Back to the Top
Dear Colleagues,
I would need some more information on drug transport mechanisms that
I hope any of you could help me with.
How does the charge dependence influence the uptake in the liver? We
use a small molecule to couple 2 different linkers to it; in vivo
they show different characteristics/kinetics in mice; and we have no
explanation for it. One linker was observed to be taken up in the
liver to a high extent, while the other linker was not. The factors
we could think of: charge dependence, lipophilicity and molecule
size. Is there any other aspects that we have missed? and what effect
the electrical charge have on hepatic uptake/accumulation? Your
contribution would be helpful. Thank you
Back to the Top
The following message was posted to: PharmPK
Dear Thuy Tran,
charge may influence 'transportability' of a compound depending on which
type of 'energy' (electrochemical gradient e.g.) drives translocation
across
the plasma membrane. Since 'inside cells' is more negative compared to
outside of a cell, such electrochemical gradient may offer a driving
force
to energize transport of cationic type compounds. How well this
transport
goes depends on the affinity for the transporter and the amount of
transporter (Km and Vmax).
Anyway, have a look at the plethora of data on organic cation
transporters(SLC22A or OCTs as they were named before HUGO came into
existence) or OATPs organic anion transporting polypeptides ( this
family is
now called SLC(O)21). Of both OCTs and OATPs some are (highly)
expressed in
the basolateral plasma membrane of the hepatocytes. Reviews in Pubmed
should be easy to find on OCTs (not the transcription factors!) and
OATPs.
Chemicals that have a cationic charge at physiological pH and are either
permeant enough to diffuse through biological membranes or are
transported
by some transport protein in intracellular organelles is that these
molecules can accumulate in (acidic) cell organelles. Or they
'simply' get
stuck in biological membranes (have a look at Rodgers, Leahy and Rowland
about tissue distribution of basic compounds JPS 2005).
One other feature that may influence the PK behavior is protein binding.
Anyway hope this helps
Regards
Hans
PharmPK Discussion List Archive Index page
Copyright 1995-2010 David W. A. Bourne (david@boomer.org)