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The following message was posted to: PharmPK
Hi Dr Wang,
I saw your reference to a probable increase in volume of distribution
with age for diazepam and it makes me ask the question of how this
could actually occur because the populations I am more familiar with
tend to reduce body fat with age, so you would expect a lipophilic
molecule to find a smaller volume of distribution. Hence, I'm bound to
ask which population was in the study or studies that you quoted.
If increased Vd is proposed simply to explain a lower Cmax then of
course I would suggest that slower absorption could be an alternative
explanation. Personally, I think that is a more likely reason than
increased volume of distribution, not only for physiological reasons
but because it could also explain the higher trough values, although I
do agree that renal function fades with age so renal clearance is
likely to make the greater contribution.
Thanks for any clarification you can provide
Andrew (Sutton)
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The following message was posted to: PharmPK
Dear Andrew:
Dr. Leslie Z. Benet provided that paper in his 12/24/09 reply to my
comment on the topic of clearance.
"So for diazepam you should look at the original study clearly showing
that half-life changes with age but clearance doesn't (Klotz et al. J.
Clin. Invest. 55:347-359, 1975), and that the half-life change was due
to increased volume with age as I explained previously."
His previous explanation refers to his 12/21/09 reply to my earlier
comment on the same topic.
"The change in half-life is due to the redistribution of body fluids
with age causing more diazepam to distribute out of the fluids delivered
to the liver, the organ of elimination".
The authors of that paper observed this increased volume of distribution
with age based on PK models, but concluded "The distribution of a drug
such as diazepam is so complex that it is difficult to identify
precisely the specific biological causes of the change in the kinetic
findings."
The increased volume of distribution is derived from data that were
based on IV dosing. Also the drug is primarily metabolized by CYP3A4 and
2C19 (product labels:
http://www.accessdata.fda.gov/drugsatfda_docs/label/2005/020648s008lbl.pdf
and
http://www.accessdata.fda.gov/drugsatfda_docs/label/2008/013263s083lbl.pdf
The full article of Klotz et al. J. Clin. Invest. 55:347-359, 1975 can
be accessed online at
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC301753/pdf/jcinvest00166-0144.pdf
Best regards,
"The contents of this message are mine personally and do not necessarily
reflect any position of the Government or the Food and Drug
Administration."
Yaning Wang, Ph.D.
Team Leader, Pharmacometrics
Office of Clinical Pharmacology
Office of Translational Science
Center for Drug Evaluation and Research
U.S. Food and Drug Administration
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The following message was posted to: PharmPK
Dear Yaning
Thanks. I appreciate the information and note that the observation is
model based and not physiological. As I see it your quotation (copied
below) from the Benet paper is saying that elimination is reduced
rather than the volume of distribution being increased.
"The change in half-life is due to the redistribution of body fluids
with age causing more diazepam to distribute out of the fluids delivered
to the liver, the organ of elimination".
Which could be explained by a reduced rate of absorption from the gut.
I think the same effect would be caused by a reduced hepatic
extraction capacity although that seems less likely due to the small
amounts involved. On the other hand it's perhaps more probable as part
of a physiological ageing process than a reduced absorption since I
have not encountered that particular mechanism before.
Andrew
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