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Dear all,
How can one explain the difference in the apparent half-lives when
the same drug is applied in different dose. In particular, half-life
with higher dose is shorter than half-life with lower dose.
Thanks.
Alex
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Hi Alex,
In some cases, a particular drug which is a very good substrate for
liver pGP could (at high doses) saturate this efflux pathway. Thus,
more drug is available for metabolism. Of course this is if your drug
is eliminated via the hepatic metabolic pathways.
In case your compound is eliminated mainly through renal route, and
the net process for elimination is renal re-absorption (rather than
secretion), at high doses the re-absorption will be saturated and
more drug will remain in urine, thus increasing the value of apparent
CL (and accordingly apparent half-life). I am including the citation
from a reference that addresses the second possibility. I hope this
helps.
Murad Melhem, Ph.D.
Cognigen Corporation
Buffalo, NY
Clin Exp Pharmacol Physiol. 2005 Jan-Feb;32(1-2):13-8.
Pharmacokinetics of high doses of cyanocobalamin administered by
intravenous
injection for 26 weeks in rats.
Nava-Ocampo AA, Pastrak A, Cruz T, Koren G.
Division of Clinical Pharmacology and Toxicology, The Hospital for Sick
Children, Toronto, Canada
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Dear Alex
To answer your question, it will be important to know if it was a
intravenous dosing or oral dosing and also if the compound was dosed
in animals or in humans
Pavan
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The following message was posted to: PharmPK
Dear Alex
The difference in the apparent half-lives may be appeared by nonlinear
plasma protein binding, in other words saturation of plasma protein
binding
of a drug. In case of multiple dose, self enzyme induction may be the
reason, for example, carbamazepine. Hope this would be help.
Kwon KI
CNU
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You would have to consider whether the dose was administered as an IV
dose or an oral dosage form, as mentioned earlier. One of the other
important aspects of this type of alteration to the half life could
be related to capacity and/or flow issues with metabolic processes in
the liver. If in fact this is the case and you are overwhelming the
system, your half lives would increase. If you are activating the
system, i.e. CYP isoform switching, then you may see increased
metabolic clearance. From a transport standpoint, biliary transport
could be increased over a limited range; however, this would have
limitations on the capacity of the system to manage to dose
presented. There are many factors that would play in here, as some
of the other contributors have alluded to. A more detailed view
would be helpful in providing really meaningful feedback in this case.
Sanjeev Thohan, PhD
Director, DMPK
Exelixis, Inc
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