title: Scalable preparation and differential pharmacologic and toxicologic profiles of primaquine enantiomers.
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.
authors.affiliation: National Center for Natural Products Research, Research Institute of Pharmaceutical Sciences, University of Mississippi, University, Mississippi, USA dhammika@olemiss.edu.
authors.forename: N P Dhammika
authors.initials: NP
authors.lastname: Nanayakkara
authors.affiliation: 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.
authors.forename: Babu L
authors.initials: BL
authors.lastname: Tekwani
authors.affiliation: National Center for Natural Products Research, Research Institute of Pharmaceutical Sciences, University of Mississippi, University, Mississippi, USA.
authors.forename: H M T Bandara
authors.initials: HM
authors.lastname: Herath
authors.affiliation: National Center for Natural Products Research, Research Institute of Pharmaceutical Sciences, University of Mississippi, University, Mississippi, USA.
authors.forename: Rajnish
authors.initials: R
authors.lastname: Sahu
authors.affiliation: Department of Veterinary Medicine, U.S. Army Medical Component, Armed Forces Research Institute of Medical Sciences (AFRIMS), Bangkok, Thailand.
authors.forename: Montip
authors.initials: M
authors.lastname: Gettayacamin
authors.affiliation: Department of Veterinary Medicine, U.S. Army Medical Component, Armed Forces Research Institute of Medical Sciences (AFRIMS), Bangkok, Thailand.
authors.forename: Anchalee
authors.initials: A
authors.lastname: Tungtaeng
authors.affiliation: Department of Veterinary Medicine, U.S. Army Medical Component, Armed Forces Research Institute of Medical Sciences (AFRIMS), Bangkok, Thailand.
authors.forename: Yvonne
authors.initials: Y
authors.lastname: van Gessel
authors.affiliation: Department of Microbiology and Immunology, SUNY Upstate Medical University, Syracuse, New York, USA.
authors.forename: Paul
authors.initials: P
authors.lastname: Baresel
authors.affiliation: Department of Microbiology and Immunology, SUNY Upstate Medical University, Syracuse, New York, USA.
authors.forename: Kristina S
authors.initials: KS
authors.lastname: Wickham
authors.affiliation: Department of Pathology and Laboratory Medicine, Indiana University School of Medicine, Indianapolis, Indiana, USA.
authors.forename: Marilyn S
authors.initials: MS
authors.lastname: Bartlett
authors.affiliation: Department of Chemistry, Louisiana State University, Baton Rouge, Louisiana, USA.
authors.forename: Frank R
authors.initials: FR
authors.lastname: Fronczek
authors.affiliation: Department of Experimental Therapeutics, Walter Reed Army Institute of Research, Silver Spring, Maryland, USA.
authors.forename: Victor
authors.initials: V
authors.lastname: Melendez
authors.affiliation: Department of Experimental Therapeutics, Walter Reed Army Institute of Research, Silver Spring, Maryland, USA.
authors.forename: Colin
authors.initials: C
authors.lastname: Ohrt
authors.affiliation: Department of Experimental Therapeutics, Walter Reed Army Institute of Research, Silver Spring, Maryland, USA.
authors.forename: Gregory A
authors.initials: GA
authors.lastname: Reichard
authors.affiliation: Ironstone Separations, Inc., Etta, Mississippi, USA.
authors.forename: James D
authors.initials: JD
authors.lastname: McChesney
authors.affiliation: Department of Microbiology and Immunology, SUNY Upstate Medical University, Syracuse, New York, USA.
authors.forename: Rosemary
authors.initials: R
authors.lastname: Rochford
authors.affiliation: 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.
authors.forename: Larry A
authors.initials: LA
authors.lastname: Walker
mesh_terms: D000818:Animals; D000962:Antimalarials / Q000302:isolation & purification / Q000493:pharmacokinetics* / Q000633:toxicity; D004285:Dogs; D017707:Erythrocyte Transfusion; D004912:Erythrocytes / Q000187:drug effects / Q000469:parasitology; D005260:Female; D005955:Glucosephosphate Dehydrogenase Deficiency / Q000378:metabolism; D006461:Hemolysis / Q000187:drug effects*; D006801:Humans; D007928:Lethal Dose 50; D008288:Malaria / Q000188:drug therapy* / Q000469:parasitology; D051379:Mice; D008807:Mice, Inbred BALB C; D008813:Mice, Inbred ICR; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D010962:Plasmodium berghei / Q000187:drug effects / Q000502:physiology; D045363:Pneumocystis carinii / Q000187:drug effects / Q000502:physiology; D011020:Pneumonia, Pneumocystis / Q000188:drug therapy* / Q000382:microbiology; D011319:Primaquine / Q000302:isolation & purification / Q000493:pharmacokinetics* / Q000633:toxicity; D013237:Stereoisomerism; D014183:Transplantation, Heterologous
chemical_list: D000962:Antimalarials; D011319:Primaquine