Mechanisms for the hepatic uptake and biliary excretion of tributylmethylammonium:Studies with rat liver plasma membrane vesicles

Hepatic organic cation transport in vitro, using tetraethylammonium (TEA) as a substrate, consists of at least two steps: sinusoidal uptake is stimulated by an inside-negative membrane potential and canalicular membrane transport is mediated by organic cation:H+ exchange (Moseley et al., 1992b). In vivo, however, TEA is poorly excreted into bile. In contrast, larger, more hydrophobic organic cations, such as tributylmethylammonium (TBuMA), undergo significant hepatobiliary excretion. To better characterize hepatic organic cation transport, TBuMA transport was examined in rat canalicular liver plasma membrane (cLPM) and basolateral liver plasma membrane (blLPM) vesicles. In cLPM vesicles, under voltage-clamped conditions, an outwardly directed H+ gradient stimulated [H-3]TBuMA uptake consistent with electroneutral TBuMA:H+ exchange; H+-dependent [H-3]TBuMA uptake was not the result of a H+ diffusion potential. In the absence of a H+ gradient, intravesicular TBuMA trans-stimulated [H-3]TBuMA uptake. Substrates for renal and hepatic organic cation:H+ exchange cis-inhibited H+-dependent [H-3]TBuMA uptake. No ATP-dependent [H-3]TBuMA uptake was detected in cLPM vesicles, and the P-glycoprotein substrate, daunomycin, did not cis-inhibit H+-dependent [H-3]TBuMA uptake. Carrier-mediated [H-3]TBuMA uptake exhibited saturability (K-m of 0.5 mM and V-max of 0.5 nmol/mg prot/5 s). In blLPM vesicles, in contrast, a valinomycin-induced intravesicular-negative K+ diffusion potential stimulated [H-3]TBuMA uptake. These findings suggest that hepatic transport of TBuMA is similar to TEA but fundamentally different from that of P-glycoprotein substrates, indicating the involvement of at least two separate processes for the hepatobiliary excretion of organic cationic drugs

CMS Physics Technical Design Report: Addendum on High Density QCD with Heavy Ions

This report presents the capabilities of the CMS experiment to explore the rich heavy-ion physics programme offered by the CERN Large Hadron Collider (LHC). The collisions of lead nuclei at energies $\sqrt{s_{NN}}= 5.5\,{\rm TeV}$ , will probe quark and gluon matter at unprecedented values of energy density. The prime goal of this research is to study the fundamental theory of the strong interaction \u2014 Quantum Chromodynamics (QCD) \u2014 in extreme conditions of temperature, density and parton momentum fraction (low- x ). This report covers in detail the potential of CMS to carry out a series of representative Pb-Pb measurements. These include "bulk" observables, (charged hadron multiplicity, low p T inclusive hadron identified spectra and elliptic flow) which provide information on the collective properties of the system, as well as perturbative probes such as quarkonia, heavy-quarks, jets and high p T hadrons which yield "tomographic" information of the hottest and densest phases of the reaction