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For a drug that is totally cleared by the lung, the maximum clearance
cannot exceed cardiac output. Measurement of pulmonary clearance
would appear to be impossible because it would involve sampling blood
entering and leaving the lung. Measurement of clearance of a
pulmonary cleared drug using systemic blood levels would give a false
answer. Can anyone make a suggestion as to how to get a reasonable
value for clearance for a drug totally eliminated via the lung, and,
in particular, how to compare values in healthy subjects to those with
reduced pulmonary function or reduced cardiac output.
Thank you in advance
Brian
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Reply
You should be able to get a good estimate of pulmonary clearance by
comparing arterial concentrations to concentrations of drug from the
right heart chambers taken at the same time. This essentially
samples blood before and after flow through the lungs. (easier said
than done). There are patients with pulmonary disease/heart
failure/trauma/etc. that will require a swan-ganz catheter and an
arterial line in the same time period. Provided that the drug does
not pose safety concerns in this population, one could administer
the drug and take several measurements for determining lung
clearance. Getting this information form healthy subjects
is another issue. Swan-ganz catheters and arterial lines have been
inserted in volunteer subjects before. However, in my view, their must
be very clear benefits (not just knowing the lung clearance) derived from
such a study to justify the potential risks.
It is true that blood clearance cannot exceed cardiac output provided
that you are measuring whole blood concentrations of drug. If you
are measuring plasma concentrations and the drug is not particioned
into RBC's then plasma clearance should not exceed (1-HCT)*cardiac
output. In limited cases RBC particioning may be high and may
provide apparent cleance values > cardiac output when plasma
concentrations are measured in place of whole blood concentrations.
David Nix
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Thoughts on pulmonary clearance for Brian Davies:
I would have guessed that clearance could not exceed cardiac output
multiplied by (1-F), where F is the hematocrit fraction, unless the drug
distributes into the erythrocytes.
Could you measure the drug or its metabolites in expired air? Or perhaps
you could label the drug with tritium and measure expired radioactivity.
Another possibility might be to measure the rate constant for
disappearance from systemic blood. Since the rate constant is the flux
normalized to a unit of drug mass and the clearance is the flux
normalized to a unit concentration, both contain the vital information.
Under the assumption that the drug is cleared entirely by the lung, the
rate constant will provide a measure of pulmonary clearance that can be
compared in healthy subjects and in patients with cardiopulmonary
insufficiency.
Hoping for feedback...
Regards,
Bob
--
Robert D. Phair, Ph.D. rphair.at.ix.netcom.com
BioInformatics Services http://www.webcom.com/rphair
Partnering and Outsourcing for Computational Biology
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Dear Dr. Davies:
This is one of the many situations where NONINVASIVE measurerements are
uniquely indicated. Does the drug(s) you want to measure have either a nuclide
that can be uniquely detected by NMRS, or is the chemical shift of the
intrinsic 1H atoms in a region of the spectrum where they can be resolved
from the miriad of other 1H-containing compounds present? If so, NMRS might be
uniquely suitable. If not, can you radiolabel the compound with a gamma
emitter to perform nuclear medicine measurements?
I will be glad to expand on this if you wish.
=========================================================================| Professor Walter Wolf, Ph.D. E-Mail: wwolfw.aaa.hsc.usc.edu |
| Director, Pharmacokinetic Imaging Program |
| Department of Pharmaceutical Sciences Telephone: 213-342-1405 |
| University of Southern California Fax: 213-342-9804 |
| 1985 Zonal Ave., Los Angeles, CA 90033 |
| |
| Center for Noninvasive Pharmacology, Los Angeles Oncologic Institute |
| MRI at St. Vincent Medical Center Telephone: 213-484-7235 |
| 2131 Third St., Los Angeles, CA 90057 Fax: 213-484-7447 |
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Date: Mon, 7 Apr 1997 22:02:27 -0600
From: DuncanMFE.-a-.aol.com
Subject: Pulmonary clearance
In response to Brain Davies' query about pulmonary clearance.
Clearance could in principle be defined in relation to a concentration
anywhere in the body, but the result is often not a time-invariant
dose-independent constant unless a suitable site is chosen (and indeed can be
poorly defined for concentrations close to zero when elimination is still
occurring). Usually the blood concentration entering an organ is
physiologically useful, and it is clearance based on is this value which is
limited by and normally compared with blood flows. I presume your problem
with pulmonary clearance arises because a peripheral sampled blood
concentration is likely to represent the exit rather than entry concentration
for the lung (but entry concentration for the liver and kidney). However
whilst clearances of the parallel kidney/liver circuits are additive, the
series component of the lung is not exactly additive without a weighting
factor (approximate additivity is obtained for only low clearance drugs:
Cutler, J. Pharmacokinet.&Biopharm 7,101 (1979)). It is possible to define a
total clearance which weights all contributions in a self-consistent way:
recirculatory theories (see for example Weiss&Forster, Eur J Clin Pharmacol 16
287(1979), or Collins&Dedrick J Pharm Sci 71 66 (1982)) usually refer all
elimination clearances to the concentration entering the heart or lung.
