Here is the abstract.
ABSTRACT: The hepatic bile acid uptake transporter sodium
taurocholate cotransporting polypeptide (NTCP) is less well
characterized than its ileal paralog, the apical sodium
dependent bile acid transporter (ASBT), in terms of drug
inhibition requirements. The objectives of this study were (a)
to identify FDA approved drugs that inhibit human NTCP,
(b) to develop pharmacophore and Bayesian computational
models for NTCP inhibition, and (c) to compare NTCP and
ASBT transport inhibition requirements. A series of NTCP
inhibition studies were performed using FDA approved drugs,
in concert with iterative computational model development.
Screening studies identified 27 drugs as novel NTCP
inhibitors, including irbesartan (Ki = 11.9 μM) and ezetimibe
(Ki = 25.0 μM). The common feature pharmacophore indi-
cated that two hydrophobes and one hydrogen bond acceptor
were important for inhibition of NTCP. From 72 drugs
screened in vitro, a total of 31 drugs inhibited NTCP, while
51 drugs (i.e., more than half) inhibited ASBT. Hence, while there was inhibitor overlap, ASBT unexpectedly was more permissive to drug inhibition than was NTCP, and this may be related to NTCP possessing fewer pharmacophore features. Findings reflected that a combination of computational and in vitro approaches enriched the understanding of these poorly characterized transporters and yielded additional chemical probes for possible drug−transporter interaction determinations
This paper is also fascinating, since it clarifies the mystery, recently discussed directly in the ezetimibe thread, how ezitimibe works to block Hbv entry, as shown by ulrike prozer in the hepaRG system. It is simply a NTCP blocker, moderatly potent. Of note, blockage of this receptor, NTCP, is also the mechanism by which Myrcludex works as an entry inhibitor. It is the membrane protein that normally transports bile acids from the portal blood into the hepatocytes for recycling. No wonder upon sufficient Myrcludex dosing, the bile acids start accumulating in the systemic circulation.
i see it has no relevant sides and no toxicity, a combo ezetimibe plus irbesartan is for sure very very interesting.
shall i wait for next hbsag quant test before trying this add on?i also have relatives using these drugs and they confirmed no sides at all from this drug
There is an interesting way to test the efficacy of the blockage of the HBV receptor, the NTCP, by measuring your bile acids in the blood. You should check them right now for a baseline. Too bad we dont have a pre ezetimibe value, but they could be mildly elevated. Irbesartan should increase them further, witinin days. We already know, that myrcludex increases the bile acids strongly, which is a beautiful confirmation of its blocking effect on the NTCP. Thus the bile acids could be used as a quick surrogate marker of blockage of the HBV entry receptor. I would expect that one week after irbesartan add on the bile acids w
With regard to the question of waiting how the quant hbsag further responds to the 50mg ezetimibe, before trying the irbesartan, there is no simple answer.
In my opinion, if the ezetimibe blocks HBV reinfection mildly to moderatly, we should expect a shift of the surface antigen over time to a lower value, but there is likely a new level, a new equilibrium where it will stabilize. In this case you would see again a lower than previous value, but no further clear downwards trend. It might be important to clarify that before adding the irbesartan.
If you think of using the irbesartan, remember it is a blood pressure medication. It could cause you dizziness, or even synkope if you get up too rapidly in the morning. Also, clear this approach with your doctors in Pisa. I expect that they will be quite fascinated by the chance to block hbv entry with a harmless, often rather beneficial blood pressure medication.
the research center has my frozen blood tests and they are available if necessary, i can get oct 2012 frozen blood samples to get tested for bile acids in blood.i should be able to get this value in april
i ll check hbsag quant and bile acid in blood next week then we can add on Irbesartan
One thing that we have to keep in mind is that the bile acids in serum will fluctuate during the day according to bile output during meals and concomitant reabsorption in the ileum which will raise the systemic ba levels.
Thus testing should be strictly under morning fasting conditions to allow meaningful comparisons. Also bile acid serum samples have to be sent to the lab frozen.
And again, be careful when using irbesartan regarding dizziness. It might take a while to adapt to it, since it will lower your blood pressure.
gonna get salt back in my diet....i ll be very careful
Do we have more info on next move by FDA following this discovery?
No, nobody will even take note of this. Researchers like prozer will hopefully test it soon in culture and animal models to establish if there is in vivo efficacy of hbv entry blocking.
i guess that if we reach a good level of reinfection block by these drugs we should see big hbsag drop by 6-8 months of use thanks to hepatocytes turn over indipendently from immune clearance
are there any predictions on myrcludex response in case of tdf or etv combo treatment?
Thanks for quick response.
I ll try and make contact with the drug maker as this represent a potential business opportunity although its out of patent.