Back to the Top
Hi,
If we reduce the clearance of a compound by using the ABT, invivo, does it have any impact on volume of distribution of that compound?
(Literature says that Clearance and Vd are independent parameters. But when we alter the Clearance, the increased blood exposure, have any impact on Vd???)
Regards,
Vijender
Back to the Top
The following message was posted to: PharmPK
Dear Vijender,
If We alter the clearance it will give high exposure as well high Vd and long half life.
Regards
Suresh
Back to the Top
The following message was posted to: PharmPK
Hello, I am very sorry but a Volume of distribution is not linked to a Clearance. The alteration of clearance is not correlated with a modification of the volume. On the contrary, a reduction of clearance, associated with no change in the volume of distribution, will lead to a longer half-life.
Best regards
Back to the Top
Dear Vijender,
Changes in Cl will also affect the other parameter and volume of distribution (Cl = KVd).
Dr Zafar
Back to the Top
Dear Prof Zafar,
I am not sure I agree, and this issue has been discussed here before. While they do share some physiological/biochemical/phyiocochemical determinants, Clearance and Volume of distribution are independent parameters. A change in CL does not cause a change in Vd. However, the change in CL is due to changes in the factor(s) mentioned above, which may also happen to affect Vd independently. In contrast elimination rate constant is dependent upon CL and Vd: k =CL/Vd, a purely numerical way of thinking.
Regards,
David
Back to the Top
Hi,
I feel that clearance and Vd could be dependent or independent on each other. It will depend on the property of your compound.
If clearance is decreased than if your drug has good tissue penetration than it will have high Vd. But tissue penetration is not good than drug will remain in systemic circulation with high concentration for long time. In either cases the compound could show long half life.
Anasuya Patel
Back to the Top
The following message was posted to: PharmPK
Dear Group
As indicated by Dr. David Foster, even though both clearance (CL) and volume of distribution (Vd) share some physiological parameters and physicochemical properties, they are considered as independent parameters.
In terms of physiology, CL is dependent on hepatic blood flow, fraction of unbound drug, intrinsic capability of hepatic enzymes to metabolize molecule. Hence any change in these parameters may change CL. However the distribution of drugs is independent on their CL. Distribution depends on permeability of molecule to tissues, tissue perfusion, volume of body water etc. Any alterations in these parameters may yield changed Vd. Hence CL and Vd are independent and one might change in absence of change in another.
[Hmm - what about protein binding? Won't that effect both CL and V - db]
However, unlike CL and Vd, elimination rate constant and half-life are not dependent on any physiological process. Indeed, both are dependent on CL and Vd. This is because an increase in CL results in increased elimination rate constant (reduced t1/2). An increase in Vd results in prolonged half-life (reduced k). Hence the correct way of describing relationship between all parameters would be k=CL/Vd and t1/2=(0.693*Vd)/CL.
Please refer the following articles for better understanding about relationship and interdependency among various pharmacokinetic parameters.
1. Reza Mehvar. The Relationship among Pharmacokinetic Parameters: Effects of Altered Kinetics on the Drug Plasma Concentration-Time Profiles. American Journal of Pharmaceutical Education. 68(2): 1-9, 2004.
2. Reza Mehvar. Interdependency of Pharmacokinetic Parameters: A Chicken-And-Egg Problem? Not!. J Pharm Pharmaceut Sci. 9(1): 113-116, 2006
Best Regards
Sivacharan Kollipara
Research Scientist
Metabolism & Pharmacokinetics
Ranbaxy Research Laboratories
India
Back to the Top
Dear David,
Thanks a lot. you are right normally it do not effect the Vd but in kidney failure or severe renal diseases if clearance is effected clearance then what about Vd.
Dr Zafar
Back to the Top
hi
Vd majorly depends on the lipophilicity of compound , if the compound is lipophilic it can penetrate the tissues easily it leads to increases the Vd. Where as hydrophilic compounds will stay in Blood ( Vd is less)
in my view Cl and Vd are independent.If you block the clearance (metabolism), Vd may increase or no change but half life will go longer.
Regards
Ravindra reddy
Back to the Top
The following message was posted to: PharmPK
Dear David and Prof Zafar:
This subject has been discussed ad nauseam in the past. One version
of this discussion is below, after which it subsided until now.
Dear All:
Let us return once again to the question of kel and clearance. I
would like to respond to several recent comments.
