dc.contributor.author | Yang, Sihyung | |
dc.contributor.author | Wenzler, Tanja | |
dc.contributor.author | Miller, Patrik N. | |
dc.contributor.author | Wu, Huali | |
dc.contributor.author | Boykin, David W. | |
dc.contributor.author | Brun, Reto | |
dc.contributor.author | Wang, Zhuo | |
dc.date.accessioned | 2015-12-31T18:17:44Z | |
dc.date.available | 2015-12-31T18:17:44Z | |
dc.date.issued | 2014-05-05 | |
dc.identifier.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 | en_US |
dc.identifier.uri | http://hdl.handle.net/1808/19371 | |
dc.description | This is the published version. | en_US |
dc.description.abstract | 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. | en_US |
dc.publisher | American Society for Microbiology | en_US |
dc.relation.isversionof | 10.1128/AAC.02605-14 | en_US |
dc.title | Pharmacokinetic Comparison To Determine the Mechanisms Underlying the Differential Efficacies of Cationic Diamidines against First- and Second-Stage Human African Trypanosomiasis | en_US |
dc.type | Article | |
kusw.kuauthor | Wang, Zhuo | |
kusw.kudepartment | Pharmaceutical Chemistry | en_US |
dc.identifier.orcid | https://orcid.org/0000-0003-1751-4975 | |
kusw.oaversion | Scholarly/refereed, publisher version | |
kusw.oapolicy | This item meets KU Open Access policy criteria. | |
dc.rights.accessrights | openAccess | |