- On 29 Apr 1998 at 10:40:52, "Randy Trinkle" (rtrinkle.-a-.skylite.datanet.ab.ca) sent the message
I've scoured MEDLINE and pharmacology texts for some clear
info about the nature of the renal clearance of phenytoin.
No joy.
What I'm particularly interested in is
(1) is it filtered, and/or
(2) removed by the proximal tubule acid transport system
(3) is the extent of clearance of the parent drug by this route a
function of the pH of the ultrafiltrate?
Thanks.
***************************************
Randy Trinkle, BScPharm, BA
Clinical Pharmacist
Cross Cancer Institute
Edmonton, AB
mailto:rtrinkle.at.datanet.ab.ca
Health Science links:
http://www.datanet.ab.ca/users/rtrinkle
***************************************
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- On 30 Apr 1998 at 11:42:34, David_Bourne (david.-at-.pharm.cpb.uokhsc.edu) sent the message
[A few replies - db]
Date: Wed, 29 Apr 1998 12:17:46 -0700 (PDT)
From: rajesh krishna
X-Sender: rkrishna.-a-.netinfo2.ubc.ca
To: PharmPK.at.pharm.cpb.uokhsc.edu
Subject: Re: PharmPK renal clearance of phenytoin
MIME-Version: 1.0
Following articles may be useful to you:
1. Borga, O., et al. Plasma levels and renal excretion of
phenytoin....Clin Pharmacol Ther., 26: 306-14, 1979.
2. Eadie, MJ et al. Elimination of phenytoin in man. Clin Exp Pharmacol
Physiol. 3: 217-24, 1976.
3. A good resource is Applied Pharmacokinetics: Principles of TDM, edited
by WE Evans et al., 1992.
---
Date: Wed, 29 Apr 1998 16:47:42 -0400 (EDT)
From: VINCENT EARL PEARSON
To: PharmPK.-at-.pharm.cpb.uokhsc.edu
cc: Multiple recipients of PharmPK - Sent by >
Subject: Re: PharmPK renal clearance of phenytoin
MIME-Version: 1.0
Greetings, Randy!
Dixon Woodbury reviews these topics in his book chapter on the absorption,
distribution, and excretion of phenytoin. It appears in Antiepileptic
Drugs, 3rd. ed. edited by Levy, et al. He cites Bochner et al. (Clin
Pharmacol Ther 1973;14:791-6) when he says that the renal clearance of
phenytoin =3D 3-23 cc/min, depending on urine flow. This is much lower than
GFR, thus tubular secretion is cited as the primary mechanism. He also
noted that substantial tubular reabsorption takes place for the final
clearance to be this low. The HPPH glucuronide metabolite's clearance =3D
76-420 cc/min, again depending on urine flow. Alkalinization of the urine
enhances PHT excretion since more drug exists in the ionized form, thus
tubular secretion predominates. The chapter makes no distinction as to
where along the tubule PHT is secreted.
I hope this information proves useful
With best regards,
Vince Pearson, Pharm.D., BCPS
Clinical Coordinator, Drug Information
The Johns Hopkins Hospital
Baltimore, Maryland USA
---
From: "CHARLES"
Organization: School of Pharmacy
To: PharmPK.at.pharm.cpb.uokhsc.edu
Date: Thu, 30 Apr 1998 09:37:42 +1000
MIME-Version: 1.0
Subject: Re: PharmPK renal clearance of phenytoin
Priority: normal
Randy,
I am curious as to why this information would be important when it is
metabolised >98% .
Cheers,
BC
+ + + + + + + + + + + + + + + + + + + + + + + + + + + + +
Bruce CHARLES, PhD
School of Pharmacy
The University of Queensland
Brisbane, Qld, Australia 4072
Telephone : +61 7 336 53194
Facsimile : +61 7 336 51688
Email : Bruce.Charles.-a-.pharmacy.uq.edu.au
+ + + + + + + + + + + + + + + + + + + + + + + + + + + + +
---
From: Olof.Borga.-a-.draco.se.astra.com
To: PharmPK.-at-.pharm.cpb.uokhsc.edu
Subject: RE: PharmPK renal clearance of phenytoin
Date: Thu, 30 Apr 1998 11:25:09 +0200
Mime-Version: 1.0
Regarding renal handling of phenytoin
We published a paper on the subject in 1979 which still should be very
accurate. In short, fenytoin is mainly in the unionized form at all
physiological pH-es, since this very weak acid has got a pKa of 8.3. It
turns out that the urine concentrations are very close to unbound
concentrations in plasma. The interpretation of that is that, regardless
of whether the drug is mainly filtered or actively secreted, the
majority of it is passively reabsorbed in the tubuli until distribution
equilibrium between urine conc and unbound conc in plasma is approached.
For such a drug one will find a positive correlation between urine flow
(mL/min) and renal clearance. The reference is: Borga et al.,
Clin.Pharm.Ther., 26: 306-314, 1979.
Sincerely
Olof Borg=E5, Ph.D.