It is disappointing to hear some of the discussants trying to "get away from
theoretical arguments and deal with real data". Really now, if we don't have
theory, what do we have, after all? Isn't that what we, as scientists, are
really trying to develop - a firm theory that helps us explain, predict, and
control drug behavior? What about other theories, such as those of quantum
mechanics and Einstein? Once we can construct them, we have a firm
foundation and rationale for our actions. We have had so many words about
this issue that some theory might, after all, be helpful. It was Kurt Lewin,
I think, who said, "there is nothing as practical as a good theory".
Why shouldn't we base our discussion on theoretical arguments?
If we don't do this, what basis do we have for what we actually do, and what
is our scientific rationale for our actions? Let's look at the data, and
the theory, that will help us evaluate the utility of K and Cl. In my view,
K and Cl are both equally useful. The beauty is in the eye of the beholder.
No one is more "biologically relevant" than the other, unless someone thinks
so. Then that is a belief, not a fact.
No one is more "orthogonal" than the other. That depends upon the
particular model parameter values. The correlation between Cl and V simply
depends on the model parameter values one is dealing with. By itself, Cl is
no more orthogonal than K with respect to V.
The result presented, Corr(CL&V)=0 gets one's attention. Is this
real or an accident? Answer - an accident of the values for V, CL and K that
were used. In an earlier discussion, the model used was
ln(y)= ln(1/V) - Kt + noise
Alan Schumitzky says it is straightforward to calculate analytically
the formula for the asymptotic covariance matrix between CL and V. The
off-diagonal term, Corr(CL&V), is exactly
Corr(CL&V)= -((1/4)*V-CL)*V
The stated parameter values were V=1, K=0.25, which implies CL=V*K=0.25 and
Corr(CL=0.25&V=1)=0
But what if K=0.35? Fixing V=1, Alan then shows a short table for CL vs.
Corr (CL&V)
CL Corr(CL&V)
0.0500 -0.2000
0.1500 -0.1000
0.2500 0
0.3500 0.1000
0.4500 0.2000
0.5500 0.3000
0.6500 0.4000
0.7500 0.5000
0.8500 0.6000
0.9500 0.7000
So the correlation between Cl and V simply depends on the model
parameter values one is dealing with. By itself, Cl is no more orthogonal
than K with respect to V.
In addition, it is clear, as described by David Bayard, that "a
fundamental property of the maximum likelihood estimator is the result that
the maximum likelihood estimate of a function of the parameters can be
computed by taking the function of the maximum likelihood estimates of the
parameters. This property is known as the principle of invariance" [1].
Because of this, the MLE estimation of = (K, V) gives exactly the same
result as the MLE estimation of g() = (Cl, V). If you estimate it in
clearance form (Cl,V) and then convert it to elimination form (K,V), you get
the same estimate as if you had originally estimated it in elimination form.
And vice versa.
The examples of losing a kidney or losing 2 legs are interesting
examples. I am not sure what they settle. If you lose 2 legs you lose
volume. Renal perfusion probably stays the same, though. Lose a kidney and
you lose renal elimination - that is intuitive. For a drug eliminated from
the body only by glomerular filtration, for example, then ke is roughly
equivalent to creatinine clearance, as a relatively crude but easily
obtained estimate of GFR. Oral ganciclovir and the aminoglycoside
antibiotics are good examples of this.
In addition, there has been recent discussion about K and T1/2. In
our MM-USCPACK software, we often model ke as the product of knr + ke-slope
times CLCr. Therefore, if you lose a kidney and your CLCr halves (at least
until the other kidney hypertrophies to compensate), then ke will also
halve. By the way, there has been more recent discussion of the
misperception of ke as the percentage of drug eliminated over a period of
time. The precise way to view ke is the instantaneous rate of drug
elimination, i.e. when the slice of time is infinitely small.
Further, from another perspective, if the kidneys are responsible
for getting rid of the drug, then removing one will halve that function, and
will halve the fractional elimination of the drug. Alternatively, since we
have already agreed that CL and k are algebraically related by V, and the
argument has been made that if CL halves, then for a constant V, or for
constant renal perfusion, ke must halve as well.