Entry concentrations to the lung can be measured by invasive pulmonary artery
probe methods in animals, or less efficiently at the heart entry via the
jugular vein; I would hope that sooner or later non-invasive imaging methods
manage to do this more routinely in man (anybody know of studies published
already?). If your drug is stable in blood and your admin is venous iv, then
you can calculate the concentration going into the lung by mass balance from
the infusion rate and the cardiac output. Noninvasive cardiac output (Q)
measures exist (eg impedance cardiography) although I cannot vouch for their
accuracy.
For a venous infusion, if your steady state exit concentration from the lung
is exactly zero and the drug is stable in blood, then the pulmonary blood
clearance based on entry concentration will be equal to the cardiac output.
More generally the pulmonary clearance CLpul will be given by CLpul=Q.Epul
where Epul the pulmonary extraction ratio is given by
Epul=1-(Css,out/Css,in). The utility of this depends somewhat on the
sensitivity of your assay.
Hope this helps
Duncan Edwards
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PS on my previous comment to Brian Davies about using infusion rate and Q for
lung entry concentration. A simple Rate/Q mass balance would of course only
apply, at steady state, for highly extracted drugs where the recirculatory
component was negligible vs input.
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I hope this discussion is not going to be a monlogue (maybe 'cause its
Saturday) but as I read your query again I realise that are several ways to
take and answer your question. So one more comment and then I'll shut up and
let somebody else add or correct.
If you are interested in drugs which you know are cleared by the lung but no
other organ, and not necessarily in one passage, and the drugs are not too
volatile for iv studies, then I think the steady state lung input blood
concentration can be calculated by mass balance for pulmonary input with
intravenous infusion including the recirculated portion as
Css,in = Infusionrate/Q+Css,peripheral
and
Css,out=Css,peripheral
Over and out.
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Dear Brian,
If you are sure the drug you've mentioned is eliminated exclusively
via the lung, the total clearance after IV administration you estimate
as Div/AUCiv will just give you the pulmonary clearance. If not, you
need additional experiments with IV dosing and arterial blood sampling
or intra-arterial dosing and venous sampling. The following
references, perhaps, will help you:
Hayashi, Y.; Sumikawa, K.; Yamatodani, A.; Kamibayashi, T.; Mammoto,
T., and Kuro, M. Quantitative analysis of pulmonary clearance of
exogenous dopamine after cardiopulmonary bypass in humans. Anesthesia
and Analgesia. 1993; 76(1):107-112.
Mehvar, R. Relationship of Apparent Systemic Clearance to Individual
Organ Clearances - Effect of Pulmonary Clearance and Site of Drug
Administration and Measurement. Pharmaceut Res. 1991; 8(3):306-312.
Vladimir
--------
Vladimir Piotrovsky, Ph.D. Fax: +32-14-605834
Janssen Research Foundation Email: vpiotrov.at.janbe.jnj.com
Clinical Pharmacokinetics vpiotrov.-a-.janbelc1.ssw.jnj.com
B-2340 Beerse
Belgium
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One suggestion that come to mind is use an isotope (radio- or stable-)
and have the patient exhale into a sampling bag. Then analize the
isotope in the bag via Mass-Spectroscopy.
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From: NAME: SWANG
To: SMTP%"PharmPK.at.pharm.cpb.uokhsc.edu".-a-.HERLVX.-at-.MRGATE.-at-.HERLVX
I agree Edwards's comments. Using recirculatory theory already shown the
relationship between total body clearance and tissue clearance, which is
for tissues paralell connected, the contribution of tissue clearance to
total body clearance is additive, however, to lung which is seriesly
connected with all the other tissues, it is not additive (need a correcting
factor). The published results using recirculatory theory deals with a
linear system. Our results obtained for both linear and nonlinear systems
show that this is true no matter the system is linear or nonlinear.
For nonsteady state case, using mean clearance and mean extraction ratio,
similar results can be obtained about clearance and blood flow rate.
xioafneg Wang
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Copyright 1995-2010 David W. A. Bourne (david@boomer.org)