Hi Dear Nonmem user,
I am trying to model the kinetics of a compound that exhibits enzyme
auto-inhibition.I have found some previously suggested literature by nonmem
users, but all of them were auto-induction cases. Does anyone know any
enzyme auto-inhibition PK model paper published ?
Thanks so much!
Sincerely,
Yuyan Jin
Graduate student
University of Pittsburgh
enzyme auto inhibition PK model
Hi Yuyan,
We modeled the autoinduction of artemisinin (Gordi T, Xie R, Huong NV,
Huong DX, Karlsson MO, Ashton M.: A semiphysiological pharmacokinetic
model for artemisinin in healthy subjects incorporating autoinduction of
metabolism and saturable first-pass hepatic extraction.Br J Clin
Pharmacol. 2005 Feb;59(2):189-98.) The model includes a hepatic
compartment, whose drug concentrations increases the production rate of
an enzyme compartment. The increased enzyme levels result in increased
intrinsic clearance, which affect the extraction ratio (EH) of the
compound assuming a well-stirred model. The changes in EH influence both
the bioavailability as well as the clearance of the compound. The model
should work in your case (inhibition) as well: all you'll need to do is
to let the hepatic drug amounts to inhibit the production (or increase
the elimination) of the enzyme compartment. I believe the nice thing
about the model is that it assumes hepatic, and not plasma, drug levels
to change the enzyme amounts. This has two advantages: it is more
physiologically relevant (most of the time), and the effect is not
influenced by changes in plasma concentrations, which are the
consequence of induction or inhibition.
Let me know if you want the NONMEM control stream for the model.
Toufigh
Quoted reply history
________________________________
From: [EMAIL PROTECTED] [mailto:[EMAIL PROTECTED]
On Behalf Of Yuyan Jin
Sent: Thursday, June 05, 2008 2:07 PM
To: [email protected]
Subject: [NMusers] enzyme auto inhibition PK model
Hi Dear Nonmem user,
I am trying to model the kinetics of a compound that exhibits enzyme
auto-inhibition.I have found some previously suggested literature by
nonmem users, but all of them were auto-induction cases. Does anyone
know any enzyme auto-inhibition PK model paper published ?
Thanks so much!
Sincerely,
Yuyan Jin
Graduate student
University of Pittsburgh
You will probably have to write your own model.
One suggested model would be:
V = Vmax x S/[Km + S x (1 + S/Ki)]
Where
V = velocity,
S = substrate concentration,
km = substrate concentration at half maximal velocity
ki = inhibition constant
Vmax = maximal velocity
See:
Mutlib AE GT, Bauman JN, Williams JA, Kulkarni S, Kostrubsky S. Kinetics of acetaminophen glucuronidation by UDP-glucuronosyltransferases 1A1, 1A6, 1A9 and 2B15. Potential implications in acetaminophen-induced hepatotoxicity. Chem Res Toxicol. 2006;19(5):701-709.
Regards
David
At 09:06 a.m. 6/6/2008, Yuyan Jin wrote:
> Hi Dear Nonmem user,
>
> I am trying to model the kinetics of a compound that exhibits enzyme auto-inhibition.I have found some previously suggested literature by nonmem users, but all of them were auto-induction cases. Does anyone know any enzyme auto-inhibition PK model paper published ?
>
> Thanks so much!
>
> Sincerely,
> Yuyan Jin
> Graduate student
> University of Pittsburgh
Dr David Reith MBBS FRACP MMedSc(Pharm) PhD
Associate Professor
Dunedin School of Medicine
University of Otago
New Zealand
Phone: +64 3 4740999 Fax: +64 3 4747817
Hi Yuyan,
Mechanistic models incorporating an auto-inhibition component would be more
desirable. However, you may be able to describe the PK data of your compound
empirically by adding an additional inhibition compartment. Depending on the
concentration in this empirical compartment, systemic CL from the central
compartment is inhibited. Over time, you can allow the CL to take
values between
0 and 100% of the original value estimated for the time of the first
administration.
A good reference for such an empirical approach is:
Plock N, Buerger C, Joukhadar C, Kljucar S, Kloft C. Does linezolid inhibit
its own metabolism? Population pharmacokinetics as a tool to explain the
observed nonlinearity in both healthy volunteers and septic patients. Drug
Metab Dispos. 2007 Oct;35(10):1816-23.
I hope this helps.
*Murad Melhem, PhD*
*Assistant Director PK/PD*
*Cognigen Corporation*
*Buffalo, NY*
Quoted reply history
On Thu, Jun 5, 2008 at 5:06 PM, Yuyan Jin <[EMAIL PROTECTED]> wrote:
>
> Hi Dear Nonmem user,
>
> I am trying to model the kinetics of a compound that exhibits enzyme
> auto-inhibition.I have found some previously suggested literature by nonmem
> users, but all of them were auto-induction cases. Does anyone know any
> enzyme auto-inhibition PK model paper published ?
>
> Thanks so much!
>
> Sincerely,
> Yuyan Jin
> Graduate student
> University of Pittsburgh
>
Thanks Murad,
I read the article you suggested tonight. this is the first paper I read so
far modeled enzyme auto-inhibition and it is really useful. it is also nice
to see that the article differentiate the inhibitable CL and non-inhibitable
Cl. but I am wondering if these two CL could be accurately estimated without
corresponding metabolites data? also, I still could not figure out what the
inhibition component refers to physiologically?
and why def equation for the auto-inhibition comparment was written as:
dA4/dt=Kic*( A2 / V2-A4)
isn't unit of A2 and A4 the same?
Can anyone give me some hint?
Sincerely,
Yuyan
Quoted reply history
On 6/5/08, Murad Melhem <[EMAIL PROTECTED]> wrote:
>
> Hi Yuyan,
> Mechanistic models incorporating an auto-inhibition component would be more
> desirable. However, you may be able to describe the PK data of your compound
> empirically by adding an additional inhibition compartment. Depending on
> the concentration in this empirical compartment, systemic CL from the
> central compartment is inhibited. Over time, you can allow the CL to take
> values between 0 and 100% of the original value estimated for the time of
> the first administration.
>
> A good reference for such an empirical approach is:
> Plock N, Buerger C, Joukhadar C, Kljucar S, Kloft C. Does linezolid inhibit
> its own metabolism? Population pharmacokinetics as a tool to explain the
> observed nonlinearity in both healthy volunteers and septic patients. Drug
> Metab Dispos. 2007 Oct;35(10):1816-23.
>
> I hope this helps.
>
> *Murad Melhem, PhD*
> *Assistant Director PK/PD*
> *Cognigen Corporation*
> *Buffalo, NY*
>
>
> On Thu, Jun 5, 2008 at 5:06 PM, Yuyan Jin <[EMAIL PROTECTED]> wrote:
>
>>
>> Hi Dear Nonmem user,
>>
>> I am trying to model the kinetics of a compound that exhibits enzyme
>> auto-inhibition.I have found some previously suggested literature by nonmem
>> users, but all of them were auto-induction cases. Does anyone know any
>> enzyme auto-inhibition PK model paper published ?
>>
>> Thanks so much!
>>
>> Sincerely,
>> Yuyan Jin
>> Graduate student
>> University of Pittsburgh
>>
>
>
--
Yuyan Jin