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Hello,
Is there somebody who can explain an amateur in the field the importance of
hepatic extraction ratio (E) for new interaction steady state
concentrations? What is the predictive value of an extraction ratio figure
for the magnitude of pharmacokinetic effects?
Kind regards
Erik F.O. Pomp
tel. +47 55 97 53 61
fax. +47 55 29 07 18
<<...>>
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[A few replies - db]
Date: Wed, 8 Sep 1999 08:26:00 +0100
From: cawello.at.schwarzpharma.com
Sender: cawello.-at-.schwarzpharma.com
Reply-To:
Organization: Schwarz Pharma Group
To: efpo.-at-.haukeland.no (Multiple recipients of PharmPK - Sent by),
PharmPK.-at-.boomer.org
Subject: re: PharmPK
Importance: Normal
X-SMF-Hop-Count: 1
Form: Reply
Text: (49 lines follow)
Dear Erik,
The extraction (elimination) of a drug from the central compartment (blood)
by an eliminating organ (liver, kidney, lung) may be considered from the
fundamental concepts of mass balance, the rate of drug entry and the rate of
drug leaving. Steady-state conditions are assumed in this model i.e. drug in
the eliminating organ is assumed to have reached distribution equilibrium;
the sole reason, therefore, for any difference between the arterial and
venous concentrations is elimination. For the major eliminating organs liver
and kidney this situation will usually be reached very rapidly after
intravenous administration owing to high blood flow through these organs.
The rate of drug entry into an organ of elimination is the product of blood
flow, Q, and concentration in blood entering on the arterial side, CA.
Correspondingly, the rate at which a drug leaves on the venous side is Q *
CV, where CV is the concentration in the returning venous blood. The rate of
extraction (elimination of the drug by the eliminating organ) is calculated
by multiplying the blood flow and the extracted portion of dose (=
difference in rates of drug entry and leaving).
If the rate of drug extraction is compared to the rate of drug entry, the
extraction ratio E is obtained; this is an important parameter for
calculating the clearance: E = (CA-CV)/CA
E can have any value between the limits of 0 and 1 indicating that the drug
is either not at all or completely extracted, respectively.
Hepatic extraction can be reduced or increased by effects on the drug
metabolising enzymes (e.g. cytochrome P450 inhibition or induction), which
strongly influences the hepatic clearance of low extraction ratio drugs.
Hepatic elimination may be limited if two or more drugs (co-medication)
compete with the same enzyme capacity or if this capacity is saturated
because of a high dosage. Such a dose dependent metabolism during the first
liver passage (first pass effect) has been reported for several drugs such
as propranolol, metoprolol, lorcainide and phenytoin.
An increase of the intrinsic clearance (e.g. by enzyme induction during a
drug interaction study) will effect in an increase of E (and
bioavailability) of the target drug. For inhibition of enzymes (e.g. during
a drug interaction study) E (and the bioavailability) will decrease.
For more detail see chapter 6 of my new text book 'Parameters for
Compartment-free Pharmacokinetics' (Shaker Verlag 1999, ISBN 3-8265-4767-5).
******************************************
Willi Cawello, PhD
Schwarz Pharma AG
Humanpharmacology
Alfred-Nobel-Str.
D40770 Monheim, Germany
cawello.-a-.schwarzpharma.com
******************************************
---
From: Erik Fred Oscar Pomp
To: PharmPK.aaa.pharm.cpb.uokhsc.edu
Subject: CYP450 interactions and hepatic extraction ratio 2 (More spesific
)
Date: Wed, 8 Sep 1999 11:25:03 +0200
Hello
Referring to my earlier mail "CYP450 interactions and hepatic extraction
ratio".
As changes in liver enzyme activity will influence both clearance and
bioavailability I do not readily understand that inhibition and induction
effects are most important for low extraction drugs. I suppose a decrease in
E normally leads to a rise in F (bioavailability)as F(max)=1-E. I tried to
show the that changes in Css are bigger for low extraction drugs by using
the formulas Css=(F*D)/(Cl*tau)and F=1-E. But I am either stupid or using
the wrong formulas, or more likely a combination of both. Please enlighten
my spirit.
