It is well accepted that drug transporters play a pivotal role in hepatobiliary excretion of anionic drugs, in which drug-drug interactions and genetic polymorphisms are known to cause variations. However, PET probes for in vivo functional characterization of these transporters have not been established yet. We used PET to investigate hepatic uptake and subsequent canalicular efflux of 11 C-labeled (15R)-16-m-tolyl-17,18,19,20-tetranorisocarbacyclin methyl ester [(15R)-11 C-TIC-Me)] in healthy subjects. Methods: Serial PET scans of the abdominal region in healthy male subjects were obtained with or without the organic anion-transporting polypeptide (OATP) inhibitor rifampicin after intravenous injection of (15R)-11 C-TIC-Me as a radiotracer. Venous blood samples and PET images were obtained at frequent intervals up to 30 min after administration of the PET tracer. Dynamic imaging data were evaluated by integration plots of data collected for 2-10 min and for 10-30 min after tracer administration for the determination of tissue uptake clearance and biliary efflux clearance, respectively. Results: After rapid hydrolysis in blood, the acid form-11 C-labeled (15R)-16-m-tolyl-17,18,19,20-tetranorisocarbacyclin [(15R)-11 C-TIC]-accumulated in the liver (37% of the dose by 17 min), and the radioactivity was then excreted into the bile (6.2% by 30 min). Rifampicin (600 mg by mouth), a potent OATP inhibitor, significantly reduced the radioactivity excreted into the bile (by 44%) by inhibiting both uptake (by 45%) and subsequent canalicular efflux (by 62%). (15R)-11 C-TIC is an in vitro substrate of OATP1B1 and OATP1B3, and clinically relevant concentrations of rifampicin inhibited uptake by OATP1B1 and OATP1B3. These results demonstrated that in humans, (15R)-11 C-TIC-associated radioactivity is excreted into the bile by organic anion transport systems. Conclusion: We demonstrated that PET image analysis with (15R)-11 C-TIC-Me is useful for investigating variations in OATP function in the human hepatobiliary transport system.
BackgroundFatigue can be classified as mental and physical depending on its cause, and each
type of fatigue has a multi-factorial nature. We examined the effect of mental
fatigue on the central nervous system using electroencephalography (EEG) in eighteen
healthy male volunteers.MethodsAfter enrollment, subjects were randomly assigned to two groups in a single-blinded,
crossover fashion to perform two types of mental fatigue-inducing experiments. Each
experiment consisted of four 30-min fatigue-inducing 0- or 2-back test sessions and
two evaluation sessions performed just before and after the fatigue-inducing
sessions. During the evaluation session, the participants were assessed using EEG.
Eleven electrodes were attached to the head skin, from positions F3, Fz, F4, C3, Cz,
C4, P3, Pz, P4, O1, and O2.ResultsIn the 2-back test, the beta power density on the Pz electrode and the alpha power
densities on the P3 and O2 electrodes were decreased, and the theta power density on
the Cz electrode was increased after the fatigue-inducing mental task sessions. In
the 0-back test, no electrodes were altered after the fatigue-inducing sessions.ConclusionsDifferent types of mental fatigue produced different kinds of alterations of the
spontaneous EEG variables. Our findings provide new perspectives on the neural
mechanisms underlying mental fatigue.
We used magnetoencephalography (MEG) to determine whether increasingly complex forms constituted from the same elements (lines) activate visual cortex with the same or different latencies. Twenty right-handed healthy adult volunteers viewed two different forms, lines and rhomboids, representing two levels of complexity. Our results showed that the earliest responses produced by lines and rhomboids in both striate and prestriate cortex had similar peak latencies (40 ms) although lines produced stronger responses than rhomboids. Dynamic causal modeling (DCM) showed that a parallel multiple input model to striate and prestriate cortex accounts best for the MEG response data. These results lead us to conclude that the perceptual hierarchy between lines and rhomboids is not mirrored by a temporal hierarchy in latency of activation and thus that a strategy of parallel processing appears to be used to construct forms, without implying that a hierarchical strategy may not be used in separate visual areas, in parallel.
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