Pharmacokinetic Comparison To Determine the Mechanisms Underlying the Differential Efficacies of Cationic Diamidines against First- and Second-Stage Human African Trypanosomiasis
Issue Date
2014-05-05Author
Yang, Sihyung
Wenzler, Tanja
Miller, Patrik N.
Wu, Huali
Boykin, David W.
Brun, Reto
Wang, Zhuo
Publisher
American Society for Microbiology
Type
Article
Article Version
Scholarly/refereed, publisher version
Published Version
10.1128/AAC.02605-14Metadata
Show full item recordAbstract
Human African trypanosomiasis (HAT), a neglected tropical disease, is fatal without treatment. Pentamidine, a cationic diamidine, has been used to treat first-stage (hemolymphatic) HAT since the 1940s, but it is ineffective against second-stage (meningoencephalitic, or central nervous system [CNS]) infection. Novel diamidines (DB75, DB820, and DB829) have shown promising efficacy in both mouse and monkey models of first-stage HAT. However, only DB829 cured animals with second-stage infection. In this study, we aimed to determine the mechanisms underlying the differential efficacies of these diamidines against HAT by conducting a comprehensive pharmacokinetic characterization. This included the determination of metabolic stability in liver microsomes, permeability across MDCK and MDR1-MDCK cell monolayers, interaction with the efflux transporter MDR1 (P-glycoprotein 1 or P-gp), drug binding in plasma and brain, and plasma and brain concentration-time profiles after a single dose in mice. The results showed that DB829, an azadiamidine, had the highest systemic exposure and brain-to-plasma ratio, whereas pentamidine and DB75 had the lowest. None of these diamidines was a P-gp substrate, and the binding of each to plasma proteins and brain differed greatly. The brain-to-plasma ratio best predicted the relative efficacies of these diamidines in mice with second-stage infection. In conclusion, pharmacokinetics and CNS penetration influenced the in vivo efficacies of cationic diamidines against first- and second-stage HAT and should be considered when developing CNS-active antitrypanosomal diamidines.
Description
This is the published version.
Collections
- Pharmacy Scholarly Works [293]
Citation
Yang, S., T. Wenzler, P. N. Miller, H. Wu, D. W. Boykin, R. Brun, and M. Z. Wang. "Pharmacokinetic Comparison To Determine the Mechanisms Underlying the Differential Efficacies of Cationic Diamidines against First- and Second-Stage Human African Trypanosomiasis." Antimicrobial Agents and Chemotherapy 58.7 (2014): 4064-074. http://dx.doi.org/10.1128/AAC.02605-14
Items in KU ScholarWorks are protected by copyright, with all rights reserved, unless otherwise indicated.
We want to hear from you! Please share your stories about how Open Access to this item benefits YOU.