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Dear Colleages
I would like some opinions from members of the group on the practise of
determining plasma concentrations of a drug from urinary excretion data. I
have recently come across this method in a paper and wondered how accurate
or valid data (eg t1/2z) based on this method actually are. In addition, I
also know the drug undergoes active renal excretion.
The method is used when plasma concentrations fall below the limit of
quantitation and the urinary excretion rate for the drug is used to
determine plasma concentrations situated in the middle of the collection
interval by dividing the excretion rate in the interval (dAe/dt) by the
renal clearance calculated from when plasma levels could be determined (CLR
0-x hr).
I thank you in advance for your assistance.
Cheers
Dave Boulton
Dave Boulton
School of Pharmacy
University of Otago Phone: +64 3 479 7199 (wk) +64 3 477 2712 (hm)
P.O. Box 913 Facsimilie: +64 3 479 7034
Dunedin e-mail: david.boulton.-a-.stonebow.otago.ac.nz
New Zealand
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Urine PK analyses are better than nothing and can provide useful
estimates of K and, therefore, half-life. The absolute
bioavailability (F) can be obtained if the drug is excreted totally unchanged,
or provided all metabolites are identified, are known to be excreted in urine,
and all can be measured (often easier said than done). Renal clearance can be
calculated by dividing the total amount excreted unchanged during a
urine collection interval by the plasma during that interval, although it
is better
to have urine collections and AUC to infinity.
Clearance (systemic) and volume of distribution cannot be obtained
from urine data alone.
In switching from plasma to urine one has to ensure of course that
assay peformance is adequate and comparable in both biological fluids.
The major problem occurs with drugs of very short ( say <1 hr) and
very long half-life (> 24 hr) -- The former makes it difficult to
get enough data, while the latter is susceptible to problems from missed
samplings since all urine should be taken over several days. Furthermore,
unless the pre-terminal (distribution) phases are inordinately long then it
is unlikely that subjects can pass a sufficient number of urine samples to
capture this part of the PK profile. This also occurs for non-intravenous
administration in that the absorption phase is often so rapid that no more
than 1 or 2 samples of urine can be collected even when subjects are
"pre-hydrated" before dosing (which in itself can be problematical, e.g.
with oral administration of solid dosage forms).
Nonetheless, urine measurements can provide useful data for PK. For
example, we recently used urinary excretion data to study the mechanism
of absorption of amoxycillin (see : Eur J Pharm Biopharm 40,374-378,1994;
Br J Clin Pharmac 38,274-277,1994). Hope this is of some help.
Best wishes,
Bruce Charles
Pharmacy Department,
Univ. Queensland,
Brisbane, Australia.
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The validity of this depends on the constancy of renal clearance and
the quality of the urine excretion data. This is one method that can
be used to check for long terminal half-lives which are not evident
from the plasma data, provided the two criteria mentioned above are
fulfilled.
Leon Aarons
Leon Aarons
Pharmacy Department
University of Manchester
Manchester, M13 9PL, U.K.
tel +44-161-275-2357
fax +44-161-275-2396
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Dear Dave,
A good deal of our research involves following the excretion rates of
drugs because we do not have the facilities for taking blood samples from
human volunteers. The assumption that must be met for urinary analysis
is that drug is excreted from the central compartment by a definable
process, usually first order. The other consideration is that you will
only get information on the fate of that portion of the parent compound
that is analized in urine; ie - analysis of a metabolite will only give
information on that fraction of the dose that is excreted as the metabolite.
Set up your spreadsheet with columns for time, midpoint, volume, and
concentration. Time is the time since the dose was taken. midpoint is
the center of the sampling interval (sample at 1 and 2 hours; the
midpoint for the 2 hour sample is 1.5 hours). Volume is the TOTAL
urinary output since the last sample; your subjects must give you
virtually every drop they produce from time 0 to the end of the sampling
period (12 hours, 24, 36 ... just have to measure it to know for sure).
Concentration is determined in the normal manner by HPLC or whatever
instrument you use.
CALCULATIONS:
1. mg recovered = concentration * volume
2. urinary clearance = dU/dt= (mg recovered)/(sampling interval)
Some spreadsheets can't handle subtracting a cell from the next
one in the column. In that case, dudt=mg_recov/(2*(time-midpoint))
Under ideal conditions, a plot of urinary clearance vs. midpoint will
exactly parallel plasma concentration (with an arbitrary scaling
factor). We have used this fact in the formulation of several
bioequivalent products under the assumption that if two formulations are
bioequivalent, then they should be excreted in a bioequivalent manner.
Urinary clearance gives you a non-invasive tool 0th early formulation
work for bioequivalence; you switch to blood when you're close.
Urinary clearance is especially powerful when combined with a
deconvolution program such as PCDCON by Bill Gillespie. Using dUdt as
the input function and Ke (either from literature or from clearance by
subjects taking an immediate release dose of the drug under
investigation) as the impulse response, you can get both the cumulative
input of drug into the previous compartment and the rate of input.
NOTE: I said previous compartment. If you are measuring a drug that is
excreted intact, then the input calculated by deconvolution is input into
the central compartment. If you are measuring a metabolite, then you are
measuring the input of drug from the central compartment into the
metabolizing organ/enzymatic system. So with intact drug, you are
measuring Ka. If the drug is in an SR or CR formulation and you assume
that absorbance is much faster than dissolution, then the input rate from
deconvolution is the in vivo dissolution rate.
I hope that this will help you decide whether to use urinary clearance or
not. If you have any further questions, e-mail directly.
Kris Holt
Graduate Research Assistant
Oregon State University
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May be the originator of this string could post the citation which prompted
this question. Some of us with limited experience in this area may benefit
significantly. Thanks!!
VORA.-a-.Butler.EDU
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Dear Leon
Thanks for your comprehensive reply to my query regarding conversion of
urinary excretion rate to plasma concs. I must admit I initially thought
this practise would be a little suspect for quality quantitative work but
the responses I have recieved have changed my mind and I see that the
technique is useful in qiute a number of situations. Thanks again.
Best wishes for Christmas and the holiday season
Dave
Dave Boulton
School of Pharmacy
University of Otago Phone: +64 3 479 7199 (wk) +64 3 477 2712 (hm)
P.O. Box 913 Facsimilie: +64 3 479 7034
Dunedin e-mail: david.boulton.-a-.stonebow.otago.ac.nz
New Zealand
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