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Hi all,
I am seeking a reference (unable to find one) on determination of renal
clearance. The study involved a continuous 3-day i.v. infusion of
indomethacin in chronically instrumented fetal lambs and urine samples
collected twice daily during the steady state period. Cumulative amounts
of drug excreted could not be calculated since urine samples were only
collected over a half- to one hour period at each blood sampling
interval. Renal clearance was estimated by plotting the average urinary
excretion rate versus drug concentration and fitting the least squares
straight line forced through the origin. The slope of this line provided
the CLr in ml/min. Though I understand this method of calculating Clr is
applicable in i.v. bolus studies, I am unable to obtain a literature
reference citing such an application for i.v. infusion studies (steady
state). If somebody can provide me with the reference/suggestions etc it
would be great!
Raj Krishna
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> Renal clearance was estimated by plotting the average urinary
> excretion rate versus drug concentration and fitting the least squares
> straight line forced through the origin. The slope of this line provided
> the CLr in ml/min.
This method is just fine irrespective of the rate or route of
administration.
> Though I understand this method of calculating Clr is
> applicable in i.v. bolus studies, I am unable to obtain a literature
> reference citing such an application for i.v. infusion studies (steady
> state). If somebody can provide me with the reference/suggestions etc it
> would be great!
Any (competent) textbook of PK will confirm that clearance can be
determined from rate of excretion and plasma conc. But really I cant see
that you need a reference for such an obvious method. If a journal
referee asks for a reference you should tell the journal editor that
that the referee is either incompetent or a trivial nit-picker :-)
So my suggestion to not to worry - you dont have a problem.
--
Nick Holford, Dept Pharmacology & Clinical Pharmacology
University of Auckland, Private Bag 92019, Auckland, New Zealand
email:n.holford.-at-.auckland.ac.nz tel:+64(9)373-7599x6730 fax:373-7556
http://www.phm.auckland.ac.nz/Staff/NHolford/nholford.html
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At 06:29 PM 12/8/96 -0600, you wrote:
>PharmPK - Discussions about Pharmacokinetics
> Pharmacodynamics and related topics
>Hi all,
>
>I am seeking a reference (unable to find one) on determination of renal
>clearance. The study involved a continuous 3-day i.v. infusion of
>indomethacin in chronically instrumented fetal lambs and urine samples
>collected twice daily during the steady state period. Cumulative amounts
>of drug excreted could not be calculated since urine samples were only
>collected over a half- to one hour period at each blood sampling
>interval. Renal clearance was estimated by plotting the average urinary
>excretion rate versus drug concentration and fitting the least squares
>straight line forced through the origin. The slope of this line provided
>the CLr in ml/min. Though I understand this method of calculating Clr is
>applicable in i.v. bolus studies, I am unable to obtain a literature
>reference citing such an application for i.v. infusion studies (steady
>state). If somebody can provide me with the reference/suggestions etc it
>would be great!
>
>Raj Krishna
Dear Raj:
Assuming that you are able to accurately measure the rate of urinary
elimination, your approach for estimating renal clearance is ideal. You are
essentially using the most basic of clearance definitions: CL = elimination
velocity/substrate concentration. The largest difficulty with this
calculation lies in uncertainty in the concentration of drug in blood (Cb)
in conditions where Cb is changing rapidly (i.e. after an iv bolus).
Application of this approach under steady-state conditions (as you have
done) should increase your confidence in the estimation of renal clearance.
A good renal clearance reference is given in:
Tucker GT, Measurement of the renal clearance of drugs. British Journal of
Clinical Pharmacology 12(6): 761-70, 1981.
- Joe Balthasar
SUNY at Buffalo
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Raj,
Clearance = excretion rate / plasma conc.
Thus, to calculate renal plasma clearance of a subatance z, you need to:
1- Attain a steady-state plasma concentration (mass/unit volume) of z. You
sound like you have that.
2- Determine the urinary excretion rate (mass / unit time) during the
steady-state above.
To do that you need an accurately timed urine collection; this can be
obtained by collecting urine over a period of one hr. The animal should be
well hydrated to establish a good urine flow rate. Of course you also need
to determine the volume of urine collected and urinary concentration of z to
calculate the excretion rate of z.
Note: If the urine flow is low, use longer collection intervals and make
sure to rinse the bladder and add the rinse to the collected urine to ensure
complete recovery of all the mass of z excreted. The additional rinse water
has no negative effect on the results (the important issue is to recover the
mass of z excreted during the collection interval; the true urine flow rate
is not essential).
Let me know if I can of further help.
Dr. Anaizi, PhD RPh
Assoc Prof of Pharmacol and Physiol
Univ of Rochester Med Cntr
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>
> Clearance = excretion rate / plasma conc.
