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Dear All,
We observed a compound with high total clearance in vivo (Cl/Q=30%),
no renal elimination of parent compound, and high bioavailability
(F=80%) after PO dosing. The IV and PO pk curves have parellel
terminal phase. F is the dose corrected AUC ratio between PO and IV.
My thinking is there is biliary and intestinal secretion and
elimination from gut for this compound. Anyone has any suggestions
for the possible reasons of the above phenomena?
Thank you!
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The following message was posted to: PharmPK
Your data looks fine to me. What's the problem?
(First, I would call CL/Qh = 30% moderate instead of high clearance.)
Given the error involved in these types of calculations, your %F could,
for example, actually be 75% and your CL/Qh 25%
Then you have an extraction ratio of 1 - 0.75 = 0.25 (a "text book"
example of the relationship between max theoretical %F and hepatic
extraction ratio for metabolically cleared drugs).
You should publish ;-)
Peter Rix
Kalypsys, Inc.
San Diego, CA
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Dear Dan,
actually your observed total plasma clearance is not so high
(extraction ratio = 0.3 in a first pass effect in the liver),
considering that the hepatic blood flow is around 30% of cardiac
output the overall extraction ratio (Ebody) is around 10%.
Anyway, about your question: you are considering that your total
plasma clearance is due to only hepatic metabolism, but there could
be also the contribution from the lung for example.
In addition, if this would be the case, your computation of the
clearance after iv administration could give an artifact not
considering the lung first pass effect (overestimation of the
clearance).
Hope this will help
best regards,
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The following message was posted to: PharmPK
Have you examined red cell or plasma enzyme activity towards your
drug or
plasma binding?
Ed O'Connor, Ph.D.
Laboratory Director
Matrix BioAnalytical Laboratories
25 Science Park at Yale
New Haven, CT 06511
Web: www.matrixbioanalytical.com
Email: eoconnor.-a-.matrixbioanalytical.com
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