Back to the Top
Hi,
I teach PK to third year pharmacy students and had the students
answer the following question for a class quiz recently:
Which of the following factors does NOT influence glomerular filtration:
molecular size, protein binding, lipid solubility, number of
functioning nephrons, renal blood flow
Could anybody out there answer this question for me? I will
appreciate if someone gives me details about the factors affecting
the glomerular filtration process. In my opinion the lipid solubility
is not a limiting factor but many students have answered renal blood
flow as the factor which would not influence the filtration process.
I looked up several books on pk but could not find a substantial
justification to renal blood flow being the answer.
Can anyone enlighten me more on this?
I will appreciate any help in this regard.
Thanks.
Pankaj
Back to the Top
[Quite a few answers, ... replies - db]
Date: Sat, 01 Apr 2000 12:39:38 -0500
From: "Tom Dowling"
To:
Subject: Re: PharmPK Question regarding glomerular filtration process
Pankaj-
Changes in RBF can alter GFR, i.e. ANG2-induced vasoconstriction at
efferent arteriole leading to reduced RBF. In this case, although RBF
is reduced, GFR will increase (due to increased pressure in Bowman's
space), resulting in increased filtration fraction (and filtration of
unbound drug).
Hope this helps,
Tom
------
Thomas C. Dowling, PharmD, PhD
Assistant Professor
Department of Pharmacy Practice and Science
Pharmacokinetics and Biopharmaceutics Laboratory
UMAB
100 N. Penn St., Rm. 540D
Baltimore, MD 21201
410.706.0884 phone
410.706.6580 fax
410.492.9888 page
---
From: "Melethil, Srikumaran K."
To: "'PharmPK.at.boomer.org'"
Subject: RE: PharmPK Question regarding glomerular filtration process
Date: Sat, 1 Apr 2000 16:13:22 -0600
Dear Pankaj,
Of the factors, listed, I would have picked lipid solubility.
You are right, blood flow does affect GFR. The students may have missed the
connection between plasma flow rate and blood flow rate in the "heat of the
battle"; normal GFR is based on plasma flow rate. Of course, one does get
"strange" answers on exams. Hope this helps.
Sri
Srikumaran Melethil, Ph.D.
Professor of Pharmaceutics and Medicine
University of Missouri-KC
203 B Katz Hall, School of Pharmacy
5005 Rockhill Road
Kansas City, MO 64110
816-235-1794 (voice); 816-235-5190 (fax)
---
Date: Sat, 01 Apr 2000 17:36:09 -0700
From: David Nix
Reply-To: nix.aaa.Pharmacy.Arizona.EDU
Organization: College of Pharmacy
X-Accept-Language: en
To: PharmPK.-a-.boomer.org
Subject: Re: PharmPK Question regarding glomerular filtration process
> Which of the following factors does NOT influence glomerular filtration:
> molecular size, protein binding, lipid solubility, number of
> functioning nephrons, renal blood flow
molecular size should not influence glomerular filtration unless your
considering macromolecules (e.g.) proteins >~30,000 daltons
Only free drug can be filtered through the glomerulas; thus, protein
binding will have a substantial influence on glomerular filtration rate.
High lipid solubility will probably lead to binding to various
lipoproteins in serum. Some of these lipoproteins are filtered then
reabsorbed in the proximal tubule. I'm not sure which of the
lipoproteins (if any) are too large to be filtered, but this could be
answered by looking at physiology references.
Loss of functional nephrons certainly would reduced glomerular
filtration rate overall since one usually refers to all nephrons
collectively. There is a hypothesis of hyperfiltration where remaining
nephrons can compensate for partical loss of nephrons, but this remains
to be proven.
Renal blood flow. In theory, renal blood flow will not affect
glomerular filtration rate unless that the increased hydrostatic
pressure actually leads to greater filtration. As long as the patient
had normal perusion to the kidney to begin with, I would doubt that
glomerular filtration rate would increase if blood flow increases within
usual physiologic limits.
---
Date: Sun, 02 Apr 2000 12:54:29 +0200
From: "Dr. Harald Mertes"
To: PharmPK.-at-.boomer.org
Subject: Re: PharmPK Question regarding glomerular filtration process
It will be a difficult situation for you by putting five distractors
without any correct answer in a MCQ. All 5 choices influence glomerular
filtration.
Lipid solubility for instance is often coupled with binding to plasma
proteins. Thus it is recommended in acute barbiturate poisoning to
alkalize blood for enhancing glomerular fiiltration. The negative
charged barbutrate ion will be filtrated whereas the uncharged acid will
be retained by lipoproteins.
