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Dear All,
We have a drug delivery system, where a same hydrophilic drug
encapsulated in various peglyated liposomes (5-6 different
formulations). We measure the amount of drug in whole blood/plasma
following IV bolus administration in rat, with the first time point of
5min. The C5min-15min conc. of drug was dramatically different among
investigated groups, but with almost the same terminal elimination
T1/2. And therefore the CLs calculated with NCA were quite different:
higher CL with lower initial conc. My question is:
Is it true that C0 should be the same for all liposome formulations,
as long as a same drug encapsulated? If yes, why the initial conc.
was different in the current study? Is the sample not collected early
enough to catch early kinetics? How to assign a biological
interpretation?
Any information will be
appreciated greatly.
Best Regards,
Yan
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Hello
The initial concentration in Plasma is depends on the amount of free
in the Liposomal formulations and nature of the lipids used. Was it
all the formulations were same Entrapment efficiency? I do agree that
initially high plasma concentrations it might be due to that free drug
adsorbed on the surface of the liposomes. But elimination phase would
be very slow because of controlled release rate from the vesicles.
Comments are welcome. Please correct me in this aspect.
Best wishes
A.Karthik
Manipal
MCOPS
India.
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Dear Yan,
your C0 concentration should obviously be the same if you dose the
same amount of drug per IV.
The trouble with the IV route is the hepatic first pass effect. This
is particularly the case with nanovectors such as liposomes. This is
the reason why the pegylated liposomes were created. They are supposed
to be stealth liposomes that should not be massively uptaken by the
liver. In fact depending on the formulations this massive uptake will
occur or not and is probably a reason for such differences in your
C5-15min differences.
When using such delivery systems the kinetics you are observing is in
fact the kinetics of the complex (drug-loaded liposomes) in the first
part and probably the free drug in a second part.
Best regards,
Frederic
fdoc.aaa.acriter-consulting.com
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Hello
There could be several reasons for this variation.
Firstand foremost is experimental errors. there are several steps
right from liposome preparation, estimation, injection, blood sampling
and bioanalysis. the copmounding of errors may have occured.
Secondly
1. Liposome behavior in the first few minutes may be the major reason
2. Intravenous injection rats could become erroneous even with expert
hands, leakage of liquid being injected outside vein may have
happened. there is no way to check for this in rats as they have thick
tails. Comparatively it is easier in mice to detect leakge while doing
experiment.
Regards
Dr.Prashant
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The following message was posted to: PharmPK
Dear Yan,
You mentioned about 5-6 different pegylated liposomes. Whether these
formulations vary in their lipid composition or all formulations were
with same lipid composition of varyig degree of PEGylation?
In both these cases, you can't expect same drug release profiles. This
can be inferred from the in vitro drug release profile of the
different liposomal formulation.
Was there any difference in their cumulative % drug release profile?
Did you observe any burst effect from the formulations and if so,
where they different?
Your varying initial C5-C15 drug levels of the formulations might be
due to different amount of surface adhered drug on liposomes.
Although same drug was loaded in all these liposomes, PK will be
highly influenced by the nature of carrier system.
Regards,
Chandra Durairaj,
Univ of Colorado Denver
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