Effects of parasitic infection on the pharmacokinetics and disposition of pentamidine analogs Public Deposited

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  • March 20, 2019
  • Generaux, Claudia N.
    • Affiliation: Eshelman School of Pharmacy
  • Diamidine analogs of pentamidine are under evaluation as new and safer alternatives for treatment of first- and second-stage human African trypanosomiasis (HAT). Bis-O-methylamidoxime prodrugs of diamidines depend on hepatic biotransformation for generation of the pharmacologically active diamidines. The goal of this dissertation project was to investigate whether trypanosomal infection attenuates biotransformation of bis-O-methylamidoxime prodrugs, with the consequent potential to alter systemic exposure to prodrug and/or active diamidines. Biotransformation of the prodrug DB868 to the active diamidine, DB829, under investigation for second-stage HAT, mirrored biotransformation of the prodrug for first-stage HAT, pafuramidine, highlighting the central role of biotransformation for bis-O-methylamidoxime prodrug activation. In addition to the O-demethylation and N-dehydroxylation reactions preceding DB829 generation, a previously unrecognized N-demethoxylation reaction was observed in human and rat liver microsomes. Formation of DB829 in cultured primary hepatocytes from both species was rapid; however, basolateral export and/or intracellular sequestration limited appearance of DB829 diamidine in culture medium. In a rat model of first-stage trypanosomiasis, developed and characterized during this investigation, infection altered significantly the pharmacokinetics of both the prodrug, pafuramidine, and active diamidine, furamidine. Compared to uninfected animals, systemic exposure (AUC) of both prodrug and active diamidine was increased significantly in infected animals, by 1.3- and 3-fold, respectively. The increase in pafuramidine AUC during infection was dependent on dose and route of administration, and conformed to expected behavior for a blood-flow limited compound according to the well-stirred model of hepatic clearance. The increase in furamidine AUC during infection was explained, in part, by decreased biliary excretion of furamidine. Simulations of decreased enzyme capacity using different doses and routes of administration provided a framework for considering the impact of infection on pharmacokinetics. This dissertation project showed that trypanosomal infection is capable of altering the pharmacokinetics of bis-O-methylamidoxime prodrugs and corresponding diamidines. Knowledge gained from this work provides a basis for making predictions of pharmacokinetic outcomes during infection and inflammation.
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  • In Copyright
  • "... in partial fulfillment of the requirements for the degree of Doctor of Philosophy in the School of Pharmacy."
  • Paine, Mary F.
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  • Chapel Hill, NC
  • Open access

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