Hepatocellular Shuttling and Recirculation of Sorafenib-Glucuronide Is Dependent on Abcc2, Abcc3, and Oatp1a/1b

Abstract

Recently, an efficient liver detoxification process dubbed ‘hepatocyte hopping’ was proposed based on findings with the endogenous compound, bilirubin glucuronide. According to this model, hepatocytic bilirubin glucuronide can follow a liver-to-blood shuttling loop via Abcc3 transporter-mediated efflux and subsequent Oatp1a/1b-mediated liver uptake. We hypothesized that glucuronide conjugates of xenobiotics, such as the anticancer drug sorafenib, can also undergo hepatocyte hopping. Using transporter-deficient mouse models, we show here that sorafenib-glucuronide can be extruded from hepatocytes into the bile by Abcc2 or back into the systemic circulation by Abcc3, and that it can be taken up efficiently again into neighboring hepatocytes by Oatp1a/1b. We further demonstrate that sorafenib-glucuronide excreted into the gut lumen can be cleaved by microbial enzymes to sorafenib which is then reabsorbed, supporting its persistence in the systemic circulation. Our results suggest broad relevance of a hepatocyte shuttling process known as “hepatocyte hopping” – a novel concept in clinical pharmacology - for detoxification of targeted cancer drugs which undergo hepatic glucuronidation, such as sorafenib.

Sorafenib metabolism, transport, and enterohepatic recycling: physiologically based modeling and simulation in mice

“…The recycling is accounted for by a continuous fraction of bile released into the gut (30% - default value) with subsequent bile dump every 8 hours. The β -glucuronidase activity was estimated ex-vivo in mouse cecal material treated with SG both with and without neomycin [19]. …”

“…WT; Oatp1a/1b KO; Abcc3 KO; Abcc2 KO; Oatp1a/1b and Abcc2 KO; Oatp1a/1b and Abcc3 KO; Oatp1a/1b, Abcc2 and Abcc3 KO [19] (used for simulations and hypothesis testing)…”

“…This suggests that Oatp1 transport of the glucuronide into the hepatocytes is an important step in SG clearance. Using in vitro studies and in vivo studies with wildtype and knockout mice, it was determined that once SG is transported into hepatocytes, its disposition depends on Abcc2 (Mrp2) which shuttles SG into bile as well as Abcc3 (Mrp3) which shuttles SG back into circulation [19]. The fate of SG in the bile and intestinal lumen was assessed ex vivo with mouse luminal contents.…”

“…The fate of SG in the bile and intestinal lumen was assessed ex vivo with mouse luminal contents. It was demonstrated using neomycin, a non-systemic antimicrobial that eliminates gastrointestinal flora, that deconjugation was mediated by β- glucuronidase [19]. In vivo , sorafenib was found in plasma of mice following a single SG dose and absent when SG was co-administered with neomycin [19] demonstrating the importance of β- glucuronidase in sorafenib disposition in mice.…”

“…It was demonstrated using neomycin, a non-systemic antimicrobial that eliminates gastrointestinal flora, that deconjugation was mediated by β- glucuronidase [19]. In vivo , sorafenib was found in plasma of mice following a single SG dose and absent when SG was co-administered with neomycin [19] demonstrating the importance of β- glucuronidase in sorafenib disposition in mice. In healthy volunteers treated with neomycin, the systemic exposure of a single 400 mg dose of sorafenib was reduced by 54% (Nexavar® package insert) and it has been estimated that the sorafenib exposure in humans is increased by 50% due to enterohepatic circulation (EHC) following oral administration [20].…”