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Dear all,
The mouse iv plasma concentration time curves of one investigated
compound exhibits an apparent 'absorption phase'. Does anyone have
similar experience before? Any idea of the potential reasons, besides
precipitation at injection site?
Thanks,
Yan
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The following message was posted to: PharmPK
Dear XU YAN
I had this problem, and i repeted the study with the same results in
monkeys. it was a soluble NCE, I didnt find the reason until now. The
only posible explication was a uptake for some cells,with strange
equilibrium. But i hadn't the solution.
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Dear Yan
There have been reports of extravasation occuring from peripheral
veins to the interstitial space resulting in a depot of drug then
slowly redistributed over time, akin to an absorption process. Even
if no rupture is visible, or hematoma at the injection site, small
veins can be very permeable particularly if the rate of
administration on a volume base is just too much for they to maintain
their integrity. This is normally confirmed by lowering the volume or
the injection rate. Your thought about precipitation is much more
serious since you don't want solid particles being injected running
the risk of killing the animal. Furthermore the homework must be done
previously determining solubility, acid-base equilibria, partitioning
and all possible physical reasons for precipitation to be avoided.
Cheers
Luis
--
Luis M. Pereira, Ph.D.
Assistant Professor, Biopharmaceutics and Pharmacokinetics
Massachusetts College of Pharmacy and Health Sciences
179 Longwood Ave, Boston, MA 02115
Luis.Pereira.at.bos.mcphs.edu
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Dear Luis,
Could you site a literature reference for the extravasation and re-
absorption?
Thank you,
David
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Hi David
I think this phenomenon should be better called redistribution rather
than reabsorption, and it is not necessarily bad, depending on the
therapeutic objectives. The PK modeling just needs to take its
kinetics into consideration.
Just copying and pasting from my references I can list these, but
more may be found in the literature:
In mice:
"Extravasation of proteins in the joint tissue: Differential
behaviour of native BSA and cationic mBSA" Jan Willem Lens et al.,
Inflammation Research 16:1-2, 1985
"Direct measurement of the extravasation of polyethyleneglycol-coated
liposomes into solid tumor tissue by in vivo fluorescence microscopy"
Unezaki S. et al., International Journal of Pharmaceutics,
144:1,11-17, 1996
In humans:
"Visualization in the Ipsilateral Lymph Nodes Secondary to
Extravasation of a Bone-Imaging Agent in the Left Hand: A Case
Report" Wei-Jen Shih et al., Journal of Nuclear Medicine Technology
29:3,154-155, 2001
"Extravasation of intravenous contrast into the mediastinum" Colin
Schieman et al., Injury Extra 37:5, 173-175, 2006
Clinical Info:
"Extravasation of idarubicin during i.v. administration can cause
severe local tissue necrosis. Extravasation may occur with or without
an accompanying stinging or burning sensation even if blood returns
well on aspiration of the infusion needle (see Dosage). If signs or
symptoms of extravasation occur the injection or infusion should be
terminated immediately and restarted in another vein." In RxMed
"Care must be taken to avoid extravasation during injection as the
high pH of fluorescein solution can result in severe local tissue
damage. The following complications resulting from extravasation of
fluorescein have been noted to occur: Sloughing of the skin,
superficial phlebitis, subcutaneous granuloma, and toxic neuritis
along the median curve in the antecubital area.", in DailyMed
Cheers
Luis
--
Luis M. Pereira, Ph.D.
Assistant Professor, Biopharmaceutics and Pharmacokinetics
Massachusetts College of Pharmacy and Health Sciences
179 Longwood Ave, Boston, MA 02115
Phone: (617) 732-2905
Fax: (617) 732-2228
Luis.Pereira.at.bos.mcphs.edu
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