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Dear All
Greeting for day.
We are carrying out some drug interaction studies with flavonoids in
rats as animal model. The oral dosing of the drugs was by 0.5% Sodium
Carboxymethyl Cellulose. Most of the published reports mentioned that
favonoid was orally administered in rats using distilled water as
vehicle.
If flavonoids will be administered using 0.5% Sodium Carboxymethyl
Cellulose, is there any effect on CYP3A activity?
Thank you in advance
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Generally speaking, CMC formulations do not have excipient effects
that are different from those of water. The 0.5%CMC is used as a
suspension agent for compounds that will not be readily soluble and
require a homogeneous suspension. The one issue to control is that
the dose suspension/solution is well stirred and mixed.
Sanjeev Thohan
SARxConsult.-a-.Gmail.com
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Generally surfactants do impact CYP activity, polymers do not.
Kindly check following references to get an insight to role of
excipients
and solvents at the designated concentrations on CYPs.
International Journal of Pharmaceutics 211 (2000) 89-92
Human & Experimental Toxicology (2006) 25: 715-721
Drug metabolism and disposition, Vol. 29, No. 2, 2001, 141-144.
To my knowledge and understanding, the precedence of usage of 0.5% NaCMC
over the years in discovery research, provides a degree of understanding
that it should not have any significant impact on CYP.
regards,
Vaibhav Sihorkar
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Another paper that might be of interest in this regard is:
Ren et al 2008 Pharmaceutical excipients inhibit cytochrome P450
activity in cell free systems and after systemic administration
European Journal of Pharmaceutics and Biopharmaceutics
regards
David
David Turner, PhD
Principal Scientist - Modelling and Simulation
Simcyp Limited
Blades Enterprise Centre, John Street, Sheffield, S2 4SU, UK
www.simcyp.com
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Vaibhav,
I see your notation on the effects of solvents on CYP-related
activites and they are excellent resources, but these are for in vitro
assays and no the in vivo situation. The relative concentration of the
CMC delivered in vivo wold not approach the 1-2% noted for other
solvents in an in vitro situation. Basedon a noraml physiological
dose, liver blood flow and absorption of the excipient, you would not
be able to reach high enough concentrations for long enough to impact
the capacity of the liver to metabolize a substrate molecule. The in
vitro situation is a static incubation where there can be a relatively
stable concentration of a solvent/excipeint in the enzyme mileu.
Solvent effects on membrane fluidity, accociation of the proteins
therein and thier coupling to result in altered metabolic rates in
vitro has been known from early reconstitution studies in the 70's
from Judd Coon and Anthony Lu's work. The in vivo situation would
require a different study design.
--
Sanjeev Thohan, PhD
SARx Consulting
SARxconsult.at.Gmail.com
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I agree with your views as the literature I shared focuses more on pre-
systemic metabolism and offers insight on cell based assays. However,
most of these excipients used in early discovery may not necessarily
get absorbed to systemic circulation to impact or modulate the CYP 3A
activity. But as yo suggested, if they do, in vivo situation may be
difficult to simulate and could be different than in vitro assays.
regards,
Vaibhav Sihorkar
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I agree with your views as the literature I shared focuses more on pre-
systemic metabolism and offers insight on cell based assays. However,
most of these excipients used in early discovery may not necessarily
get absorbed to systemic circulation to impact or modulate the CYP 3A
activity. But as you suggested, if they do, in vivo situation may be
difficult to simulate and could be different than in vitro assays.
regards,
Vaibhav Sihorkar
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