to M1?
1-C: Renal and Hepatic Elimination
Following a 400 mg of moxifloxacin to Mr BB, the following
concentrations of parent and metabolite are observed. It is known
that about ~18% of the moxi dose in this patient is excreted into the
urine unchanged. How much is metabolised through to M1?
Slope of the terminal
phase is likely to yield a value
for which exponential ??…
1-C: Renal and Hepatic Elimination
Following a 400 mg of moxifloxacin to Mr BB, the following
concentrations of parent and metabolite are observed. It is known
that about ~18% of the moxi dose in this patient is excreted into the
urine unchanged. How much is metabolised through to M1?
Slope of the terminal
phase is likely to yield a value
for which exponential ??…
Metabolite profile is parallel
to the elimination of the
parent compound…
therefore, the terminal
phase is likely to yield a
value for K.
1-C: Renal and Hepatic Elimination
Following a 400 mg of moxifloxacin to Mr BB, the following
concentrations of parent and metabolite are observed. It is known
that about ~18% of the moxi dose in this patient is excreted into the
urine unchanged. How much is metabolised through to M1?
Slope of the terminal
phase is likely to yield a value
for which exponential ??…
K
And the method of residuals
from plasma metabolite data
will like yield a value
for what exponential?
1-C: Renal and Hepatic Elimination
Following a 400 mg of moxifloxacin to Mr BB, the following
concentrations of parent and metabolite are observed. It is known
that about ~18% of the moxi dose in this patient is excreted into the
urine unchanged. How much is metabolised through to M1?
Slope of the terminal
phase is likely to yield a value
for which exponential ??…
K
And the method of residuals
from plasma metabolite data
will like yield a value
for what exponential?
kme
1-C: Renal and Hepatic Elimination
Following a 400 mg of moxifloxacin to Mr BB, the following
concentrations of parent and metabolite are observed. It is known
that about ~18% of the moxi dose in this patient is excreted into the
urine unchanged. How much is metabolised through to M1?
Plasma analysis has calculated a
K = 0.0694 hr-1, T½ = 10 hr,
ClT = 10.42 L/hr, ClR of 1.86 L/hr,
71.5 mg of moxi in the urine
and a ke of 0.0124 hr-1.
1. Introduce principles of
metabolite profiles.
2. Analysis of metabolite [ ].
3. What will analysis of the
metabolite profile yield?
4. What will we need to know
to determine how much moxi
is metabolised through to M1?
1-C: Renal and Hepatic Elimination
Following a 400 mg of moxifloxacin to Mr BB, the following
concentrations of parent and metabolite are observed. It is known
that about ~18% of the moxi dose in this patient is excreted into the
urine unchanged. How much is metabolised through to M1?
What will we need to know
to determine how much
Moxi is metabolised
through to M1?
1-C: Renal and Hepatic Elimination
Following a 400 mg of moxifloxacin to Mr BB, the following
concentrations of parent and metabolite are observed. It is known
that about ~18% of the moxi dose in this patient is excreted into the
urine unchanged. How much is metabolised through to M1?
What will we need to know
to determine how much
Moxi is metabolised
through to M1?
Since we made the assumption
that all M1 was excreted into
the urine, the amount of
metabolite found in the
urine (Ame0-∞)
Ame0-∞ = ------km
-----------Dose
K
1-C: Renal and Hepatic Elimination
Following a 400 mg of moxifloxacin to Mr BB, the following
concentrations of parent and metabolite are observed. It is known
that about ~18% of the moxi dose in this patient is excreted into the
urine unchanged. How much is metabolised through to M1?
What would we observe if we
had a pure sample of M1
and we administered it
IV?
1-C: Renal and Hepatic Elimination
Following a 400 mg of moxifloxacin to Mr BB, the following
concentrations of parent and metabolite are observed. It is known
that about ~18% of the moxi dose in this patient is excreted into the
urine unchanged. How much is metabolised through to M1?
What would we observe if we
had a pure sample of M1
and we administered it
IV?
Elimination rate would be
kme, and the value would be
the same as if we had
completed the method of
residuals on the
metabolite profile.
1-C: Renal and Hepatic Elimination
Metabolite Summary
Metabolites are chemically distinct
and differ from the parent compound.
A metabolite will have its own :
Distribution space
Clearance
“Fate”
Compartmental Model
[ ]vs. time profile
Metabolite
A metabolite can be excreted into
the urine or bile directly
or further metabolised.
1-C: Renal and Hepatic Elimination
Metabolite Summary
Since
K = ke + km1 + km2 + kNR
and
ClT = ClR + Clm1 + Clm2 + ClNR
and the clearance of individual processes
can be calculated using
the volume which is common
ClT = KV
ClR = keV
Clm1 = km1V
Clm2 = km2V
In this case Clm2 is the clearance
of parent drug through the process
of creating metabolite M2…
not the clearance of metabolite M2!
1-C: Renal and Hepatic Elimination
Metabolite Summary
Since
K = ke + km1 + km2 + kNR
and
ClT = ClR + Clm1 + Clm2 + ClNR
when a metabolite is excreted
completely into the urine…
Ame
0-∞
m
m
-----------= k----= Cl
----DoseIV
K
ClT
* Amount of metabolite should be
considered on a molar basis or be
corrected for molecular weight.
1-C: Renal and Hepatic Elimination
Metabolite Summary
1-C:
Renal
and
Hepatic
Elimination
Consider Clopidogril
Clopidogril has of an active metabolite
with and known hlf-life of 8 hrs, that is
shorter than the parent compound (24hr+),
the elimination of the metabolite
will be rate limited by the elimination
of the parent compound (if you give the
parent compound, metabolites will appear to
have half-lives which are NEVER
shorter than the parent compound
... but if you give the metabolite IV
you see its actual half-life – 8 hr).
This will explain the CPS's discussion of
half-life vs. pharmacologic half-life
... and so steady state is determined by
the slowest exponential in the mix ... the half life of clopidogrel.