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To all members of PharmPK group:
Does anybody know the correct definition of "balanced clearance"? Is
that a commonly used pharmacokinetic term? What are the clinical impacts
of a balanced or non-balanced clearance?
Any comments are wellcome.
Bernhard J. Ladstetter, PhD
Institute of Pharmacokinetics and Metabolism
Merck KGaA, Germany
e-mail: Lstetter.-at-.merck.de
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[A few replies - db]
Date: Fri, 13 Mar 1998 15:38:30 -0500
From: "Vakily, Majid (BIOL;Nutley)"
Subject: RE: PharmPK Balanced Clearance
To: "'PharmPK.aaa.pharm.cpb.uokhsc.edu'"
Mime-Version: 1.0
Is this terms refer to a balance in clearance of drug via various routes
(e.g. renal and hepatic)? This is some thing that I have also recently
heard of but I have no idea about definition of it. By the way, is it
even a correct terminology!?
Majid
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From: Nick Holford
Sender: nhol004.aaa.auckland.ac.nz
Reply-To: n.holford.aaa.auckland.ac.nz
To: PharmPK.aaa.pharm.cpb.uokhsc.edu
Subject: Re: PharmPK Balanced Clearance
Date: Fri, 13 Mar 1998 18:22:39 -0500 (Eastern Standard Time)
Priority: NORMAL
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IMHO the concept of 'balanced clearance' is a fiction invented by marketing
departments. I am of course referring to what I have heard and read about as
'balanced clearance' - what you have in mind may be very different. However,
my impression of the use of the term is in the context of a drug that has
approx equal renal and non-renal clearance. When renal function is seriously
impaired (say to 10% of normal) then overall clearance will decrease by less
than a factor of two (assuming non-renal clearance is unimpaired). To the
marketing pharmacokineticist this seems to mean that the liver is balancing
drug elimination and protecting the patient from decreased renal clearance.
The worst extension of this concept tries to imply that liver clearance
actually increases but this is usually based on a serious misinterpretation
of the fact that the *fraction* of non-renal clearance has increased.
--
Nick Holford, Center for Drug Development Science
Georgetown University, 3900 Reservoir Rd NW, DC 20007-2197
email:n.holford.-a-.auckland.ac.nz tel:(202)687-1618 fax:687-0193
http://www.phm.auckland.ac.nz/Staff/NHolford/nholford.htm
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X-Sender: smelethil.at.cctr.umkc.edu
Date: Fri, 13 Mar 1998 21:58:28 -0600
To: PharmPK.at.pharm.cpb.uokhsc.edu
From: sri melethil
Subject: Re: PharmPK Balanced Clearance
Mime-Version: 1.0
I have not heard the term balanced clearance during the last 20 years or so
of reading PK literature. I can't even think what clearance can be
"balanced" for. I sure would like to know if somebody has a good
speculation on the term "balanced clearance".
Professor of Pharmaceutics and Medicine
School of Pharmacy, University of Missouri-KC
203B Katz HAll
5005 Rockhill Road
Kansas City, Mo 64110 USA
Phone: 816-235-1794 Fax 816-235-5190
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Dear Dr. Ladstetter:
Although I have not encountered the term "balanced clearance" in the
pharmacokinetic literature, the provocative term may have a range of
meanings in theoretical or practical application. It may be instructive to
think for example in relativistic terms of mass balance between precursor
and product, in determining whether clearance is balanced with respect to a
particular chemical entity. A simple hypothetical could involve a pro-drug
to active drug conversion. Assuming quantitative conversion of prodrug to
its active metabolite and approximately equivalent volumes of distribution
the empirically measured plasma concentration-time profiles might be
expected to exhibit classical precursor product relationships such as an
intersection of the two curves at the concentration maximum of the product.
Solution of a two compartment model utilizing concentration time data from
both the pro drug and its active metabolite could show an equivalence
between the clearance rate of the prodrug and the formation rate of the
active. Under such a scenario the clearance of the prodrug could be
presumed to be balanced, as the total mass of drug administered could be
accounted for in product formation.
Now let us assume that the administration of a parent drug results
in the formation of three known metabolites, and that an experiment is
conducted whereby parent drug is administered and concentrations of parent
drug and the three metabolites are empirically determined, as a function of
time. However in this hypothetical traditional compartmental modelling with
first order differential equations indicates that the clearance rate of
parent exceeds the sum total of the individual rates of formation of the
three known metabolites. The clearance of the parent drug is said to be
"unbalanced" because the total mass of drug utilized exceeds the mass of
carbon incorporated into all of its known metabolites. Clearly, there are
an infinite number of explanations for this empirical observation, there are
sampling site issues, and it may even be instructive to remodel using
higher order differential equations if the individual rate parameters are
not additive.
>
In my research experience with the kinetics of intermediary
metabolites I have encountered "unbalanced clearance" of plasma lactate
relative to plasma glucose clearance. In fact in certain animal species the
clearance rate of lactate may be 5 to 10 times greater than the glucose
clearance. This observation cannot be sufficiently reconciled by the
differences in distribution volumes of the metabolites (Vd glucose 20-25%
body weight extracellular water; Vd lactate greater than body weight)
because the empirically determined total body poolsizes of the two
metabolites are roughly equivalent (Mehler, Lactic Acid Metabolism). One
can postulate endogenous or extraneous sources of lactate other than
glucose to account for this mass imbalance, however to my knowledge there is
at present no data to substantiate such a theory.
The term "balanced clearance" then, may be examined in relativistic
terms, to evaluate mass accountability in the conversion of a drug to its
metabolite(s).
Regards,
Howard S Mehler
Howard S Mehler PhD JD & Assoc Inc
6399 Wilshire Blvd Suite 310
Los Angeles, CA 90048
Voice: (310) 271-0755
FAX: (213) 782-9342
e-mail: hmehler.at.mehler.com
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I have not come across this term in pharmacokinetic literature over the
last 20 years or so.
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