title: Pharmacokinetic comparison to determine the mechanisms underlying the differential efficacies of cationic diamidines against first- and second-stage human African trypanosomiasis.
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.
authors.affiliation: Department of Pharmaceutical Chemistry, School of Pharmacy, University of Kansas, Lawrence, Kansas, USA.
authors.forename: Sihyung
authors.initials: S
authors.lastname: Yang
authors.affiliation: Medical Parasitology & Infection Biology, Swiss Tropical and Public Health Institute, Basel, Switzerland University of Basel, Basel, Switzerland.
authors.forename: Tanja
authors.initials: T
authors.lastname: Wenzler
authors.affiliation: Department of Pharmaceutical Chemistry, School of Pharmacy, University of Kansas, Lawrence, Kansas, USA.
authors.forename: Patrik N
authors.initials: PN
authors.lastname: Miller
authors.affiliation: Department of Pathology and Laboratory Medicine, School of Medicine, The University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA.
authors.forename: Huali
authors.initials: H
authors.lastname: Wu
authors.affiliation: Department of Chemistry, Georgia State University, Atlanta, Georgia, USA.
authors.forename: David W
authors.initials: DW
authors.lastname: Boykin
authors.affiliation: Medical Parasitology & Infection Biology, Swiss Tropical and Public Health Institute, Basel, Switzerland University of Basel, Basel, Switzerland.
authors.forename: Reto
authors.initials: R
authors.lastname: Brun
authors.affiliation: Department of Pharmaceutical Chemistry, School of Pharmacy, University of Kansas, Lawrence, Kansas, USA michael.wang@ku.edu.
authors.forename: Michael Zhuo
authors.initials: MZ
authors.lastname: Wang
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000378:metabolism*; D000578:Amidines / Q000378:metabolism / Q000493:pharmacokinetics* / Q000494:pharmacology; D000818:Animals; D001550:Benzamidines / Q000378:metabolism / Q000493:pharmacokinetics / Q000494:pharmacology; D001812:Blood-Brain Barrier; D002460:Cell Line; D004285:Dogs; D005663:Furans / Q000378:metabolism / Q000493:pharmacokinetics / Q000494:pharmacology; D061985:Madin Darby Canine Kidney Cells; D008297:Male; D051379:Mice; D010419:Pentamidine / Q000378:metabolism / Q000493:pharmacokinetics* / Q000494:pharmacology; D011485:Protein Binding; D014344:Trypanocidal Agents / Q000378:metabolism / Q000493:pharmacokinetics* / Q000494:pharmacology; D016833:Trypanosoma brucei rhodesiense / Q000187:drug effects*; D014353:Trypanosomiasis, African / Q000188:drug therapy / Q000469:parasitology
chemical_list: C504229:6-(5-(4-amidinophenyl)furan-2-yl)nicotinamidine; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000578:Amidines; D001550:Benzamidines; C555517:CPD 0801; D005663:Furans; D014344:Trypanocidal Agents; D010419:Pentamidine; C033286:furamidine