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The following message was posted to: PharmPK
We rencently completed a study on drug interactions
among two highly protein-bound compounds. The
interesting finding is after addition of the second
compound, the AUC and CL of compound 1 did not change,
whereas the Vss (Vc, Vp) and t1/2 significantly
increased. This could be due to Fu or F change, but
highly unlikely. Any thoughts about it? Thanks.
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The following message was posted to: PharmPK
Dear Dr China,
Could you please provide some details on:
1) How did you administer the drugs?
2) What were the dose levels for the treatments?
3) Did you measure total or unbound plasma (?) concentrations?
4) How did you determine the PK parameters (NCA or modelling?)
5) By how much did the PK parameters for drug 2 change?
6) Do you have estimates for "highly" protein bound?
Best regards
Juergen
--
Juergen Bulitta, M.Sc., Scientific Employee, IBMP,
Paul-Ehrlich-Str. 19, D-90562 Nuernberg,
Germany
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The following message was posted to: PharmPK
Hi,
What you describe could very well be due to changes in protein binding
(fu) of a compound with a high extraction degree. For such a compound,
changes in fu does not affect its clearance (which is more related to
hepatic blood flow) but changes the volume of distribution, which
results in changes in half-life.
Toufigh Gordi
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Boy China,
You really needed to provide more information. However, if one
assumes that you measured total (bound + unbound) drug
concentrations; that both drugs were given intravenously (you
calculated CL and Vss so this should be a valid assumption); and that
Compound 1 is characterized by high systemic clearance, then a simple
plasma protein binding displacement will explain the volume of
distribution and T1/2 increases found. The percent change in T1/2
relative to the change seen in the volume of distribution will depend
on whether Compound 1 inherently exhibits a low or high volume of
distribution.
What confused me is your reference to F (bioavailability), which
leads me to believe that you did not administer these drugs
intravenously. If this is the case, then your calculations of Vss
and CL are not valid unless, a priori, you know MRT (after oral
administration you are actually measuring MGT + MRT) and F,
respectively.
Regardless of the above, after oral administration, a plasma protein
binding displacement of a drug with high systemic clearance will
again result in increases in both the volume of distribution and T1/2
of this drug, and in theory, the bioavailability (F) for a high
systemic clearance drug can also be influenced by a plasma protein
binding displacement.
Hope this helps,
Hank Pieniaszek
HPP Consulting & Services
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