It was also said that "no one makes any dose adjustments based
on volume of distribution changes". This actually contradicts much clinical
experience with acutely ill and unstable patents who have significant
changes in several parameters, including volume of distribution of the
central compartment, during their therapy. Most fitting methods do not
permit parameter values to change during data analysis. However, Marcus
Haug and Peter Slugg at the Cleveland Clinic in the 1980's fitted individual
clusters of TDM data, and found, for example, significant changes in
gentamicin volume of distribution. They would say that a patient had "VD
collapse", and that this decreasing gentamicin volume of distribution meant
that the patient would get well.
And they were right. This was about the time that it was becoming
known that ICU patients had larger volumes of distribution than general
medical patients. At about the same time we became aware that each patient
would often increase his/her aminoglycoside central compartment VD upon
becoming sicker, and later on decrease it as they recovered, perhaps due to
changes in capillary permeability. Clearly while they were sicker they
needed larger doses to achieve effective serum concentrations, and lower
doses later. So we, and quite a few others, I think, have quite often made
dose adjustments based on volume of distribution. We have even developed an
interacting multiple model (IMM) sequential Bayesian procedure to deal
specifically with this problem [2]. This method tracks the behavior of
gentamicin and vancomycin in post cardiac surgical patients better that any
other method [3]. The method comes from the aerospace community where it is
widely used to track and hit hostile targets trying to take evasive action.
"The half time following multiple dosing is only calculated when
dosing has ended and the kinetics are in the terminal phase". Clearly not
so. Clinically, using target oriented, model based TDM, one computes all
relevant parameter distributions during therapy, and uses that patient's
Bayesian posterior model to develop the next, adjusted, dosage regimen.
About digoxin. We use the equations described by Reuning and his
colleagues back in 1973 [4]. They clearly showed that the inotropic effect
of digoxin correlates not with the serum concentrations, but with
concentrations in the peripheral, nonserum, compartment. We have used his
model to develop a clinical model for the use of digoxin. It has worked very
well for us. You can see relationships between dose, serum concentration,
and clinical effect that you cannot see otherwise. And you can select target
therapeutic goals in either the central, but better in the peripheral
compartment, (especially in acute situations) and develop dosage regimens to
achieve them, not for a steady state, but NOW. You can control patients
clinically in acute situations when the simple raw data of serum
concentrations are not at all helpful. Good models and good software are the
thing. Further, using this model, it is clear that quinidine does not reduce
the clearance of digoxin - it simply reduces the uptake in the peripheral
compartment, raising the serum concentrations, and resulting in a smaller
apparent volume of distribution in the central compartment. If you add up
the total amount in digoxin in the central and peripheral compartments when
a patient is on quinidine in the steady state, and then off quinidine a week
later, there is surprisingly little difference in the total amount of
digoxin in the patient.
We have a number of materials in our web site www.lapk.org that
bear on these subjects. If you like, go there and click around. You can go
to Teaching Topics and to New Advances and download and print a bunch of
stuff.
Best regards to you all,
Roger Jelliffe
Back to the Top
The following message was posted to: PharmPK
That was my point Roger, and I said as much :-)
Regards,
David
Back to the Top
The following message was posted to: PharmPK
Since lipophilic compounds have good tissue penentrability, Vd will be
high for the compound. Does it mean that, all high Vd compounds are
necessarily highly lipophilic?
Regards,
Vinayak
Vinayak Nadiger
Manager, Bioanalytical
Forma Therapeutics(Singapore)
11,Biopolis Way ,Helios # 08-05
[No,specific tissue binding is also important. See http://www.boomer.org/c/p4/c18/c1802.html
- db]
Back to the Top
Dear David,
Thanks a lot
Dr Zafar
--
Dear Roger,
I am grateful for detail reply and points are very clear.
Thanks a lot
Dr Zafar
Back to the Top
Dear All,
Thank you very much for all your replies. Honestly i have gone through PharmPK archive before asking this doubt abt Vd and CL.
If you come from physiological point of view, until we change free fraction either in plasma or tisse, we should not expect a change in Vd. But in a regular PK, we are not measuring free levels either in plasma or tissues (atleast my lab. ofcourse we use fu from ppb).
As a fresher to the field of Pharmcokinetics, I always depend on PK equations to calculate the parameters.
For example, for calculating Volume of distribution we use, Dose/C0 or Dose/k*AUC or CL*MRT .
I thought by using a CYP inhibitor (in this case ABT), we are altering C0/k/AUC by decreasing CL. Hence i thought the value of Volume of distribution may change. (ofcourse MRT and CL has to change in equal propotions to keep the V constant). Ofcourse this is purely mathematical way of looking at.
