Orally administered drugs targeted against human diseases may have undesired side effects because of unforeseen interactions with enzyme activities encoded by the symbiotic microbiome in the gastrointestinal tract. A prime example is that of the common colon cancer chemotherapeutic CPT-11, a prodrug that is activated in the liver and becomes excreted as a glucuronidated end product; this inactivated product becomes reactivated in the intestine by the action of bacterial β-glucuronidases encoded by the microbiome, which remove the glucuronate moiety. Thus released, CPT-11 causes grave side effects in the intestinal epithelium leading to severe diarrhea and bloody diarrhea. A potential solution consists of a combined therapy where anticancer prodrugs as CPT-11 are supplied in conjunction with selective inhibitors against the bacterial enzymes that reactivate the liver-inactivated drug. Here we review efforts to design inhibitors against bacterial β-glucuronidases based on biochemical and structural analyses aimed at combination therapies with CPT-11 as a brilliant illustration of the complex interactions between the microbiota and current drug therapies, and discuss further examples of drugs that undergo microbiota-induced modifications that alter their pharmacological properties. Indeed, the realization that the microbiota's enzymatic repertoire has a greater than anticipated impact on therapeutic molecules given to human and animal patients has become a turning point in pharmacology and the medical sciences, and, therefore, a deeper and fuller understanding of the biotransformations of drugs catalyzed by the symbiotic flora can help the discovery of more effective treatments (and with far fewer side effects) than ever before.
Keywords: Irinotecan, β-glucuronidase, drug metabolism, toxicity, pharmacomicrobiomics, combination therapy, microbiota, microbiome, diabetes, obesity
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Published on: 03 April, 2012
Page: [218 - 228]