Numerous clinically used agents contain the ester chemotype, a moiety frequently added to small molecules to improve their water solubility and bioavailability. However the inclusion of this function in these compounds makes them substrates for carboxylesterases (CEs), enzymes that can either inactivate or activate these agents. Typically examples include the anticancer agent CPT-11 (irinotecan, Camptosar) that is a prodrug of SN-38, a potent topoisomerase I poison, and the antiviral drug oseltamivir phosphate (Tamiflu) that requires hydrolysis to the carboxylate form to yield the active neuraminidase inhibitor. Hence, compounds that might inhibit the hydrolysis reactions would limit the efficacy of these drugs. We have identified a class of compounds (tanshinones) that are present within the Chinese herbal medicine Danshen. Extracts from this material can potently inhibit human CEs and modulate drug activity in vitro. Importantly however, the FDA has just approved the use of Danshen in clinical trials. Hence any esterified drug that is administered in conjunction with the herbal medicine might lead to reduced molecule hydrolysis, thereby mitigating the efficacy of the agent. We seek therefore, to evaluate the active component(s) in Danshen and to assess whether these molecules can modulate drug activity in defined animal models.
The specific aims of this application are: 1) To determine the inhibitory compounds present within Danshen;2) to assess the mechanism of enzyme inhibition by these compounds;3) to assess the biological activity of these extracts in vitro;and 4) to determine the effect of such compounds/extracts on drug efficacy in animals models. We anticipate that compounds present within Danshen will inhibit the CEs in vivo, resulting in significantly reduced drug hydrolysis, and as a consequence, reduced drug efficacy. Since this material is currently in clinical trials, the information derived from these studies may identify novel drug:drug interactions that potentially would impact the effectiveness of clinically used esterified compounds. We envisage that the studies proposed here will validate this hypothesis and provide information concerning the use of such extracts in defined patient populations.
This project seeks to identify components of a herbal Chinese medicine (Danshen) that can significantly alter the metabolism of clinically used drugs. Potentially, co-administration of Danshen with these prescribed medications may result in marked alterations in drug efficacy.
|Hatfield, M Jason; Chen, Jingwen; Fratt, Ellie M et al. (2017) Selective Inhibitors of Human Liver Carboxylesterase Based on a ?-Lapachone Scaffold: Novel Reagents for Reaction Profiling. J Med Chem 60:1568-1579|
|Argikar, Upendra A; Potter, Philip M; Hutzler, J Matthew et al. (2016) Challenges and Opportunities with Non-CYP Enzymes Aldehyde Oxidase, Carboxylesterase, and UDP-Glucuronosyltransferase: Focus on Reaction Phenotyping and Prediction of Human Clearance. AAPS J 18:1391-1405|
|Hatfield, M Jason; Umans, Robyn A; Hyatt, Janice L et al. (2016) Carboxylesterases: General detoxifying enzymes. Chem Biol Interact 259:327-331|
|Wierdl, Monika; Tsurkan, Lyudmila; Hatfield, M Jason et al. (2016) Tumour-selective targeting of drug metabolizing enzymes to treat metastatic cancer. Br J Pharmacol 173:2811-8|