Pharmacokinetic Expert
Kinetics and Metabolism
Preclinical R&D
Astra Draco AB, P.O. Box 34, S-221 00 Lund, Sweden
Tel: +46 46 33 60 00 Direct: +46 46 33 68 75
Fax: +46 46 33 66 66 Direct: +46 46 33 71 64
e-mail: olof.borga.at.draco.se.astra.com
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- On 1 May 1998 at 10:06:54, "Randy Trinkle" (rtrinkle.-a-.skylite.datanet.ab.ca) sent the message
Thanks to all for the info. As to why the interest
We recently had an inpatient who started seizuring when she
got cipro. Got loaded with phenytoin and after two days of
maintenance (300mg/day) her phenytoin concentration was
37 mcmol/L.
There was a relatively recent exchange of letters in Annals
of Pharmacotherapy about low phenytoin concentrations in
patients receiving ciprofloxacin. One of the letters hypothesized
that cipro reduced gut flora that normally deconjugate phenytoin
metabolites and increased phenytoin clearance by reducing
enterohepatic recirculation. I was interested in how much
the effect of cipro could be attributed to renal handling of
phenytoin. One investigator found more than double the
concentration of phenytoin in the urine of rats given cipro:
Eur J Drug Metab Pharmacokinet 1997 Jan;22(1):35-39
Ciprofloxacin decreases plasma phenytoin concentrations in the rat.
al-Humayyd MS
I have the idea that part of cipro's effect on phenytoin
concentration (and clearance) is due to preventing its
tubular reabsorption. Yeah, most of the drug is metabolized.
But if the metabolic pathway becomes saturated, then
something that can increase the renal clearance of parent drug
could account for at least part of the lower concentration.
Thanks again.
***************************************
Randy Trinkle, BScPharm, BA
Clinical Pharmacist
Cross Cancer Institute
Edmonton, AB
mailto:rtrinkle.at.datanet.ab.ca
Health Science links:
http://www.datanet.ab.ca/users/rtrinkle
***************************************
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- On 4 May 1998 at 11:51:09, Olof.Borga.-a-.draco.se.astra.com sent the message
I am quite positive that you can disregard any renal mechanisms. The
reabsorption of phenytoin is clearly a passive process and can't be
affected. The total amount via the renal route is negligible. Well, what
if the metabolism is saturated as suggested in the previous discussion.
Well, if it really is (normally it only in the Michaelis-Menten range,
seldomly it reaches the zero order range) then that is enough to cause
major problems in itself. /OLOF BORGA
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- On 5 May 1998 at 09:58:00, "Randy Trinkle" (rtrinkle.aaa.skylite.datanet.ab.ca) sent the message
Well, I'm not so sure. The results reported in the paper by al-Humayyd
clearly showed more than double the concentration of parent drug in
urine. Not enough, I think, to entirely account for the decrease in
AUC and half-life, but something is causing an increase in urinary
excretion. I don't think it's due to inhibition to reabsorption or a
change in urine pH. The mechanism is simply unknown.
***************************************
Randy Trinkle, BScPharm, BA
Clinical Pharmacist
Cross Cancer Institute
Edmonton, AB
mailto:rtrinkle.aaa.datanet.ab.ca
Health Science links:
http://www.datanet.ab.ca/users/rtrinkle
***************************************
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- On 6 May 1998 at 14:09:05, Olof.Borga.-at-.draco.se.astra.com sent the message
The reason why I am sure you can disregard renal secretion in the
overall elimination of phenytion can be illustrated by some simple
arithmetics: Let's assume a patient has a Cp of 80 umol/liter=20
mg/liter. The urine conc. is then approximately 2mg/liter, i.e., equal
to the unbound conc. in plasma. (The renal handling of phenytoin is
mainly governed by its passive tubular reabsorption, which should be
unaffected by the presence of other drugs. In essence the urine conc.
and the unbound conc. in plasma are virtually identical. The situation
is similar wiht an other antiepileptic, carbamazepine). With a urine
flow of 3 liters/day that means a total renal secretion of 6 mg/day,
which corresponds to 2% of a daily dose of 300 mg. Increase the urinary
secretion by a factor of 2 and it still corresponds to only 4% of the
daily dose. Not enough to explain any major changes in Cp.
We once studied a patient that used to drink copious amounts of beer, 18
liters/day. The doctor in charge was worried that the patient would lose
most of his phenytoin dose in the urine. Analysis of urine samples from
the patient demonstrated that the renal excretion in this guy amounted
to approximately 15% of the daily dose./OLOF
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- On 6 May 1998 at 14:10:14, Dave (psycho.-at-.merlin.net.au) sent the message
Randy Trinkle scibbled:
"Got loaded with phenytoin and after two days of maintenance (300mg/day)
her phenytoin concentration was 37 mcmol/L."
Recently decided to acquire wisdom and attended a seminar presented by a
pharmacologist on TDM. He presented some interesting data on phenytoin
which clearly demonstrated that for the majority of patients who were
loaded and then placed on the routine 300mg/day maintenance of phenytoin
in his hospital, levels were typically below the "therapeutic range". He
argued that for most patients we were actually underdosing them using
this regimen. It would seem that this is a more likely explanation for
the "low" phenytoin level in this patient. After all, 37 micromol/L is
not all that far off from the lower end of the "range" of 40micromol/L.