> Thus, to calculate renal plasma clearance of a subatance z, you need to:
> 1- Attain a steady-state plasma concentration (mass/unit volume) of z. You
> sound like you have that.
The definition of clearance holds true at all times. There is no need to
be at steady state. The key is to use a conc that reflects the average
conc during the urine collection interval. With a constant rate input
(e.g. IV infusion) that reaches steady state then a single conc at any
time during the urine collection is just fine. Much more commonly,
however, steady state or not, concs will be varying during the urine
collection. A conc at the mid-point of the collection may be a
reasonable value to use. You should at least think about the expected
plasma conc profile during the collection interval before deciding on
the time(s) to sample plasma concs.
> To do that you need an accurately timed urine collection; this can be
> obtained by collecting urine over a period of one hr. The animal should be
> well hydrated to establish a good urine flow rate.
Note that hydrating to encourage high urine flow may change the urine
clearance from the more typical value representative of a normally
hydrated animal.
--
Nick Holford, Dept Pharmacology & Clinical Pharmacology
University of Auckland, Private Bag 92019, Auckland, New Zealand
email:n.holford.at.auckland.ac.nz tel:+64(9)373-7599x6730 fax:373-7556
http://www.phm.auckland.ac.nz/Staff/NHolford/nholford.html
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>
> > To do that you need an accurately timed urine collection; this can be
> > obtained by collecting urine over a period of one hr. The animal
>should be
> > well hydrated to establish a good urine flow rate.
> Note that hydrating to encourage high urine flow may change the urine
> clearance from the more typical value representative of a normally
> hydrated animal.
Not only does it change the urine clearance, it will I presume add on to
the difficulties of drugs that alter the urinary output by a
pharmacological mechanism (for instance, indomethacin reduces
significantly the urinary output; hence its applicability in conditions
such as polyhydramnios).
Raj
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At 10:58 AM 12/19/96 -0600, you wrote:
>PharmPK - Discussions about Pharmacokinetics
> Pharmacodynamics and related topics
>
>>
>> > To do that you need an accurately timed urine collection; this can be
>> > obtained by collecting urine over a period of one hr. The animal
>>should be
>> > well hydrated to establish a good urine flow rate.
>> Note that hydrating to encourage high urine flow may change the urine
>> clearance from the more typical value representative of a normally
>> hydrated animal.
>
>Not only does it change the urine clearance, it will I presume add on to
>the difficulties of drugs that alter the urinary output by a
>pharmacological mechanism (for instance, indomethacin reduces
>significantly the urinary output; hence its applicability in conditions
>such as polyhydramnios).
>
>Raj
>
>Also see: http://www.cpb.uokhsc.edu/pkin/pkin.html
I am suprised by your objections to the basic principle of maintaining an
adequate state of hydration during clearance determination. Whether you are
dealing with experimental animals or pts, hydration (not over-hydration) is
highly desirable, particulary in the case of indomethacin, where net
filtration pressure, GFR, and urine flow are all significantly reduced.
Dr. N. Anaizi
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What would be appropriate hydration? If one wants to collect samples,
presumably one has to offer subjects some water. Inadequate water
would also presumably alter elimination. Is "ad libitum" a reasonable
amount?
Joan K-B
korthbj.aaa.war.wyeth.com
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Joan ! You asked:
>What would be appropriate hydration? If one wants to collect samples,
presumably one has to offer subjects some water. Inadequate water would
also presumably alter elimination. Is "ad libitum" a reasonable amount?
>Joan K-B
We should distinguish between two situations:
1- Acute experiments under anesthesia - in this setting the animal is
unable to maintain water balance (input < output) mainly due to inability
to sense and respond to thirst triggered by evaporative water losses and
enhanced fluid secretion by the respiratory passages during anesthesia. In
addition, there is also the sitiuation where blood volume is lost in the
course of surgical procedures (even minor ones). How can you tell how fluid
and what kind of fluid you need to give the animal?? The answers lie in
monitoring arterial blood pressure, pulmonary wedge pressure or central
venous pressure, urine flow rate, urine osmolality, and if necessary plasma
osmolality. These allow evaluation of the status of both ECF volume and
total body water (TBW).
2- Chronic experiments in non-anesthesized animals, in which case drinking
"ad libitum" is often adequate. However, the investigator should monitor
parameters of fluid status and ascertain adequate hydration which is
critical in these types of experiments.
In any case, it should be emphasized that very low urine flows can be the
source of major problems in estimating clearances, because of errors in
quantifying the excreted mass of the substance in question.
Dr. N. Anaizi
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