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Dear 'PharmPkers',
I have a question for the group re. the determination of Volume of
distribution of alcohol (or of any drug demonstrating Michaelis-
Menten elimination kinetics) subsequent to an iv loading dose and
concomitant infusion (assuming a one compartment model).
I recently came across a 1978 paper by John Wagner's group {Lin, Y-J
et al., J, Pharmacokin. Biopharm., 6 (3), 197-207)} in which a
"novel" - but rather complicated - method of estimating the V of EtOH
was described. V (in cats) was estimated by solving a cubic equation
derived by the authors, subsequent to obtaining values of Vmax and Km
by fitting the postinfusion conc-time data to the integrated form of
the M-M equation.
Typical concentration-time data from this study (Loading dose = 1.874
g plus infusion of 125 mg/kg/h for 4 h in 4.0 kg cat) follows:
Time EtOH Conc
(h) (mg/100ml)
0.083 89.1
1 72.2
1.5 73.5
2 67.9
3 69.5
4 69.5 (end of infusion)
4.5 61.6
5 50.9
5.5 39.8
6 34.9
6.5 24.7
7 17.9
7.5 8.6
8 1.9
8.5 0.3
(Using NonLin, Vmax and Km were found to be 21 mg/100ml/h and 6.0 mg/
100ml, respectively; V was 0.609 L/kg.)
I may have missed the point of this study but the whole approach
(cubic eqn, etc.) seems overly complicated. What simple alternative
approach for estimating V from such data using the integrated M-M
equation would you suggest? (e.g. Why not just V = total dose/C0?)
Thanks,
Peter
Peter W. Mullen, PhD, FCSFS
KEMIC BIORESEARCH
Kentville
Nova Scotia, B4N 4H8
Canada
Tel. (902) 678-8195 Fax (902) 678-2839 E-mail pmullen.aaa.kemic.com
[I just happen to have that reprint ;-) That does seem to be the hard
way to fit the data. I think the problem is that they weren't able or
didn't want to solve the model using numerical integration (in 1978).
- db]
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The following message was posted to: PharmPK
We published a reasonably detailed pharmacokinetic analysis of
ethanol disposition in humans using the Michaelis-Menten approach and
multiple doses to the same individuals to assess the modeling
approach that
best fit the observed concentration vs time data. This may help you
with
your issues surrounding estimation of Vd and attempts at model
simplification. We found that a two-compartment model most rigorously
defined the disposition of ethanol after iv administration, and
variability
in estimation of Vd is addressed bottom of p671 and top of p672.
(Rangno RE
et al, Br J Clin Pharmacol 12, 667-73, 1981). In the end it depends
on what
outcome you are assessing on how rigorous your modeling exercise
needs to
be.
Hope this is somewhat helpful.........Dan Sitar
Dr. Daniel S. Sitar
Professor and Head, Dept. of Pharmacology and Therapeutics
Professor, Dept of Internal Medicine (Clinical Pharmacology)
Web Address: www.umanitoba.ca/medicine/pharmacology
Email: sitar.-a-.cc.umanitoba.ca
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