In addition, given cipro has a relatively short half life, by the time
anyone ever got around to giving the phenytoin, most of it would have
been gone, and there wouldn't have been lots there to interact with. :-)
Although I must admit to being a numnut on phenytoin clearance, I have
read the previous posts, and read the abstracts (yes, yes...one should
not read abstracts, but anyway) on the case studies.The cases reported
are spectacular cases, but I don't think they could be explained by
renal mechanisms either. For a drug which is predominantly metabolised,
how can inhibition of renal reabsorbtion result in such a massive drop
in plasma levels?
Without going to the library and pulling out al-Humayyd's paper, and
seeing as you said the conc of phenytoin levels doubled in urine (from
2% to 4%?), may I present an alternate hypothesis. Could cipro somehow
increase the metabolism of phenytoin? Did the investigators look at
phenytoin conc (or metabolite) in bile?? If phenytoin is conjugated (and
this is increased), the length of time between urine
production/collection/storage could result in de-conjugation and
therefore the doubling of phenytoin conc in urine. Then again, does
cipro induce enzymes, given its other interaction with theophylline
which results in an increase in levels?? Just a thought to keep everyone
amused a little longer....
Cheers,
Dave
psycho.-a-.merlin.net.au
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- On 11 May 1998 at 11:19:37, "Randy Trinkle" (rtrinkle.-at-.skylite.datanet.ab.ca) sent the message
>. He
> argued that for most patients we were actually underdosing them using
> this regimen. It would seem that this is a more likely explanation for
> the "low" phenytoin level in this patient.
Agreed that underdosing in general is a problem. I still would have
expected a bit higher concentration in this patient.
> In addition, given cipro has a relatively short half life, by the time
> anyone ever got around to giving the phenytoin, most of it would have
> been gone, and there wouldn't have been lots there to interact with. :-)
Patient was still on cipro at the time the blood sample for phenytoin
assay was taken. Wasn't stopped until after the assay result came
back.
Patient was rebolused (maintenance therapy the same) and two days
later the phenytoin concentration was 77 mcmol/L.
> Although I must admit to being a numnut on phenytoin clearance, I have
> read the previous posts, and read the abstracts (yes, yes...one should
> not read abstracts, but anyway) on the case studies.The cases reported
> are spectacular cases, but I don't think they could be explained by
> renal mechanisms either. For a drug which is predominantly metabolised,
> how can inhibition of renal reabsorbtion result in such a massive drop
> in plasma levels?
I don't think an increase in renal clearance is the whole story
either, but it looks like part of it. Ciprofloxacin's effect on
phenytoin pharmacokinetics--smaller AUC, shorter half-life--
is as yet unexplained.
> Without going to the library and pulling out al-Humayyd's paper, and
> seeing as you said the conc of phenytoin levels doubled in urine (from
> 2% to 4%?), may I present an alternate hypothesis. Could cipro somehow
> increase the metabolism of phenytoin? Did the investigators look at
> phenytoin conc (or metabolite) in bile??
Not that he reported in the paper--and he also mused about the
possibility of increased metabolism. As you say, this would be
an unexpected property of a fluoroquinolone, but it could be
the major player.
One of the recent discussants in the Annals suggested
disruption of enterohepatic recirculation of phenytoin as
a possible mechanism.
Cheers,
Randy
***************************************
Randy Trinkle, BScPharm, BA
Clinical Pharmacist
Cross Cancer Institute
Edmonton, AB
mailto:rtrinkle.-a-.datanet.ab.ca
Health Science links:
http://www.datanet.ab.ca/users/rtrinkle
***************************************
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- On 12 May 1998 at 11:35:26, Dave (psycho.at.merlin.net.au) sent the message
Randy scribbled:"One of the recent discussants in the Annals suggested
disruption of enterohepatic recirculation of phenytoin as
a possible mechanism."
If this was the case, then which bug in our guts does cipro kill that the
other broad spectrum antibiotics don't?? If enterohepatic recycling was one
possible reason, then would we not expect to see a heck of a lot more people
with weird phenytoin levels given the vast amount of broad spectrum
antibiotics that are currently being used?
BTW, "Patient was rebolused (maintenance therapy the same) and two days
later the phenytoin concentration was 77 mcmol/L."
Rebolused with........(?) mg, if this was a significant amount, and with t1/2
approx 20 hours, saturable metabolism/nonlinear PK, 77micromol/L may not be
surprising, be nice to see another when he/she is a little more stable at
steady state a little further down the road. :-)
Have fun ....
Cheers,
Dave
E-mail: psycho.-a-.merlin.net.au
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- On 14 May 1998 at 15:37:37, rajesh krishna (rkrishna.aaa.unixg.ubc.ca) sent the message
Question - if biliary excretion is significant for phenytoin elimination:
how much phenytoin/metabolites is present in bile? What % of CLtb is
CLbil? In other words, is it relavent? Does cipro alter/inhibit
phenytoin's biliary excretion? Effect of disease states...??
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