I guess your students have read about autoregulation of the kidneys.
Thus renale blood gets independent from cardiac output within a broad
range. But if renale blood flow gets impaired glomerular filtration will
be affected, too.
I advise to withdraw this question.
--
Harald Mertes, MD
Anaesthesiologist
Rastatt/Germany
mailto:harald.at.mertes.inka.de
http://sites.inka.de/sites/mertes/index.html
---
From: HRr1234.-a-.aol.com
Date: Sun, 2 Apr 2000 07:37:48 EDT
Subject: Re: PharmPK Question regarding glomerular filtration process
To: PharmPK.at.boomer.org
Renal blood flow can NOT be the correct answer.
GFR (approx) = (Conc urine) (Q urine flow rate) / (Conc plasma), therefore
GFR is dependant upon renal blood flow. This is further evidenced by the us
if inulin as the gold standard marker to quantify GFR, due to the fact that
it is freely filtered through the pores of the glomerulus, not bound to
plasma proteins or tissues, not secreted, reabsorbed, or metabolized in the
renal tubules, nor is it eliminated by non-renal routes.
---
From: "Stephen Duffull"
To:,
Subject: RE: PharmPK Question regarding glomerular filtration process
Date: Mon, 3 Apr 2000 08:21:09 +1000
X-Priority: 3 (Normal)
Importance: Normal
Pankaj,
Your question:
Which of the following factors does NOT influence
glomerular filtration:
a) molecular size,
b) protein binding,
c) lipid solubility,
d) number of functioning nephrons,
e) renal blood flow
The answer seems straightforward (which makes me think I've
missed something obvious). In the extreme case it is easy
to show that "d" and "e" do influence filtration. We know
that "a" and "b" represent drug characteristics that affect
its filtration. This leaves "c" - which based on our
understanding seems a good choice.
Hope this helps
Steve
=================
Stephen Duffull
School of Pharmacy
University of Queensland
Brisbane, QLD 4072
Australia
Ph +61 7 3365 8808
Fax +61 7 3365 1688
---
Reply-To: "Anaizi"
From: "Anaizi"
To:,
"Multiple recipients of PharmPK - Sent by"
Subject: Re: PharmPK Question regarding glomerular filtration process
Date: Sun, 2 Apr 2000 20:16:05 -0400
X-Priority: 3
Dear Pankaj,
The correct answer to the following multiple choice question (notice the
changes):
Which of the following factors has the least influence on the glomerular
filtration rate of a drug?
a - Molecular size
b- Protein binding
c- Lipid solubility
d- Number of functioning nephrons
e- Renal blood flow
is c (lipid solubility). The reason is simply that it is the least relevant
in this context. Filtration occurs by convective transport and applies to
water soluble molecules that are able to transverse the glomerular barrier.
Molecules above a certain size and protein-bound molecules cannot get
through a healthy barrier. Lipid soluble molecule (e.g, fatty acids, steroid
hormones, etc) tend to bind to albumin, so in this sense lipid solubility
indirectly influences glomerular filtration.
The passage of molecules through the glomerular barrier is also hindered by
the presence of negative charges.
The flaw of the above question is the mixing of physicochemical factors
(e.g., mol wt) with physiologic factors (blood flow and number of
nephrons). I would make up two questions one for each group of factors.
I hope this is helpful
Nasr Anaizi, PhD
Associate Prof Pharmacol & Physiology
U of Rochester Med Cntr
nasr_anaizi.-a-.urmc.rochester.edu
http://www.thedrugmonitor.com
Back to the Top
Two replies - db]
Date: Mon, 3 Apr 2000 02:25:48 -0700 (MST)
X-Sender: ml11439.-a-.pop.goodnet.com
To: PharmPK.at.boomer.org
From: ml11439.-a-.goodnet.com (Michael J. Leibold)
Subject: Re: PharmPK Question regarding glomerular filtration process
Pankaj,
"Which of the following factors does NOT influence glomerular filtration:
molecular size, protein binding, lipid solubility, number of
functioning nephrons, renal blood flow"?