Other point i felt, if a compound is liphophilic and metabolically unstable, to reach a certian levels in blood and hence penetrate the tissues.
In this case, by using ABT, artificially we are increasing blood levels and giving compound sufficient time to penetrate the tissues and have a certain volume of distribution.
Once again thank you very much for all your time.
Regards,
Vijender
Back to the Top
The following message was posted to: PharmPK
Dear Vijender,
Some physiological conditions may affect both CL and V (e.g. inhibition of UGT for a compound undergoing significant conjugation followed by partial EHC), so that both will be affected despite CL and V are conceptually considered independent. In the case of ABT, if it truly affects only CYP450s one might expect V not to be much affected.
Another issue that may affect the calculation of V is the influence of the data collected (depending on plasma concentrations and bioanalytical method performance) on the determination of the parameters. With a high clearance drug (such as you may have in your discovery programmes) you may not be able to follow the PK for very long, whilst after abolition of CYP450 activity you may define the profile for much longer. This will affect the determination of the elimination constant and hence have a large impact on volume determination (note that AUC and CL calculated as Dose/AUC are not influenced as much because data "lost" under the LLOQ has limited influence on total area). So differences in calculated volumes may not represent real physiological differences but only "mathematical" problems.
Clearly this has little to do with theory and very much with dealing with real data (but isn't it what we have to do most of the time?).
It would be interesting if you shared your experience with this issue, as you have been doing these evaluations.
Do you find changes in V when using ABT for compounds for which CL is significantly affected (or not)?
Are the changes in V with ABT of the same entity for the different formulae you use (Dose/C0 or Dose/k*AUC or CL*MRT)? In general are the V calculated with the different equations consistent or do they give different estimates?
When changes are observed do you have the same tlast, more importantly do you always define a final phase, are the regressions performed on the same time intervals?
Thank you
Regards
Patrice
Back to the Top
The following message was posted to: PharmPK
Dear Roger,
As you might expect, I don't agree with your (repeated) arguments about the question of kel and clearance. As I have explained earlier, the argument of orthogonality is not convincing, since it is a purely mathematical argument.
Again, the fundament of clearance:
"The rate of elimination is driven by the drug concentration; in the case of linear pharmacokinetics the rate of elimination is proportional to drug concentration, and the proportionality constant is clearance."
I cannot find any argument against this fundament in your reasoning.
best regards,
Hans Proost
Johannes H. Proost
Dept. of Pharmacokinetics, Toxicology and Targeting
University Centre for Pharmacy
Antonius Deusinglaan 1
9713 AV Groningen, The Netherlands
--
The following message was posted to: PharmPK
Dear Vijender,
You wrote:
"I thought by using a CYP inhibitor (in this case ABT), we are altering C0/k/AUC by decreasing CL. Hence i thought the value of Volume of distribution may change. (of course MRT and CL has to change in equal propotions to keep the V constant). Of course this is purely mathematical way of looking at."
Vd will not change, since both k and AUC are affected, in opposite direction, by a change in clearance.
best regards,
Hans Proost
Johannes H. Proost
Dept. of Pharmacokinetics, Toxicology and Targeting
University Centre for Pharmacy
Antonius Deusinglaan 1
9713 AV Groningen, The Netherlands
Back to the Top
I agree with David, change in clearance although may not directly impact Vd, there are instances where the physiology may be altered. Let's take an extreme example (may not be realistic, but for logic). Assume a scenario where the subject experiences protein delpletion, thereby increasing the free drug concentrations. In such a scenario, since the free drug is subject to metabolism/clearance, there may be an increase in CL. Simultaneously, reduction in protein binding may also reflect as increase in Vd, not influenced by CL, but due to increase in free drug available for distribution.
Once again consider this as an extreme (unrealistic) example only to understand the concept. Increase in free fraction due to reduced protein binding, may also result in increase CL for drugs that are rapidly cleared, and may not bring out a considerable change in Vd.
Hope this helps to understand the concept and not direcly correlate CL anf Vd,
Regards, Jagannath
Want to post a follow-up message on this topic?
If this link does not work with your browser send a follow-up message to PharmPK@boomer.org with "Volume of Distribution and Clearance" as the subject | Support PharmPK by using the |
Copyright 1995-2011 David W. A. Bourne (david@boomer.org)