122 The FXR ligand INT-747 (6-ECDCA; a synthetic chenodeoxycholic acid derivate) has been tested in a phase II trial in the treatment of PBC Z-VAD-FMK purchase and preliminary results appear promising. When added in biochemical nonresponders to UDCA, INT-747 resulted in a significant reduction in alkaline phosphatase. Despite these promising results, one has to be aware that FXR activation stimulates bile flow, which may have negative effects in obstructive cholestasis (due to tumors, stones, or dominant strictures in PSC) or in vanishing bile duct syndromes with pronounced bile duct loss
such as late-stage PBC.123 In other cholestatic diseases where transporter defects are the primary event (e.g., hereditary transporter defects, reduced transporter expression in sepsis-induced cholestasis, or functional impairment of transporter activity by sex hormones or drugs) or in early stages of vanishing bile duct syndromes, an increase in bile flow may be beneficial. Other therapeutic targets in cholestasis Epigenetics inhibitor include the NRs PPARα and GR (Supporting Table 5). PPARα induces bile acid conjugation by way of UGT2B4 and UGT1A3 and represses CYP7A1124 (Fig. 3). The most important anticholestatic effects of PPARα stimulation are probably related to increased biliary phospholipid secretion reducing the aggressiveness of bile. Several studies using fibrates in PBC patients demonstrated
beneficial effects on liver function tests and also on histology (reviewed124,125). Glucocorticoids such as GR ligands are recommended in PBC medchemexpress patients not responding to UDCA therapy.126 Apart from its immunosuppressive action, GR also regulates expression of
a variety of transporters.124 Most important, GR stimulates expression of the anion exchanger AE2, thus inducing biliary bicarbonate secretion127 (Fig. 3). AE2 seems to be involved in the pathogenesis of PBC because its expression is reduced in these patients and AE2 knockout mice develop histologic and immunologic features of PBC.128 Interestingly, UDCA has also been shown to activate GR.129 The local and systemic exposure to xenobiotics including prescription medications, over-the-counter drugs, and also herbal remedies is determined by phase I (i.e., hydroxylation) and phase II (i.e., conjugation) enzymatic reactions and phase III (i.e., drug uptake and export) reactions, which are all under tight control of NRs.130 The utilization of NR knockout mice and humanized NR transgenic mice provides a unique model system to study NR-mediated regulation of enzymes and transporter involved in drug metabolism and disposition and to assess the safety of novel drug candidates.131 Candidate drugs can be administered over longer periods at doses equivalent to those in humans to study their potential to induce various detoxification enzymes, which might result in drug/drug interactions.