Recent events of bioterrorism and the rapid global spread of emerging infectious diseases has revealed a compelling need to develop effective and safe therapeutics that can be readily applied to large and genetically diverse populations, typical of the United States. In a comprehensive review of the 2001 anthrax bioterrorist attack, investigation of """"""""adherence, barriers to adherence, and adverse events associated with long-term use of antimicrobial agents"""""""" was considered to be a high priority research area. The objective of this research is to elucidate molecular mechanisms underlying adverse host responses to antimicrobial agents used to treat NIAID Priority Pathogens. This proposal focuses on the fluoroquinolones, particularly ciprofloxacin, which was the primary antibiotic used for anthrax post-exposure prophylaxis, and is an option for treatment of other NIAID Priority Pathogens. Side effects of the fluoroquinolones leading to nonadherence most commonly involve the gastrointestinal (GI) tract. The novel hypothesis to be explored in this proposal is that many of these adverse side effects result from the formation of reactive fluoroquinolone metabolites in the liver and/or GI tract. Major metabolites of the fluoroquinolones in humans are acyl glucuronides, which have a high potential for covalent adduct formation with biomolecules. In preliminary studies, we show evidence for spontaneous degradation and acyl migration of ciprofloxacin and trovafloxacin glucuronides similar to that observed with glucuronides of the nonsteroidal anti-inflammatory drugs. Consistent with the exploratory nature of an R21 Research Project, the specific aims of this proposal are as follows. Firstly, we will use primary human hepatocytes and human intestinal cell lines to quantify the Cytotoxicity of 3 fluoroquinolones frequently associated with adverse GI side effects in people (trovafloxacin, grepafloxacin and sparfloxacin) compared with 3 fluoroquinolones less commonly associated with these side effects (ciprofloxacin, ofloxacin, and norfloxacin) . Secondly, we will determine whether inhibition of enzymes potentially responsible for reactive metabolite formation (UGT, CYP and acyl CoA ligase) minimizes the in vitro toxicity of these drugs. By the completion of these studies we will have developed an understanding of the biochemical pathways potentially responsible for clinically important adverse side effects of the fluoroquinolones. In future work we will verify these findings through in vivo studies and identify host genetic factors that may account for individual variability in side effect susceptibility. Our ultimate goal is to optimize the broader clinical application of these drugs through a pharmacogenetic approach in situations where long-term treatment of large and genetically diverse populations is necessitated. ? ? ?

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Exploratory/Developmental Grants (R21)
Project #
5R21GM074369-02
Application #
7054675
Study Section
Xenobiotic and Nutrient Disposition and Action Study Section (XNDA)
Program Officer
Okita, Richard T
Project Start
2005-04-15
Project End
2008-03-31
Budget Start
2006-04-01
Budget End
2008-03-31
Support Year
2
Fiscal Year
2006
Total Cost
$199,573
Indirect Cost
Name
Tufts University
Department
Pharmacology
Type
Schools of Medicine
DUNS #
039318308
City
Boston
State
MA
Country
United States
Zip Code
02111
Cerundolo, Rosario; Michel, Kathy E; Court, Michael H et al. (2009) Effects of dietary soy isoflavones on health, steroidogenesis, and thyroid gland function in dogs. Am J Vet Res 70:353-60
Gan, Lu; von Moltke, Lisa L; Trepanier, Lauren A et al. (2009) Role of NADPH-cytochrome P450 reductase and cytochrome-b5/NADH-b5 reductase in variability of CYP3A activity in human liver microsomes. Drug Metab Dispos 37:90-6
Farkas, D; Volak, L P; Harmatz, J S et al. (2009) Short-term clarithromycin administration impairs clearance and enhances pharmacodynamic effects of trazodone but not of zolpidem. Clin Pharmacol Ther 85:644-50
Kwara, Awewura; Lartey, Margaret; Sagoe, Kwamena W et al. (2008) Pharmacokinetics of efavirenz when co-administered with rifampin in TB/HIV co-infected patients: pharmacogenetic effect of CYP2B6 variation. J Clin Pharmacol 48:1032-40
Volak, Laurie P; Ghirmai, Senait; Cashman, John R et al. (2008) Curcuminoids inhibit multiple human cytochromes P450, UDP-glucuronosyltransferase, and sulfotransferase enzymes, whereas piperine is a relatively selective CYP3A4 inhibitor. Drug Metab Dispos 36:1594-605
Oleson, Lauren; Court, Michael H (2008) Effect of the beta-glucuronidase inhibitor saccharolactone on glucuronidation by human tissue microsomes and recombinant UDP-glucuronosyltransferases. J Pharm Pharmacol 60:1175-82
Court, Michael H; Hazarika, Suwagmani; Krishnaswamy, Soundararajan et al. (2008) Novel polymorphic human UDP-glucuronosyltransferase 2A3: cloning, functional characterization of enzyme variants, comparative tissue expression, and gene induction. Mol Pharmacol 74:744-54
Farkas, Dora; Oleson, Lauren E; Zhao, Yanli et al. (2007) Pomegranate juice does not impair clearance of oral or intravenous midazolam, a probe for cytochrome P450-3A activity: comparison with grapefruit juice. J Clin Pharmacol 47:286-94
Kaivosaari, Sanna; Toivonen, Paivi; Hesse, Leah M et al. (2007) Nicotine glucuronidation and the human UDP-glucuronosyltransferase UGT2B10. Mol Pharmacol 72:761-8
Court, Michael H (2007) A pharmacogenomics primer. J Clin Pharmacol 47:1087-103

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