Kind regards
Erik F.O. Pomp
tel. +47 55 97 53 61
fax. +47 55 29 07 18
---
Date: Wed, 8 Sep 1999 03:31:03 -0700 (MST)
X-Sender: ml11439.-at-.pop.goodnet.com
To: PharmPK.-at-.boomer.org
From: ml11439.-a-.goodnet.com (Michael J. Leibold)
Subject: Re: PharmPK CYP450 interactions and hepatic extraction ratio
Hello Erik,
According to a rather complex derivation in Gibaldi and Perrier's
Pharmacokinetics, the clearance of a drug can be modeled physiologically as:
CL= Q[CLi/(Q + CLi)]= Q x ER
CL= systemic clearance
Q= hepatic blood flow
CLi= intrinsic clearance (metabolic capacity)
ER= hepatic extraction ratio
That is, the clearance of a drug is equal to the product of hepatic
blood flow and hepatic extraction ratio. The hepatic extraction ratio is
equal to the intrinsic clearance (i.e. hepatic metabolic capacity or Vmax)
divided by hepatic blood flow plus intrinsic clearance.
Thus, the "systemic clearance" of a drug eliminated solely by the
liver is dependent on the relationship between hepatic blood flow and the
intrinsic ability of the liver to metabolize the drug. Many drugs have low
intrinsic clearances and the above equation in these cases reduces to:
CL~= CLi since Q>>>CLi
Drugs with low intrinsic clearances are very susceptible to
interactions involving the cytochrome p450 isoenzymes, since their
systemic clearance is very dependent, or identical to their intrinsic
hepatic clearance (CLi). Thus, warfarin, anticonvulsants and hypoglycemic
agents are susceptible to enzyme inducer or inhibitor interactions since
their intrinsic clearance and systemic clearance are simultaneously affected.
In contrast, drugs with very high intrinsic clearances which exceed
liver blood flow, have sytemic clearances which are equivalent to hepatic
blood flow:
CL~= Q since Cli>>Q
Drugs with hepatic flow-dependent metabolism such as propranolol or
lidocaine exhibit systemic clearance which is dependent on factors affecting
liver blood flow, and which is relatively independent of factors affecting
drug metabolic capacity (such as metabolic inhibitors or inducers).
Drugs with intrinsic clearances between these two extremes would
have hepatic extraction ratios which are low or high, corresponding to
low or high intrinsic clearances. Obviously, according to the above
equation, a drug with a low intrinsic clearance would have a low ER since
the denominator would be dominated by the Q factor. The low ER would
reduce the influence of hepatic blood flow on systemic drug clearance.
Thus, a drug with a low extraction ratio would have a relatively low
intrinsic clearance and would exhibit systemic clearance which is
relatively more susceptible to metabolic inducer/inhibitor interactions.
The opposite is expected of a drug with a high extraction ratio, or
high intrinsic clearance. In the later case, the intrinsic clearance
is so high that systemic clearance is more affected by factors influencing
liver blood flow.
I hope this was of some help!!
Mike Leibold, PharmD, RPh
ML11439.aaa.goodnet.com
---
Date: Wed, 8 Sep 1999 14:33:00 +0100
From: cawello.-a-.schwarzpharma.com
Sender: cawello.at.schwarzpharma.com
Reply-To:
Organization: Schwarz Pharma Group
To: efpo.-at-.haukeland.no (Multiple recipients of PharmPK - Sent by),
PharmPK.aaa.boomer.org
Subject: re: PharmPK CYP450 interactions and hepatic extraction ratio
Importance: Normal
X-SMF-Hop-Count: 1
Form: Reply
Text: (24 lines follow)
Dear PharmPK member,
Erik made a point to my answer about the connection of bioavailability and
extraction ratio E. He is right and I am sorry for a little confusing?
Because of f=1-E an increase of E will result in a decrease of f... A
decrease of E will result in an increase of f....
