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Potential Effect of Polymorphisms in Prodrug Antimicrobial Therapy

Investigating the effect of genetic polymorphisms on the activation of prodrug antimicrobial therapies and their pharmacological effectiveness

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Potential Effect of Polymorphisms in Prodrug Antimicrobial Therapy

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  1. Potential Effect of Polymorphisms in Prodrug Antimicrobial Therapy Dr. Robert Kerns, Matthew Busalacchi, Iris Chen, Kevin Chiang, Austin Miller

  2. Project Goals • Identify/investigate antimicrobial prodrugs that require bioactivation • Identify known SNPs or mutations of those enzymes required for bioactivation • Investigate the impact of polymorphism on activation of those prodrugs and their subsequent pharmacologic effect

  3. Background: Pharmacogenomics • Genetic polymorphisms impact drug efficacy/action • Genetic testing to determine dosing of drug • Antibiotic resistance as cause of treatment failure • Key questions: • Is antibiotic resistance always the culprit? • Are polymorphism-activated drugs hidden polymorphisms documented as resistance?

  4. Introduction: Polymorphisms Two Areas of Affect: • Metabolizing enzymes • E.g. CYP, Carboxylesterase, etc. • Polymorphism leading to inadequate prodrug activation • Result: Antibiotic treatment failure • Drug transporters • Changes in pharmacokinetics and pharmacodynamics • Antivirals not transported across host cell; ineffective/resistant

  5. Introduction: Known Prodrugs • Ceftobiprolemedocaril • Chloramphenicol succinate • Ester of erythromycin • Bacampicillin • Tedizolid phosphate • Ceftarolinefosamil • Tribendimidine • Tenofovir • Prulifloxacin • Oseltamivir phosphate • Clindamycin palmitate • Isavuconazonium sulfate • Proguanil • Cefpodoximeproxetil • Cefditorenpivoxil • Pivampicillin

  6. Methods: Search Strategies • Goodman & Gilman, 13th ed. • Compilation of prodrugs: • Exclude pathogen-bioactivated prodrugs • Exclude nucleoside phosphorylation • PubMed • Mesh Terms: Polymorphism, Genetic; Prodrugs; Drug Resistance; Microbial; Cytochromes; Carboxylesterase • PharmGKB

  7. Category 1: Known Prodrug-Enzyme & Polymorphism • Prulifloxacin → ulifloxacin (Paraxonase) • Oseltamivir phosphate → oseltamivir carboxylate (CE1) • Clindamycin palmitate → active clindamycin (CYP3A4) • Isavuconazonium sulfate → isavuconazole (esterase) • Proguanil → cycloguanil (CYP2C19, 3A4)

  8. Example: Prulifloxacin Paraxonase Ulifoxacin Prulifloxacin

  9. Polymorphism Impact on Drug Activity • Polymorphism of paraxonase (PON1) enzyme impacts prulifloxacinbioactivation • Can result in treatment failure • Failure not always due to bacterial resistance

  10. Example: Oseltamivir Phosphate

  11. Category IIA: Non-Specific Enzyme • Tenofovirdisoproxil fumarate • Cefpodoximeproxetil • Cefditorenpivoxil • Pivampicillin • Ceftobiprolemedocaril • Chloramphenicol succinate • Ester of erythromycin • Becampicillin • Tedizolid phosphate • Ceftarolinefosamil

  12. Example: Pivampicillin

  13. Category IIB: Known Enzyme, Unknown Polymorphism VACVase

  14. Category III: Little is Known ( Tribendimidine) DADT Deacetylated amidantel Tribendimidine

  15. Why is This Important? • Lowered healthcare costs • Patient safety • Interethnic variability affecting drug transport • Avoiding possible treatment failure • Knowing patients’ specific enzyme prevalence --> adequately provides insight to correct medication dosing • Understand treatment failure rather than assume

  16. Conclusion • Bioactivated anti infectives should be further characterized in terms of activating enzymes • Further study to determine the clinical impact of this theory and how polymorphism affect the rate of drug activation --> how it affects practice • Will the drug still work even with polymorphism and why does it matter?

  17. Reference • Ieiri, I., Takane, H., Hirota, T., Otsubo, K., & Higuchi, S. (2006). Genetic polymorphisms of drug transporters: pharmacokinetic and pharmacodynamic consequences in pharmacotherapy. Expert opinion on drug metabolism & toxicology, 2(5), 651-674. • Matera, M. G. (2006). Pharmacologic characteristics of prulifloxacin. Pulmonary pharmacology & therapeutics, 19, 20-29. • Ginsberg, G., Neafsey, P., Hattis, D., Guyton, K. Z., Johns, D. O., & Sonawane, B. (2009). Genetic polymorphism in paraoxonase 1 (PON1): Population distribution of PON1 activity. Journal of Toxicology and Environmental Health, Part B, 12(5-6), 473-507.

  18. Reference • Shi, J., Wang, X., Eyler, R. F., Liang, Y., Liu, L., Mueller, B. A., & Zhu, H. J. (2016). Association of oseltamivir activation with gender and carboxylesterase 1 genetic polymorphisms. Basic & clinical pharmacology & toxicology, 119(6), 555-561 • Lai, L., Xu, Z., Zhou, J., Lee, K. D., & Amidon, G. L. (2008). Molecular basis of prodrug activation by human valacyclovirase, an α-amino acid ester hydrolase. Journal of Biological Chemistry

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