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The following message was posted to: PharmPK
Hello all,
concerning the compound bromosulfophthalein glutathione, is there any
difference in their actions at transporters when radioactive/non
radiolabelled kind is used?
it just seems my results (non radioactive BSPGSH) has given
substantially different results than those done in the papers using
radioactive compound.
i am talking specifically about extraction ratios. should be 95%. i
got around 50%.
does any one know of any processes that occur at the transporter
level which could account for these differences?
Many Thanks,
Leila
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The following message was posted to: PharmPK
Dear Leila,
As you've used non-radioactive bromosulfophthalein glutathione, it is
possible that the concentration you've used could be high over the
experiments using radiolabeled compound. If so, low extraction ratios in
your case could be the result of saturation of transporter function.
Kasiram
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The following message was posted to: PharmPK
Dear Kasiram,
no, the concentration i used was the same (20uM)...
What do you mean by transporter saturation? how might that occur?
excuse my ignorance i am very new to the field!
Thanks,
Leila
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The following message was posted to: PharmPK
Dear Leila,
The transmembrane transport of a drug that is substrate for either
efflux (such as P-glycoprotein, MRP etc) or uptake (such as OATP, OAT
etc) transporter could be saturable depending on the affinity (Km) of
the transporter for that particular substrate. A transporter with high
affinity will have low Km and gets saturated at relatively low substrate
concentrations and vice versa for transporters with low affinity. The
rate of transport (by a transporter) follows first order kinetics (i.e.,
a linear function of concentration) at substrate concentrations around
Km. However, with increase in concentration much above Km, the transport
will no longer be a linear function of substrate concentration and
eventually levels off (zero-order). This is called saturation effect.
So, for a drug that is substrate for an 'uptake' transporter, extraction
ratio obtained using drug concentrations much above the Km would be low
(as a result of saturation in uptake) compared to the ratio obtained
using drug concentrations around Km. An opposite effect is observed with
drugs that are substrates for 'efflux' transporters as saturation of
efflux transporter would increase uptake.
There are numerous papers on this subject and I suggest you refer papers
relevant to the transport model you are using.
Hope this helps.
Kasiram
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The following message was posted to: PharmPK
Hi, Leila,
Extraction ratio (E) is determined mutally by several intrinsic
clearances: intrinsic influx clearance, metabolic clearance and
biliary clearance increases E, however, intrinsic efflux clearance at
the basolateral membrane decreases E. All the intrinsic processes
could be mediated by proteins (transporters and metabolic enzymes).
Cold drug would saturate any process and thereby modulate extraction
ratio, however, radiolabelled compounds normally be present in a low
concentration and can not saturate any process (in which we say this
complies with linear kinetics). For your drug, the possible
explanation is that high dose saturate influx transporters (oatp) and/
or biliary secretory transporter (mrp2), resulting in the attenuated
vectorial transport of BSPGSH.
Hope this helps.
Best regards,
Huadong Sun
hd.sun.aaa.utoronto.ca
2006-08-08
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