Please find this examples for drugs with high or low extraction ratio:
high extraction ratio drug low extraction ratio drug
CLint 13.5 l/min -> 27.0 l/min 0.167 l/min -> 0.334 l/min
EH 0.90 -> 0.95
0.10 ->0.18
f 10% -> 5%
90% -> 82%
CL 1.35 l/min ->1.42 l/min 0.15 l/min -> 0.273 l/min
Tab. : Influence of doubling the intrinsic clearance Clint (e.g. by enzyme
induction) on bioavailability and total clearance of hepatically eliminated
drugs (QH = 1.5 l/min). For inhibition of enzymes arrows have to be reversed
(taken from Klotz U., Klinische Pharmakokinetik, G. Fischer, Stuttgart, 2nd
Edition 1984).
Best Regards,
Willi Cawello
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[Two replies - db]
From: Erik Fred Oscar Pomp
To: PharmPK.at.boomer.org
Subject: SV: PharmPK Re CYP450 interactions and hepatic extraction ratio
Date: Thu, 9 Sep 1999 10:54:18 +0200
Hello,
If I put these values (see examples from Willi Cawello for high and low
extraction drugs) into the formula relative Css changes are about the same
for both drugs. I am tempted to conclude that induction/inhibition
interactions lead to bigger differences in hepatic clearance for low
extraction drugs which is being made up for by the changes in
bioavailability. Which means clinically for orally administrated drugs that
hepatic extraction ratio would be of very limited value, if any, when
predicting changes in Css caused by induction/inhibition interactions.
As we all know clinically relevant interactions with orally administrated
drugs do happen. So something in this argumentation must be wrong. I suggest
a pharmaceutical explanation. When F<1-E or F<<<1-E because of
pharmaceutical reasons changes in F may be far less than anticipated from
changes in intrinsic clearance, which leads to clearance changes which
outweigh bioavailability changes. How much truth is there in the claim that
enzyme inhibition and induction mostly affects low extraction drugs??
Thank you all for being so helpful.
Erik F.O. Pomp
tel. +47 55 97 53 61
fax. +47 55 29 07 18
---
Date: Thu, 9 Sep 1999 03:14:32 -0700 (MST)
X-Sender: ml11439.-at-.pop.goodnet.com
To: PharmPK.-at-.boomer.org
From: ml11439.aaa.goodnet.com (Michael J. Leibold)
Subject: Re: PharmPK Re CYP450 interactions and hepatic extraction ratio
Hello Erik,
As I understand it, the major concept involving low extraction and
high extraction ratio drugs, and the susceptiblity to drug interactions, is
the concept of systemic clearance versus intrinsic clearance.
In the following steady state equation:
Css= FD/[CL*Tau*Vd]
The CL term represents systemic clearance and not intrinsic hepatic
clearance for drugs with high hepatic extraction ratios. The systemic CL is
relatively unaffected by inhibitors of CYP450 isoenzymes, as the intrinsic
CLi is so high. Hence, when exposed to inhibitors/inducers of CYP450
isoenzymes,
the Css is relatively unaffected as the systemic Cl is not affected.
In the case of drugs with low hepatic extraction ratios, the above equation
can be written as:
Css=FD/[CLi*Tau*Vd] ~= FD/[CL*Tau*Vd]
That is, the systemic clearance is approximately equal to the intrinsic
clearance, and the drugs steady state concentrations will be influenced by
inhibitors/inducers of CYP450 isoenzyme capacity. This is since the CYP450
isoenzyme capacity is equivalent to intrinsic clearance. Thus, an inhibitor
will increase Css as the CLi is reduced, and an inducer will reduce Css as
CLi is increased.
As F= 1-E (*assuming absorption is complete and F reflects first-pass
metabolism*), the F factor should always be high with low extraction drugs.
However, as the Cli is reduced or increased, so will the ER be reduced or
increased. As a result, the value of F will tend to increase Css as the CLi
is decreased, and tend to decrease Css as the CLi is increased. However, the
effect of F on Css should be less than that of CLi, since the F value should
remain high in the case of low extraction drugs.
I hope this clarifies things!
