Title

Scalable preparation and differential pharmacologic and toxicologic profiles of primaquine enantiomers

Authors

N P. Nanayakkara, National Center for Natural Products Research, Research Institute of Pharmaceutical Sciences, University of Mississippi, University, Mississippi, USA dhammika@olemiss.edu.
Babu L. Tekwani, National Center for Natural Products Research, Research Institute of Pharmaceutical Sciences, University of Mississippi, University, Mississippi, USA Department of Pharmacology, University of Mississippi, University, Mississippi, USA.
H M. Herath, National Center for Natural Products Research, Research Institute of Pharmaceutical Sciences, University of Mississippi, University, Mississippi, USA.
Rajnish Sahu, National Center for Natural Products Research, Research Institute of Pharmaceutical Sciences, University of Mississippi, University, Mississippi, USA.
Montip Gettayacamin, Department of Veterinary Medicine, U.S. Army Medical Component, Armed Forces Research Institute of Medical Sciences (AFRIMS), Bangkok, Thailand.
Anchalee Tungtaeng, Department of Veterinary Medicine, U.S. Army Medical Component, Armed Forces Research Institute of Medical Sciences (AFRIMS), Bangkok, Thailand.
Yvonne van Gessel, Department of Veterinary Medicine, U.S. Army Medical Component, Armed Forces Research Institute of Medical Sciences (AFRIMS), Bangkok, Thailand.
Paul Baresel, Department of Microbiology and Immunology, SUNY Upstate Medical University, Syracuse, New York, USA.
Kristina S. Wickham, Department of Microbiology and Immunology, SUNY Upstate Medical University, Syracuse, New York, USA.
Marilyn S. Bartlett, Department of Pathology and Laboratory Medicine, Indiana University School of Medicine, Indianapolis, Indiana, USA.
Frank R. Fronczek, Department of Chemistry, Louisiana State University, Baton Rouge, Louisiana, USA.
Victor Melendez, Department of Experimental Therapeutics, Walter Reed Army Institute of Research, Silver Spring, Maryland, USA.
Colin Ohrt, Department of Experimental Therapeutics, Walter Reed Army Institute of Research, Silver Spring, Maryland, USA.
Gregory A. Reichard, Department of Experimental Therapeutics, Walter Reed Army Institute of Research, Silver Spring, Maryland, USA.
James D. McChesney, Ironstone Separations, Inc., Etta, Mississippi, USA.
Rosemary Rochford, Department of Microbiology and Immunology, SUNY Upstate Medical University, Syracuse, New York, USA.
Larry A. Walker, National Center for Natural Products Research, Research Institute of Pharmaceutical Sciences, University of Mississippi, University, Mississippi, USA Department of Pharmacology, University of Mississippi, University, Mississippi, USA.

Document Type

Article

Publication Date

8-1-2014

Abstract

Hematotoxicity in individuals genetically deficient in glucose-6-phosphate dehydrogenase (G6PD) activity is the major limitation of primaquine (PQ), the only antimalarial drug in clinical use for treatment of relapsing Plasmodium vivax malaria. PQ is currently clinically used in its racemic form. A scalable procedure was developed to resolve racemic PQ, thus providing pure enantiomers for the first time for detailed preclinical evaluation and potentially for clinical use. These enantiomers were compared for antiparasitic activity using several mouse models and also for general and hematological toxicities in mice and dogs. (+)-(S)-PQ showed better suppressive and causal prophylactic activity than (-)-(R)-PQ in mice infected with Plasmodium berghei. Similarly, (+)-(S)-PQ was a more potent suppressive agent than (-)-(R)-PQ in a mouse model of Pneumocystis carinii pneumonia. However, at higher doses, (+)-(S)-PQ also showed more systemic toxicity for mice. In beagle dogs, (+)-(S)-PQ caused more methemoglobinemia and was toxic at 5 mg/kg of body weight/day given orally for 3 days, while (-)-(R)-PQ was well tolerated. In a novel mouse model of hemolytic anemia associated with human G6PD deficiency, it was also demonstrated that (-)-(R)-PQ was less hemolytic than (+)-(S)-PQ for the G6PD-deficient human red cells engrafted in the NOD-SCID mice. All these data suggest that while (+)-(S)-PQ shows greater potency in terms of antiparasitic efficacy in rodents, it is also more hematotoxic than (-)-(R)-PQ in mice and dogs. Activity and toxicity differences of PQ enantiomers in different species can be attributed to their different pharmacokinetic and metabolic profiles. Taken together, these studies suggest that (-)-(R)-PQ may have a better safety margin than the racemate in human.

Publication Source (Journal or Book title)

Antimicrobial agents and chemotherapy

First Page

4737

Last Page

44

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