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The following message was posted to: PharmPK
Hello,
I was wondering if there is any way to convert plasma AUC after oral
dosing to Km value in order to compare with in vitro Km and Vmax
values obtained from microsomal incubations. Is it unusual that the Cl
intrinsic from in vitro data does not correlate well with Clearance
value obtained from in vivo data.
Thanks
Avantika
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The following message was posted to: PharmPK
Dear Avantika,
You wrote:
> I was wondering if there is any way to convert plasma AUC after oral
> dosing to Km value in order to compare with in vitro Km and Vmax
> values obtained from microsomal incubations.
No. There are several problems:
1) AUC after oral dosing is affected by both clearance and
bioavailability
2) The relationship CL/F = Dose/AUC holds for linear kinetics only. If
linear kinetics apply, you cannot obtain Km or Vmax; at best, you get
intrinsic clearance = Vmax/Km.
> Is it unusual that the Cl
> intrinsic from in vitro data does not correlate well with Clearance
> value obtained from in vivo data.
No, that's not unusual. There is extensive literature about this. One
obvious reason is that in vivo clearance may be due to other organs,
e.g.
see:
De Kanter R, Monshouwer M, Draaisma AL, De Jager MH, De Graaf IAM,
Proost
JH, Meijer DKF, Groothuis GMM. Prediction of whole-body metabolic
clearance
of drugs through the combined use of slices from rat liver, lung,
kidney,
small intestine and colon. Xenobiotica. 2004; 34(3): 229-241.
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
Email: j.h.proost.-at-.rug.nl
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The following message was posted to: PharmPK
Avantika,
We have been able to fit in vivo kinetic parameters for both
metabolism and
transport with GastroPlus(tm) - but only when sufficient data exist.
These
can be even be fitted to any combination of tissues wherein metabolism
occurs using a PBPK model.
Sufficient data usually means plasma concentration-time data for several
different dose levels, as well as good physicochemical
characterization of
the compound. You always have the risk of multiple solutions in
problems of
this nature, but if there are enough observations at different dose
levels
(and, ideally metabolite concentrations and/or urine recovery of
metabolite)
then it can be possible to find a single model that explains all of the
data.
Such models are never perfect, but they can certainly be good enough
to be
very useful.
Walt Woltosz
Chairman & CEO
Simulations Plus, Inc. (NASDAQ: SLP)
42505 10th Street West
Lancaster, CA 93534-7059
U.S.A.
http://www.simulations-plus.com
E-mail: walt.at.simulations-plus.com
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