Mike Leibold, PharmD, RPh
ML11439.-at-.goodnet.com
---
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[Two replies - db]
Date: Fri, 10 Sep 1999 19:28:27 -0700 (MST)
X-Sender: ml11439.-a-.pop.goodnet.com
To: PharmPK.-at-.boomer.org
From: ml11439.aaa.goodnet.com (Michael J. Leibold)
Subject: Re: PharmPK Re CYP450 interactions and hepatic extraction ratio
Hello Erik,
Since I wrote some equations in error, I felt like making some
special effort and make a corrected version. In reality, I thought
I was familiar with the concept and the derivation of the Cl= Q*ER
equation, and the numerous drug interactions involving CYP450
isoenzymes. Beyond this, I have no other special expertise.
Here is a corrected composite of the three emails I wrote:
As I understand it, the major concept involving low extraction and
high extraction ratio drugs, and the susceptiblity to drug interactions, is
the concept of systemic clearance versus intrinsic clearance.
In the following steady state equation:
Css= FD/[CL*Tau]
The CL term represents systemic clearance and not intrinsic hepatic
clearance for drugs with high hepatic extraction ratios. The systemic CL is
relatively unaffected by inhibitors of CYP450 isoenzymes, as the intrinsic
CLi is so high. Hence, when exposed to inhibitors/inducers of CYP450
isoenzymes,
the Css is relatively unaffected as the systemic Cl is not affected.
In the case of drugs with low hepatic extraction ratios, the above equation
can be written as:
Css=FD/[CLi*Tau] ~= FD/[CL*Tau]
That is, the systemic clearance is approximately equal to the intrinsic
clearance, and the drugs steady state concentrations will be influenced by
inhibitors/inducers of CYP450 isoenzyme capacity. This is since the CYP450
isoenzyme capacity is equivalent to intrinsic clearance. Thus, an inhibitor
will increase Css as the CLi is reduced, and an inducer will reduce Css as
CLi is increased.
As F= 1-E (*assuming absorption is complete and F reflects first-pass
metabolism*), the F factor should always be high with low extraction drugs.
However, as the Cli is reduced or increased, so will the ER be reduced or
increased. As a result, the value of F will tend to increase Css as the CLi
is decreased, and tend to decrease Css as the CLi is increased. However, the
effect of F on Css should be less than that of CLi, since the F value should
remain high in the case of low extraction drugs.
In the equations that I emailed you regarding intrinsic clearance
and systemic clearance, the equations for Css should read as follows:
Css= FD/[CL*Tau]
Css=FD/[CLi*Tau] ~= FD/[CL*Tau]
There is tendency to type these equations with Vd like the form:
Css= FD/[Ke*Vd*Tau]
[This was the etiology of my pharmacokinetic typos.]
Again, the point I was making is that there is really not a change
in the F for low extraction drugs involved in inhibition/induction
interactions with the CYP450 isoenzymes. There is however, changes in
intrinsic clearance and sytemic clearance, which are essentially
equivalent for low extraction drugs. So, changes in Css will occur
without changes in F, since clearance is affected without significant
changes in F in accord with the following equation:
CL= Q[CLi/(Q + CLi)]= Q x ER ~= CLi for low extraction drugs
CL= systemic clearance
Q= hepatic blood flow
CLi= intrinsic clearance (metabolic capacity)
ER= hepatic extraction ratio
That is, Cli is so much smaller than Q that there would be
no effect on F, but significant changes in systemic clearance
and Css. So, changes in F should not enter into you calculations
of Css.
Warfarin example:
57 year old male 6'1" 145 kg
Dose= 5mg/day
F=1~=.999
CL= CLi= .1045824 L/hr
Css= FD/Cl*Tau= 5mg/(.10495824 L/hr)(24hrs)= 1.9849 mg/l
Upon exposure to metabolic inhibitor, CL= CLi= .06292045 L/hr
Css= FD/CL*Tau= 5mg/(.06292045 L/hr)(24hrs)= 3.311059 mg/l
So, using average pharmacokinetic parameters obtained from the
warfarin literature of Dr.Mungall, the Css increases from 1.98 mg/l
to 3.32 mg/l when warfarin metabolism is exposed to a metabolic
inhibitor such as septra, metronidazole or amiodarone. Needless to
say, this also has an effect of increasing the prothrombin time.
However, the clearance value of .063-.105 L/hr is infinitesimal
relative to the values of Q in the area of 90 L/hr, and F
remains relatively unaffected by this drug interaction.
