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Hi
I was asked by a friend for examples of drugs that show saturable
distribution kinetics. The idea is that the distributional process
is reversible but either the forward or reverse distributional step
into a tissue or organ shows Michelis-Menten behaviour. Note that it
not saturable elimination that he is looking for, but distribution.
Has anyone come across any examples of this behaviour.
Thanks
________
Leon Aarons
School of Pharmacy and Pharmaceutical Sciences
University of Manchester
Manchester, M13 9PL, U.K.
tel +44-161-275-2357
fax +44-161-275-2396
email l.aarons.at.man.ac.uk
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Dear All
If I understood correctly this question, which is the reversible
Michelis-Menten behaviour.
In one of my earlier studies, Wu G. Another integrated form of the
Michaelis-Menten equation, its analogy to electrical circuit model and
implication for active transporters. Med Hypotheses 2000; (in press), I have
mathematically shown that the Michaelis-Menten kinetics can run back.
Regards.
Guang Wu, MD, PhD
Laboratoire de Toxicocinetique et Pharmacocinetique
Faculte de Pharmacie
Universite de la Mediterranee Axi-Marseille II
27 Boulevard Jean Moulin
F-13385 Marseile Cedex 05
France
Tel: +33 4 91 83 56 45
Fax: +33 4 91 80 26 12
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Leon
I think Alan Boddy has worked with such a model.
Duncan
********************************************************
Duncan Jodrell, DM, MSc, FRCP (Edin.)
Reader in Oncology,
and Deputy Director, ICRF Medical Oncology Unit,
University of Edinburgh.
jodrell.-a-.icrf.icnet.uk
Tel: 0131 467 8447
Fax: 0131 332 8494
********************************************************
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[A few replies - db]
Date: Sun, 12 Mar 2000 06:46:06 +0100
=46rom: Mats Karlsson
X-Accept-Language: sv
To: PharmPK.aaa.boomer.org
Subject: Re: PharmPK Michaelis-Menten distribution kinetics
Hi Leon,
There is the Paclitaxel example, which I don't believe in. If you're
not familiar with it, paclitaxel has been claimed to have saturable
distribution. It has always been modeled as a saturable transport to
tissues, but in the paper below we showed that it could equally well be
described by saturable tissue binding. Now I think that article is
wrong. The seemingly non-linear distribution is a consequnce of varying
micellar concentration.
If you actually get any interesting answers I would be interested in
learning about them.
Mats
Karlsson MO, Molnar V, Freijs A, Nygren P, Bergh J, Larsson R.
Pharmacokinetic models for the saturable distribution of paclitaxel.
Drug Metab Dispos. 1999 Oct;27(10):1220-3.
PMID: 10497151; UI: 99428422
--
Mats Karlsson, PhD
Professor of Biopharmaceutics and Pharmacokinetics
Div. of Biopharmaceutics and Pharmacokinetics
Dept of Pharmacy
=46aculty of Pharmacy
Uppsala University
Box 580
SE-751 23 Uppsala
Sweden
phone +46 18 471 4105
fax +46 18 471 4003
mats.karlsson.at.biof.uu.se
---
X-Sender: davids.aaa.md2.huji.ac.il
Date: Sun, 12 Mar 2000 08:55:43 +0200
To: PharmPK.-a-.boomer.org
=46rom: David Stepensky
Subject: Re: PharmPK Michaelis-Menten distribution kinetics
Dear Leon,
One such example is distribution of aminoglycosides to the kidney that is
associated with aminoglycoside nephrotoxicity. Animal studies show that the
drug influx at the proximal convoluted tubule cells can be saturable,
leading to different extent of kidney exposure and nephrotoxicity for
different modes of administration of the same dose of aminoglycoside.
=46or more information, see:
=46reeman, C.D., Nicolau, D.P., Belliveau, P.P. and Nightingale, C.H.:
Once-daily dosing of aminoglycosides: review and reccomendations for
clinical practice. J Antimicrob Chemother 39: 677-86, 1997
Craig, W.A.: Pharmacokinetic/pharmacodynamic parameters: rationale for
antibacterial dosing of mice and men. Clin Infect Dis 26: 1-12, 1998.
David.
David Stepensky
PhD student
The Hebrew University of Jerusalem
---
=46rom: HRr1234.aaa.aol.com
Date: Sun, 12 Mar 2000 13:55:12 EST
Subject: Re: PharmPK Michaelis-Menten distribution kinetics
To: PharmPK.aaa.boomer.org
Phenytoin (diphenylhydantoin) shows classic MM distribution in humans. Any
good kinetics text can help with this drug.
---
=46rom: "Masson, =C9ric"
To: "'PharmPK.-a-.boomer.org'"
Subject: RE: PharmPK Michaelis-Menten distribution kinetics
Date: Mon, 13 Mar 2000 09:39:37 -0500
Yes,
Paclitaxel.
see: Sonnichsen DS, et al. J Clin Oncol 1994; 12:532-38.
Eric Masson, Pharm.D.
Scientific Director,
Anapharm inc
2050, boul Rene-Levesque West,
Ste-Foy, QC, Canada, G1V-2K8
418-527-4000 (EXT:222)
=46AX: 418-527-3456
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X-Sender: bertlum.at.pobox2
Date: Mon, 13 Mar 2000 12:07:55 -0800
To: PharmPK.aaa.boomer.org
=46rom: Bert Lum
Subject: Re: Michaelis-Menten distribution kinetics
Leon,
The antineoplastic drug, Paclitaxel, demonstrates saturable distribution
and elimination characterstics. This is both adult populations (Gianni L, J
Clinical Oncology 13:180, 1995) and in pediatrics (Sonnischen D, J Clinical
Oncology 12:532, 1994).
Bert Lum
Bert L. Lum, Pharm.D.
Associate Director, Clinical Trials Office, Room H-3249
Clinical Cancer Center at Stanford, Mail Code 5225
Stanford, CA 94305-5225
Phone: 650-498-4536 Fax: 650-498-4696
E-mail: bert.lum.-at-.stanford.edu Page: 650-571-2892
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