1) renal blood flow
An increase or decrease in renal blood flow is usually expressed as
an equal change in glomerular filtration. Although, renal blood flow is
not included in filtration clearance formulas, the GFR is physiologically
dependent on renal blood flow. The GFR and renal blood flow are autoregulated
in parallel.(1-3)
2) Molecular size, protein binding, number of functioning nephrons
The determinants of drugs ability to undergo filtration clearance are
molecular size, protein binding, glomerular integrity and the number of
functioning nephrons.(3)
a) Protein binding
Increasing the fraction unbound may increase filtration clearance(1):
Clrf= FbClcr
Clrf= filtration clearance, Fb=fraction unbound, Clcr= creatine clearance
b) Molecular size
Large moleular size can prevent glomerular filtration as is the case
for Dextran 70 which cannot be filtered, whereas Dextran 40 can. Molecules
larger than 10nm cannot be filtered.(3,4)
c) Number of functional nephrons
As the number of functional nephrons decreases, the number of functional
glomeruli decreases, and the kidneys capacity to filter decreases. This is
reflected in various regression formulae for gentamicin, vancomycin and other
drugs relating changes in serum creatinine to drug clearance.(3)
d) integrity of the nephrons
The integrity of the glomerulus can be impaired in the nephrotic syndrome
resulting in the leaking of proteins into the urine (proteinuria).(3)
3) Lipid Solubility
The ability of a drug to pass a lipid membrane is related to its
lipid solubility. Weak acids and bases which exhibit urine-pH-dependent
elimination have nonionized species which are lipid soluble enough to cross
a lipid membrane resulting in enhanced tubular reabsorption under nonionized
conditions. (3)
However, filtration clearance is dependent on molecular size and not
lipid solubility, as the filtration process involves a molecular sieving
process whereby the molecules of large molecular size and negative charge
are prevented from passing the renal basement membrane. Although, the
capillaries of Bowman's capsule are fenestrated for easy molecular
penetration, properties of the basement membrane prevent molecules larger
than 10nm and negatively charged molecules larger than albumin from being
filtered through the glomerulus.(4)
So, lipid solubility would be the one factor not affecting GFR due to
the unusual characteristics of the renal basement membrane. This membrane
filters on the basis of molecular size and negative charge, not on the
basis of lipid solubility.
Mike Leibold, PharmD, RPh
ML11439.-a-.goodnet.com
References
1) Gilbaldi, M., Perrier, D., Pharmacokinetics 2nd ed., New York, Marcel
Dekker 1982:p 342
2) Guyton, A.C., Hall, J.E., Textbook of Medical Physiology 9th ed.,
Philadelphia, W.B.Saunders 1996;297-329
3) Benet, L.Z., Massouud, N., Gambertoglio, J.G., Pharmacokinetic basis
of Drug Treatment, New York, Raven Press 1984;119-171
4) Junqueira, L.C., Carneiro, J., Kelley, R.O., Basic Histology 8th ed,
New Jersey, Appleton& Lange 1995;359-377
---
Date: Mon, 03 Apr 2000 05:33:40 -0400
From: "Ed O'Connor"
Reply-To: efoconnor.aaa.snet.net
Organization: PM PHARMA
X-Accept-Language: en
To: PharmPK.aaa.boomer.org
Subject: Re: PharmPK Re: Question regarding glomerular filtration process
General changes include effects on
1)
ERBF and GFR...Check with PAH and Inulin, we have developed a microassay for
inulin and PAH which requires as littlie at 5-10 uL of plasma and urine.
Creatinine is a poor substitute.
2) pH of the plasma (and urine) which will influence the clearance of the drug.
3) size of the drug
4) the bound vs free character of the drug and the endogenous competiton for
binding sites.
5). competion for carrier mediated sites for excretion or resorption (sugar).
6). Other drugs being taken by the subject.
Depending on the charge of the drug
---
Back to the Top
Thanks very much for responding to my question. I guess now i have a
better understanding of why i think lipid solubility is NOT one of the
factors influencing the GFR.
Thanks again.
Regards,
Pankaj
Back to the Top
> "Which of the following factors does NOT influence glomerular filtration:
> molecular size, protein binding, lipid solubility, number of
> functioning nephrons, renal blood flow"?
Perhaps a more important question is which of the above factors do not
affect the unbound renal clearance of a drug?
Only unbound clearance is relevant to understanding the pharmacokinetics
and pharmacodynamics of a drug. Total (bound+unbound) clearance is a
misleading indicator of drug elimination when plasma protein binding
changes are involved.
Protein binding must be added to lipid solubility as a non influential
factor unless the drug has a high extraction ratio due to substantial
tubular clearance. The glomerular filtration component of unbound drug
clearance is not affected by plasma protein binding.
--
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.htm
PharmPK Discussion List Archive Index page
Copyright 1995-2010 David W. A. Bourne (david@boomer.org)