ER= CLi/[Q+CLi]= .063-.105 l/hr/[90L/h +(.063-.105 L/hr)]
= .0006995- .00116531
F= 1-ER= .9993005- .99883469
So, a 60% decrease in intrinsic and systemic clearance results
in a 67% increase in Css, but only a .05% increase in F.
Summary:
Actually, all of the above resulted from my examination of the CL=Q*ER
and my familiarity with the concept of drug interactions with low extraction
drugs. Evidently, I became interested in the problem as began to answer your
question, and learned a few things myself.
In summary, the clearance of a drug is equal to the product of hepatic
blood flow and hepatic extraction ratio. The hepatic extraction ratio is
equal to the intrinsic clearance (i.e. hepatic metabolic capacity or Vmax)
divided by hepatic blood flow plus intrinsic clearance.
Thus, the "systemic clearance" of a drug eliminated solely by the
liver is dependent on the relationship between hepatic blood flow and the
intrinsic ability of the liver to metabolize the drug. Many drugs have low
intrinsic clearances and the above equation in these cases reduces to:
CL~= CLi since Q>>>CLi
Drugs with low intrinsic clearances are very susceptible to
interactions involving the cytochrome p450 isoenzymes, since their
systemic clearance is very dependent, or identical to their intrinsic
hepatic clearance (CLi). Thus, warfarin, anticonvulsants and hypoglycemic
agents are susceptible to enzyme inducer or inhibitor interactions since
their intrinsic clearance and systemic clearance are simultaneously affected.
In contrast, drugs with very high intrinsic clearances which exceed
liver blood flow, have sytemic clearances which are equivalent to hepatic
blood flow:
CL~= Q since Cli>>Q
Drugs with hepatic flow-dependent metabolism such as propranolol or
lidocaine exhibit systemic clearance which is dependent on factors affecting
liver blood flow, and which is relatively independent of factors affecting
drug metabolic capacity (such as metabolic inhibitors or inducers).
Drugs with intrinsic clearances between these two extremes would
have hepatic extraction ratios which are low or high, corresponding to
low or high intrinsic clearances. Obviously, according to the above
equation, a drug with a low intrinsic clearance would have a low ER since
the denominator would be dominated by the Q factor. The low ER would
reduce the influence of hepatic blood flow on systemic drug clearance.
Thus, a drug with a low extraction ratio would have a relatively low
intrinsic clearance and would exhibit systemic clearance which is
relatively more susceptible to metabolic inducer/inhibitor interactions.
The opposite is expected of a drug with a high extraction ratio, or
high intrinsic clearance. In the later case, the intrinsic clearance
is so high that systemic clearance is more affected by factors influencing
liver blood flow.
I hope this was of some help!!
Mike Leibold, PharmD, RPh
ML11439.-a-.goodnet.com
---
From: "Hans Proost"
Organization: Pharmacy Dept Groningen University
To: PharmPK.at.boomer.org
Date: Fri, 10 Sep 1999 15:04:11 MET
Subject: Re CYP450 interactions and hepatic extraction ratio
X-Confirm-Reading-To: "Hans Proost"
X-pmrqc: 1
Priority: normal
Dear Colleagues,
With respect to the question of Erik Pomp on enzyme activity,
extraction ratio and bioavailability, the situation may be clarified by
the following:
From the basis equation during steady state, input = output, it
follows that the relationship between dosing rate and Css is
dependent on the ratio CL / F:
Dose / tau = CL / F * Css
This ratio CL /F is proportional to the intrinsic clearance (CLint),
and thus to the metabolic capacity, IRRESPECTIVE OF THE
HEPATIC EXTRACTION RATIO.
This can be checked easily from the numerical examples given by
Willi Cawello, or by combining the equation for the hepatic clearance,
liver blood flow and intrinsic clearance given by Mike Leibold (note that
the fraction unbound should be added to the equation, but that
does not matter for the present discussion), and the equation
F = 1 - EH.
Best regards,
Johannes H. Proost
Dept. of Pharmacokinetics and Drug Delivery
University Centre for Pharmacy
Groningen, The Netherlands
tel. 31-50 363 3292
fax 31-50 363 3247
Email: j.h.proost.at.farm.rug.nl
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