Dear Offer,Back to the Top
There could be factors like suspending agent, volume of administration
and etc. in your issue. Regarding suspending agent, you can try better
wetting agent+ Methylcellulose or methocel to get proper uniform
suspension.
Another main factor is volume of administration. I feel it would be
beneficial if you can use 10 ml/kg.b.wt, then the strength of the
suspension will be diluted by which you may get more availability.
For rate of volume and all, the following website may help u.
www.eslav.org/efpia.htm
Regards,
KANTHI KIRAN
Dear Frederic,Back to the Top
Is there any alternative to Miglyol to solubilize the drug before
adding methylcellulose aqueous solution?
Hello,Back to the Top
regarding your answer I would argue that 10 mL/kg is a very large
volume of administration for rats. I know that this is used sometimes
but I would recommend not to dose more than 5 mL/kg.
Best regards,
Frederic Doc
Pfizer Global R&D
In response to a question about bioavailability of drugs in MiglyolBack to the Top
vehicle, it has been my experience with lipophilic drug that are soluble
in Miglyol, that bioavailability in rats was dependent on volume. The
same mass of drug delivered in various volumes orally to rats showed
highest bioavailability when the lowest volume (and therefore highest
concentration) was used.
Thomas L. Tarnowski, Ph. D.
Project Team Leader
Dept. Head (Dep), Drug Metabolism and Pharmacokinetics
Roche Palo Alto
3431 Hillview Avenue, Palo Alto, CA 94304
* Phone: (650) 852-3182
* FAX: (650) 852-6428
* email tom.tarnowski.aaa.roche.com
Thank you all for the interesting replies to my original question.Back to the Top
I would like to follow up on this topic:
Given that assesment of relative bioavailability in rats is highly
dependent on the experimental conditions used (vehicle volume in this
case), what is the applicability of using the rat as an animal model
for assessing the potential effects of various formulations on oral
bioavailability in humans? In other words, how am I to use the rat for
assessing the potential merit of formulating a lipophilic drug
dissolved in e.g. Miglyol (intended for use in humans as a gelatin
capsule) vs. methylcellulose suspension (intended for use in humans as
an immediate release tablet)?
Are there any other/better ways of doing so?
Thanks,
Ofer
The same mass of drug delivered in various volumes orally to rats showedBack to the Top
highest bioavailability when the lowest volume (and therefore highest
concentration) was used.
Thomas,
The correlation you observed between volumes and bioavailability is a
kinetics issue. Your lipophilic drug is more likely to keep solubilized
in a
lipophilic vehicle. so if the initial concentration is low the partition
phenomenon between Miglyol and GI hydrophilic fluids will take place
slowly.
And the absorption from the GI tract should be lowered.
And if the concentration is high the partition kinetics is supposed to
be
higher. And the absorption will be optimized.
Does it make sense?
Regards,
Frederic Doc
Pfizer Global R&D
-
Jimmy,
one alternative could be the Labrafil for instance.
We used sometimes the Labrafil M 1944 CS to solubilize lipophilic drugs
in
emulsions.
Regards,
Frederic Doc
Pfizer Global R&D
Back to the Top
The following message was posted to: PharmPK At 02:14 AM 1/6/2004,
Frederic Doc wrote:
The correlation you observed between volumes and bioavailability is a
kinetics issue. Your lipophilic drug is more likely to keep solubilized
in a
lipophilic vehicle. so if the initial concentration is low the partition
phenomenon between Miglyol and GI hydrophilic fluids will take place
slowly.
And the absorption from the GI tract should be lowered.
And if the concentration is high the partition kinetics is supposed to
be
higher. And the absorption will be optimized.
So, Frederic, are you saying that the absorption rate is dependent on
the concentration difference across the apical membrane, not just on a
constant Ka and the amount of mass in solution?
Of course, I would agree. ; )
This is an excellent example of why absorption (by passive diffusion)
should be treated using Fick's Law rather than some constant Ka times
mass of drug in solution - the same mass of drug could be at different
concentrations depending on the amount of fluid.
Walt Woltosz
Chairman & CEO
Simulations Plus, Inc. (SIMU)
1220 W. Avenue J
Lancaster, CA 93534-2902
U.S.A.
http://www.simulations-plus.com
Phone: (661) 723-7723
FAX: (661) 723-5524
E-mail: walt.aaa.simulations-plus.com
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