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A quick question to the group. I've been reading a recent review by Dr.
William Gillespie (Clin Pharmacokinetic 1991;20(4):253) on Noncompartmental
modeling. He lists one of the basic properties associated with the
derivation of noncompartmental methods as the assumption of constant total
clearance, that is the total elimination rate is proportional to systemic
drug concentration. Also mentioned is the concept of dose proportionality
and superposition. However, I've often seen noncomparmental methods applied
to drugs that clearly have non-linear kinetics, such as Michaelis-Menten
elimination. For example, volume of distribution at steady state can be
calculated using AUC, and AUMC ignoring the fact that clearance my be
non-linear. Is this an incorrect application of this methodology?
If so, it is one which appears to be violated with great frequency in the
Chris H. Takimoto, M.D., Ph.D., FACP
National Cancer Institute
Building 8, Room 5101
National Naval Medical Center
8901 Wisconsin Avenue
Bethesda, MD 20889-5105
Fax: (301) 435-8695
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[I seem to remember that some of those papers were in J. Pkin. Biopharm,
maybe 5-10 years ago - db]
While the assumption for the common usage of Noncompartmental methods do
include linearity and clearance from the Central compartment only, the
extension of the concepts to nonlinear clearance, etc. have been described
by a series of articles by WJ Jusko et al. You can search for his papers on
this subject. I can provide some of the references if you need.
Varun Garg, Ph.D.
Aronex Pharmaceuticals, Inc.
8707 Technology Forest Place
The Woodlands, TX 77381-1191
Tel: 281-367-1666 x317
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