Back to the Top
Dear all,
I am working on DDI to check the known P-gp inhibitor effect on pharmacokinetics of another drug which is P-gp substrate.As i have seen in many papers that class 2 drugs (substrate in this case) are influenced by efflux transporter (Biopharmaceutics classification system)
During the study 20 mg/kg drug was dosed (insoluble substrate) in rats and thereafter samples were analysed .Pk profile was found erratic and plateau.I thought of insolubility problem so i tried with soluble formulation and got a better PK profile.
Now for DDI study, i dosed substrate alone in one group and substrate and inhibitor in another group.Result says there is no DDI between these two drugs.
Before concluding any thing i would like to know that; is there any impact of soluble formulation verses insoluble formulation on P-gp efflux as i have doubt if formulation is soluble and there is no issue of permeability so this molecule would have bypassed the P-gp transporter and as a result i am not getting any DDI.If i would have done the same study in (0.5% CMC) i would have got the interaction.
Waiting for your expert comment
-- Regards,
Rahul Vats
BITS-Pilani, Hyderabad Campus,
Back to the Top
alternatively you can also refer to the following review by Jonathan goole....
"The effects of excipients on transporter mediated absorption"
published in International journal of pharmaceutics: it says the
following.... solubilisers or surfactants disturb the membrane
integrity and also induce fludity in them and produce a kind of
environment where there will be enhanced passive diffusion and
paracellular disposition of drug. This happens in conjuction with
decrease p-gp efflux function by which the real efflux of the drug
does not happens..
article is attached...
Thanking you and regards,
vijayabhargava.k
Suven life sciences, Hyderabad, india.
[Ref: The effects of excipients on transporter mediated absorption
Jonathan Goolea,b,, David J. Lindleya, Wyatt Rotha, Stephen M. Carla, Karim Amighib, Jean-Michel Kauffmannb, Gregory T. Knippa, International Journal of Pharmaceutics 393 (2010) 17-31 - db]
Back to the Top
The following message was posted to: PharmPK
Hi Rahul,
I forwarded your question to a colleague and his reply is below
Subject: Re: PharmPK P-gp drug-drug interaction
BCS Class 2 drugs have high permeability and low solubility. High permeability enables them to bypass uptake transporters and be absorbed by passive diffusion only. But the low solubility leads to relatively low concentrations in intestinal fluids and hence would still be affected by efflux transporters after they enter the enterocytes. For your case, when you increase the solubility, if it increases substantially you basically move the drug (substrate) into Class 1 which has high permeability and high solubility. The high solubility lead to high intestinal concentrations that can saturate P-gp (which is indeed saturable) and hence make the drug unaffected by P-gp efflux. So, in your DDI if the solubility was high enough to saturate P-gp then it basically has no role in transport of the substrate and you will see no interaction. The low solubility form (Class 2) would on the other hand show an interaction if the drug is indeed a substrate and does not have a very high bioavailability. I think th
Back to the Top
The following message was posted to: PharmPK
Hi Rahul,
It depends on the formulation whether it contains only solubilizers or
permeability enhancers that effect the absorption of the compound. As others
already mentioned, the high solubility may also affect the transporters
involved in the particular drug. Hence it is better to understand the
excipients used in clinical scenario and check the possibility of using them
in preclinical studies but it may not be feasible all the times. Hence
decreasing the dose using simple MC suspension and check the DDI effect on
it will make your understanding better. However it is better to understand
first the DDI using in vitro uptake techniques followed by above in vivo
study would be beneficial in this case.
Regards,
Kanthikiran
Back to the Top
Dear all,
Thanks for your expert comments.
I used PEG 400:Ethanol & Water combination for making a soluble formulation (40:10:50).
I am not really sure about the effect of this formulation on P-gp modulation. I have also tried less dose size (10 mg/kg) formulated in CMC but sensitivity was an issue and i got a erratic profile so i thought of increasing the dose and solubility.
Back to the Top
The following message was posted to: PharmPK
Dear Rahul,
Formulation difference i.e soluble vs Suspension will show the differential impact on P-gp efflux. Rapid Saturation of p-gp effect is possible in solution formulation and thus P-gp impact may not dominate. P-gp saturation with high permeability result in lower impact than suspension.
But it may come out in suspension if solubility is very low perticularly BCS II . Lower Solubility subsides permeability advantages for BCS II. May be it will help you?
Thanks
Vinod
|
Want to post a follow-up message on this topic?
If this link does not work with your browser send a follow-up message to PharmPK@boomer.org with "P-gp drug-drug interaction" as the subject | Support PharmPK by using the |
Copyright 1995-2011 David W. A. Bourne (david@boomer.org)