title: Trioxolane-Mediated Delivery of Mefloquine Limits Brain Exposure in a Mouse Model of Malaria.
abstract: Peroxidic antimalarial agents including the sequiterpene artemisinins and the synthetic 1,2,4-trioxolanes function via initial intraparasitic reduction of an endoperoxide bond. By chemically coupling this reduction to release of a tethered drug species it is possible to confer two distinct pharmacological effects in a parasite-selective fashion, both in vitro and in vivo. Here we demonstrate the trioxolane-mediated delivery of the antimalarial agent mefloquine in a mouse malaria model. Selective partitioning of the trioxolane-mefloquine conjugate in parasitized erythrocytes, combined with effective exclusion of the conjugate from brain significantly reduced brain exposure as compared to mice directly administered mefloquine. These studies suggest the potential of trioxolane-mediated drug delivery to mitigate off-target effects of existing drugs, including the adverse neuropsychiatric effects of mefloquine use in therapeutic and chemoprophylactic settings.
authors.affiliation: Department of Pharmaceutical Chemistry and Department of Medicine, University of California San Francisco , 1700 Fourth Street, San Francisco, California 94158, United States.
authors.forename: Erica M W
authors.initials: EM
authors.lastname: Lauterwasser
authors.affiliation: Department of Pharmaceutical Chemistry and Department of Medicine, University of California San Francisco , 1700 Fourth Street, San Francisco, California 94158, United States.
authors.forename: Shaun D
authors.initials: SD
authors.lastname: Fontaine
authors.affiliation: Departments of Pathology and Microbiology and Immunology, Stanford School of Medicine , 300 Pasteur Drive, Stanford, California 94305, United States.
authors.forename: Hao
authors.initials: H
authors.lastname: Li
authors.affiliation: Department of Pharmaceutical Chemistry and Department of Medicine, University of California San Francisco , 1700 Fourth Street, San Francisco, California 94158, United States.
authors.forename: Jiri
authors.initials: J
authors.lastname: Gut
authors.affiliation: Centre for Drug Candidate Optimisation, Monash Institute of Pharmaceutical Sciences, Monash University , Parkville, VIC 3052, Australia.
authors.forename: Kasiram
authors.initials: K
authors.lastname: Katneni
authors.affiliation: Centre for Drug Candidate Optimisation, Monash Institute of Pharmaceutical Sciences, Monash University , Parkville, VIC 3052, Australia.
authors.forename: Susan A
authors.initials: SA
authors.lastname: Charman
authors.affiliation: Department of Pharmaceutical Chemistry and Department of Medicine, University of California San Francisco , 1700 Fourth Street, San Francisco, California 94158, United States.
authors.forename: Philip J
authors.initials: PJ
authors.lastname: Rosenthal
authors.affiliation: Departments of Pathology and Microbiology and Immunology, Stanford School of Medicine , 300 Pasteur Drive, Stanford, California 94305, United States.
authors.forename: Matthew
authors.initials: M
authors.lastname: Bogyo
authors.affiliation: Department of Pharmaceutical Chemistry and Department of Medicine, University of California San Francisco , 1700 Fourth Street, San Francisco, California 94158, United States.
authors.forename: Adam R
authors.initials: AR
authors.lastname: Renslo
keywords: antimalarial; drug delivery; mefloquine; trioxolane