Implications of Efficient Hepatic Delivery by Tenofovir Alafenamide (GS-7340) for Hepatitis B Virus Therapy

Inside the Peristyle Court of Tuthmosis III, view looking north showing two granite pillars representing Upper and Lower Egypt with a statue of Amun-Re at left; Pylon IV, preceded by obelisks, is the façade of the Ipet-sut. This comprises, from the entrance inwards: a hypostyle hall dominated by the remaining obelisk of Hatshepsut; pylons V and VI; a hall with historical reliefs (the 'Annals of Tuthmosis III'); and a granite shrine of Philip Arrhidaeus (reigned 323-316 BCE) containing a 'solar bark' (the ceremonial boat of the sun-god). The sacred shrine of the Middle Kingdom was originally situated in the 'Middle Kingdom Court' behind an earlier version of the bark shrine. Source: Grove Art Online; http://www.groveart.com/ (accessed 1/19/2008

Metformin Is a Substrate and Inhibitor of the Human Thiamine Transporter, THTR-2 (SLC19A3).

The biguanide metformin is widely used as first-line therapy for the treatment of type 2 diabetes. Predominately a cation at physiological pH's, metformin is transported by membrane transporters, which play major roles in its absorption and disposition. Recently, our laboratory demonstrated that organic cation transporter 1, OCT1, the major hepatic uptake transporter for metformin, was also the primary hepatic uptake transporter for thiamine, vitamin B1. In this study, we tested the reverse, i.e., that metformin is a substrate of thiamine transporters (THTR-1, SLC19A2, and THTR-2, SLC19A3). Our study demonstrated that human THTR-2 (hTHTR-2), SLC19A3, which is highly expressed in the small intestine, but not hTHTR-1, transports metformin (Km = 1.15 ± 0.2 mM) and other cationic compounds (MPP(+) and famotidine). The uptake mechanism for hTHTR-2 was pH and electrochemical gradient sensitive. Furthermore, metformin as well as other drugs including phenformin, chloroquine, verapamil, famotidine, and amprolium inhibited hTHTR-2 mediated uptake of both thiamine and metformin. Species differences in the substrate specificity of THTR-2 between human and mouse orthologues were observed. Taken together, our data suggest that hTHTR-2 may play a role in the intestinal absorption and tissue distribution of metformin and other organic cations and that the transporter may be a target for drug-drug and drug-nutrient interactions

Dose-dependent intracellular accumulation of test ERAs in sandwich-cultured human hepatocytes.

<p>Ambrisentan displayed the lowest intracellular accumulation followed by bosentan, sitaxsentan, and macitentan. Data are presented as mean (±SD) micromolar (µM) concentration; n = 3 donors; *P<0.05 vs. corresponding intracellular accumulation value for ambrisentan at the same test concentration.</p

Uptake of bosentan and macitentan into human hepatocytes.

<p>ERAs were evaluated either in the absence or presence of the transporter inhibitors rifampicin (40 µM) and cyclosporin A (5 µM). Data presented as mean (±SD) pmol/million cells; n = 4 donors; *P<0.05 for comparisons indicated.</p

d₈-Taurocholate (d₈-TCA) total (A) and cellular (B) accumulation in sandwich-cultured human hepatocytes exposed to ambrisentan, bosentan and macitentan.

<p>Bosentan and macitentan treatment resulted in a dose-dependent reduction in total accumulation of d₈-TCA. Ambrisentan, bosentan and macitentan treatment each resulted in a dose-dependent reduction in cellular accumulation of d₈-TCA. Data presented as mean (±SD) expressed as percent of control treated; n = 3 donors; *P<0.05 bosentan vs. control; # P<0.05 macitentan vs. control.</p

Effect of Ambrisentan, Bosentan, Sitaxsentan, and Macitentan on Hepatic Uptake and Efflux Transporters.

a<p>Data presented as mean ± standard deviation for 3 independent studies performed in duplicate;</p>b<p>Data presented for a single experiment preformed in duplicate;</p>c<p>Data previously reported <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0087548#pone.0087548-Ray1" target="_blank">[35]</a>. Ambrisentan, bosentan, and macitentan were tested in concentrations ranging from 0.14–100 µM.</p><p>ND = not determined.</p