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The following message was posted to: PharmPK
Dear All,
We have a drug delivery system, where lipophilic drug is in the
phospholipid bilayer of the liposomes. Drug and liposome radiolabeled
with C14 and H3 respectively. We measure the amount of liposome in
whole blood and in plasma. The ratio of liposome in blood to plasma
equals to 0.6 in vivo (blood collected and plasma obtained from rats)
and in vitro (liposome is spiked in blood). Please note that
hematocrit was reported to be 50%, this suggests that liposomes with
RBC interaction is minimal. However, the ratio of drug in blood to
plasma equals to approximately to 1 for drug in in vivo and in vitro.
What is puzzling is that how is it possible that the concentration of
drug (very lipophilic drug) can be equal in plasma and whole blood?
In other words, how could that be that drug concentration in RBC
volume equals to plasma. So far, we were unable to find any reference
to plasma protein binding of this drug. Any information will be
appreciated greatly.
Best Regards,
Banu S. Zolnik
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The following message was posted to: PharmPK
Dear All,
We have a drug delivery system, where lipophilic drug is in the
phospholipid bilayer of the liposomes. Drug and liposome radiolabeled
with C14 and H3 respectively. We measure the amount of liposome in
whole blood and in plasma. The ratio of liposome in blood to plasma
equals to 0.6 in vivo (blood collected and plasma obtained from rats)
and in vitro (liposome is spiked in blood). Please note that
hematocrit was reported to be 50%, this suggests that liposomes with
RBC interaction is minimal. However, the ratio of drug in blood to
plasma equals to approximately to 1 for drug in in vivo and in vitro.
What is puzzling is that how is it possible that the concentration of
drug (very lipophilic drug) can be equal in plasma and whole blood?
In other words, how could that be that drug concentration in RBC
volume equals to plasma. So far, we were unable to find any reference
to plasma protein binding of this drug. Any information will be
appreciated greatly.
Best Regards,
Banu S. Zolnik
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The following message was posted to: PharmPK
Hello Banu,
Can you provide more details as to how you conducted your studies.
Most importantly, how were the liposomes labeled, what type of liposomes
(small, unilamllar, sterically stabilized, PEGylated)? Many of the
lipid-labels are not stable and will partition out of liposome
bilayer and
into RBC (e.g., Rh-PE). Particles that are not pegylated and
administered
in vivo would be expected to coated with serum proteins (CL by RES),
therefore the time you measure concentrations would also be important?
Have you attempted to measure protein binding of the drug? Have you
looked
at the ratio of free drug in the absence of liposomes? If your drug is
lipophilic and partitions into the lipid bilayer (similar to paclitaxel)
then I would expect that the drug can also associate with proteins
and any
released drug would also be able to associate in the membrane of
RBCs. When
looking at drug encapsulation you should examine the ratio of the
drug and
carrier:
(Conc drug/conc carrier)/ (conc drug/conc carrier)
This can give you an idea of drug release in each of the fractions
relative
what you started with, relative to the carrier.
Based on conventional separation assays to obtain plasma you would NOT
separate liposomes, and if the drug is that lipophilic it is not
surprising
that it would associate with RBC or plasma proteins.
I would conduct an in vitro study with only free drug and look measure
protein binding of your free drug.
If you have remaining samples you can use a combination of size
exclusion
(sephadex) to get at free vs total bound/associated.
Good luck,
Rusty
=Robert D. Arnold, Ph.D. "Rusty"
Assistant Professor
rarnold.at.rx.uga.edu
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