No abstract

Cytoplasmic citrate serves as an important regulator of gluconeogenesis and carbon source for de novo lipogenesis in the liver. For this reason, the sodium‐coupled citrate transporter (NaCT), a plasma membrane transporter that governs hepatic influx of plasma citrate in human, is being explored as a potential therapeutic target for metabolic disorders. As cytoplasmic citrate also originates from intracellular mitochondria, the relative contribution of these two pathways represents critical information necessary to underwrite confidence in this target. In this work, hepatic influx of plasma citrate was quantified via pharmacokinetic modeling of published clinical data. The influx was then compared to independent literature estimates of intracellular citrate flux in human liver. The results indicate that, under normal conditions, <10% of hepatic citrate originates from plasma. Similar estimates were determined experimentally in mice and rats. This suggests that NaCT inhibition will have a limited impact on hepatic citrate concentrations across species.

Liver cirrhosis is a disease characterized by the loss of functional liver mass. Physiologically based pharmacokinetic (PBPK) modeling was applied to interpret and predict how the interplay among physiological changes in cirrhosis affects pharmacokinetics. However, previous PBPK models under cirrhotic conditions were developed for permeable cytochrome P450 substrates and do not directly apply to substrates of liver transporters. This study characterizes a PBPK model for liver transporter substrates in relation to the severity of liver cirrhosis. A published PBPK model structure for liver transporter substrates under healthy conditions and the physiological changes for cirrhosis are combined to simulate pharmacokinetics of liver transporter substrates in patients with mild and moderate cirrhosis. The simulated pharmacokinetics under liver cirrhosis reasonably approximate observations. This analysis includes meta-analysis to obtain system-dependent parameters in cirrhosis patients and a top-down approach to improve understanding of the effect of cirrhosis on transporter-mediated drug disposition under cirrhotic conditions.