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Abstract

5-10 mg/kg in rodents over weeks. 3 The data from pharmacokinetic studies in humans would suggest that optimal tissue levels of OCA are not reached until 5-7 days of therapy, 2 and thus a 24-hour high-dose study is difficult to interpret.Finally, the interpretation of DDAH-2 being responsible for changes in eNOS function is likely erroneous. It is important to appreciate that there are two isoenzymes of DDAH: DDAH-1 predominantly in the liver and kidney accounting for over 80% of ADMA metabolism, and DDAH-2, located in the heart and vasculature with a role in promoting eNOS transcription, but little effect on ADMA.4 Therefore, the augmented DDAH-2 and improved ADMA metabolism post-OCA treatment in bile-ductligated (BDL) rats in the Verbeke et al. study is difficult to reconcile. Moreover, rodent models show increased hepatic DDAH-1 with FXR agonists, but there is no precedent for FXR agonism leading to increased hepatic DDAH-2 expression. 5In summary, whereas the Verbeke et al. study recapitulates important therapeutic effects of FXR agonists in portal hypertension, there are questions about study design and interpretation of mechanism pertaining to DDAH-2. Further studies are required to address concerns about the mechanism through which OCA reduces hepatic ADMA, and thereby portal pressure, in the BDL model.