Back to the Top
Hello,
This question is related to zero order kinetics.
Is there any example (preferably of commercially available drug) of
zero order drug
-release
-decomposition
-disposition (metabolism/clearance)
In other words, although most sustained release research claims zero
order release, is there any actual commercial example of zero (not
apparent or pseudo) order release?
Also, apart from drug delivery is there any example where a drug
undergoes degradation by zero order kinetics.
And an example where a drug undergoes zero order disposition.
Any inputs will be much appreciated.
Thank you
Back to the Top
Hello Pankaj, I do not have an example on the top of mind for a
commercial product following zero order release, but drug degradation
or metabolism can be zero order (follow nonlinear pharmacokinetics)
and is dependent upon the Km of the molecule for the enzyme
responsible for metabolism/degradation and the concentration produced
(which depends upon the the dose administered).
Valproic acid, salicylic acid are low extraction drugs and will show
zero order provided the doses are high. Generally a molecule with an
extraction ratio less than or around 0.3 will show zero order
kinetics at medium to high doses.
Disposition is what happens to the molecule after absorption so
distribution and metabolism might be summed up as disposition. I have
mentioned about the elimination following zero order. Regarding the
zero order distribution (into tissues) this will happen when
transporters are involved for influx of the drug into tissues. An
example of this could be brain and L-dopa distribution in brain. It
is advised that L-dopa should be taken with food rich in proteins as
the proteins would breakdown to form amino acids which can then
compete with absorption and distribution into brain. But similar to
zero order dependent elimination, zero order distribution will depend
upon the Km of the substrate for the transporter and concentrations
being produced (which depends upon the dose administered).
The book by RowlanD and Tozer 'Clinical pharmacokinetics: Concepts
and applications has numerous examples of different drugs following
nonlinear PK at different stages of PK (ADME) and the reason for the
nonlinearity. Hope this helps.
Indranil Bhattacharya
Ph.D candidate
Dept. of Pharmaceutical Sciences
State University of New York at Buffalo
Usa
Back to the Top
The following message was posted to: PharmPK
Dear Indranil,
You wrote:
>Generally a molecule with an extraction ratio less than
>or around 0.3 will show zero order kinetics at medium to
>high doses.
Generally, this statement is not correct. Most drugs have
an extraction ratio less than 0.3 and are given at medium
doses (of course depending on the definition of 'medium';
I would say 'medium' is about the normal dose in normal
subjects), and do not show any sign of nonlinear kinetics.
Also, the term 'zero order kinetics' should be used with
care, since at concentrations around Km the kinetics are
'nonlinear' but certainly not 'zero order'. The latter
requires much higher concentration, and as far as I know
the only example is alcohol (ethanol).
Best regards,
Hans Proost
Johannes H. Proost
Dept. of Pharmacokinetics and Drug Delivery
University Centre for Pharmacy
Antonius Deusinglaan 1
9713 AV Groningen, The Netherlands
tel. 31-50 363 3292
fax 31-50 363 3247
Email: j.h.proost.at.rug.nl
Back to the Top
The following message was posted to: PharmPK
I agree with the first part of this statement but not the last part.
> Also, the term 'zero order kinetics' should be used with
> care, since at concentrations around Km the kinetics are
> 'nonlinear' but certainly not 'zero order'. The latter
> requires much higher concentration, and as far as I know
> the only example is alcohol (ethanol).
For those who are interested in the science of ethanol PK (to be
distinguished
from the forensic crystal ball gazing used by law enforcement
authorities and
some of their advisors) I do not think one should ever describe
ethanol as
having zero order kinetics. At concs (> 800 mg/L) which exceed 90% or
more of
the elimination capacity one might be tempted to approximate the rate of
elimination as being constant but in fact there are parallel first order
processes which become important. e.g. see Holford NHG. Clinical
pharmacokinetics of ethanol. Clinical Pharmacokinetics 1987;13:273-292
Nick
--
Nick Holford, Dept Pharmacology & Clinical Pharmacology
University of Auckland, 85 Park Rd, Private Bag 92019, Auckland, New
Zealand
email:n.holford.-at-.auckland.ac.nz tel:+64(9)373-7599x86730 fax:373-7556
http://www.health.auckland.ac.nz/pharmacology/staff/nholford/
Back to the Top
The following message was posted to: PharmPK
Dear Nick,
Thank you for your correction of my lack of knowledge. Your paper is
somewhere in my pile of unread papers ...
May I conclude that you agree that 'zero-order elimination' does not
exist in real life? Apart from my notion that the situation C >> Km
is not encountered in practice, it is likely that also for other
drugs parallel pathways of elimination may become apparent only at
high concentration because of low affinity (but not necessarily low
capacity)?
Best regards,
Hans Proost
Johannes H. Proost
Dept. of Pharmacokinetics and Drug Delivery
University Centre for Pharmacy
Antonius Deusinglaan 1
9713 AV Groningen, The Netherlands
tel. 31-50 363 3292
fax 31-50 363 3247
Email: j.h.proost.aaa.rug.nl
[How does phenytoin fit into this discussion. Isn't the Km approx 4
mg/L with a therapeutic window of 10-20 mg/L? - db]
Back to the Top
The following message was posted to: PharmPK
The example of zero-order kinetics Malcolm Tozer mentions is that
of phenytoin. See eg. his paper in Ther Drug Monit. 1989;11(5):540-2.
AFAIK this drug keeps being clinically important for treatment of
epilepsy.
Best regards,
Jeroen
J. Elassaiss-Schaap
Scientist PK/PD
Organon NV
PO Box 20, 5340 BH Oss, Netherlands
Phone: + 31 412 66 9320
Fax: + 31 412 66 2506
e-mail: jeroen.elassaiss.aaa.organon.com
Back to the Top
The following message was posted to: PharmPK
The mixed order *MODEL* for drug elimination predicts that true zero-
order
elimination only occurs when drug concentration is infinite.
Practical applications of this model may not be sensitive to the
assumption
that elimination is independent of concentration but I do not know of
any.
Phenytoin elimination is best described by a mixed order model for all
purposes I know of. The usual target concentration is only about 5 x
higher
than the KM which represents less than 90% saturation of the elimination
capacity.
--
Nick Holford, Dept Pharmacology & Clinical Pharmacology
University of Auckland, 85 Park Rd, Private Bag 92019, Auckland, New
Zealand
email:n.holford.at.auckland.ac.nz tel:+64(9)373-7599x86730 fax:373-7556
http://www.health.auckland.ac.nz/pharmacology/staff/nholford/
PharmPK Discussion List Archive Index page
Copyright 1995-2010 David W. A. Bourne (david@boomer.org)