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Hello All:
Our drug in question is given IV and has shown potential to inhibit P-gp in in-vitro
studies. While I know that digoxin is used as a model substrate to determine to determine
the effect on P-gp, my assumption is that it can only be used when the drug in question is
administered orally. Since our drug is to be administered IV via infusion, what would be a
good model substrate to determine it's effect on P-gp? Also, would one still compare the
AUC and Cmax of digoxin before and after treatment with our drug or would it be something
else?
I appreciate your responses
Cynthia
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The following message was posted to: PharmPK
Cynthia,
If your drug is highly bound in plasma, you may not see much effect on
digoxin. On the other hand, if it is not, it might partition into the
enterocytes and might have a noticeable effect on digoxin absorption, as
well as bring effluxed into the gut lumen.
Best regards,
Walt Woltosz
Chairman & CEO
Simulations Plus, Inc. (NASDAQ: SLP)
42505 10th Street West
Lancaster, CA 93534-7059
U.S.A.
http://www.simulations-plus.com
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The following message was posted to: PharmPK
Cynthia,
Digoxin is still highly dependent on P-gp for renal excretion but this is usually not very
significant because oral inhibitors don't reach concentrations at the kidney high enough
to exceed IC50. But for IV drugs, renal P-gp inhibition is likely to affect digoxin PK.
You won't necessarily see it on Cmax but you will see it on AUC and CL. CL might also be
reduced due to inhibition of digoxin biliary clearance through P-gp.
Any other substrate for intestinal P-gp will not be useful since you are giving IV
(although your IV drug might be excreted into the intestine by P-gp but this will be
minor)
Hope this helps.
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