title: Pharmacokinetics and pharmacodynamics of (+)-primaquine and (-)-primaquine enantiomers in rhesus macaques (Macaca mulatta).
abstract: Primaquine (PQ) remains the sole available drug to prevent relapse of Plasmodium vivax malaria more than 60 years after licensure. While this drug was administered as a racemic mixture, prior studies suggested a pharmacodynamic advantage based on differential antirelapse activity and/or toxicities of its enantiomers. Oral primaquine enantiomers prepared using a novel, easily scalable method were given for 7 days to healthy rhesus macaques in a dose-rising fashion to evaluate their effects on the blood, liver, and kidneys. The enantiomers were then administered to Plasmodium cynomolgi-infected rhesus macaques at doses of 1.3 and 0.6 mg/kg of body weight/day in combination with chloroquine. The (-)-PQ enantiomer had higher clearance and apparent volume of distribution than did (+)-PQ and was more extensively converted to the carboxy metabolite. There is evidence for differential oxidative stress with a concentration-dependent rise in methemoglobin (MetHgb) with increasing doses of (+)-PQ greater than that seen for (-)-PQ. There was a marked, reversible hepatotoxicity in 2 of 3 animals dosed with (-)-PQ at 4.5 mg/kg. (-)-PQ in combination with chloroquine was successful in preventing P. cynomolgi disease relapse at doses of 0.6 and 1.3 mg/kg/day, while 1 of 2 animals receiving (+)-PQ at 0.6 mg/kg/day relapsed. While (-)-PQ was also associated with hepatotoxicity at higher doses as seen previously, this has not been identified as a clinical concern in humans during >60 years of use. Limited evidence for increased MetHgb generation with the (+) form in the rhesus macaque model suggests that it may be possible to improve the therapeutic window for hematologic toxicity in the clinic by separating primaquine into its enantiomers.
authors.affiliation: Department of Immunology and Medicine, Armed Forces Research Institute of Medical Science, Bangkok, Thailand David.Saunders@AFRIMS.org.
authors.forename: David
authors.initials: D
authors.lastname: Saunders
authors.affiliation: Department of Immunology and Medicine, Armed Forces Research Institute of Medical Science, Bangkok, Thailand.
authors.forename: Pattaraporn
authors.initials: P
authors.lastname: Vanachayangkul
authors.affiliation: Department of Veterinary Medicine, Armed Forces Research Institute of Medical Science, Bangkok, Thailand.
authors.forename: Rawiwan
authors.initials: R
authors.lastname: Imerbsin
authors.affiliation: Department of Immunology and Medicine, Armed Forces Research Institute of Medical Science, Bangkok, Thailand.
authors.forename: Phisit
authors.initials: P
authors.lastname: Khemawoot
authors.affiliation: Department of Immunology and Medicine, Armed Forces Research Institute of Medical Science, Bangkok, Thailand.
authors.forename: Raveewan
authors.initials: R
authors.lastname: Siripokasupkul
authors.affiliation: National Center for Natural Products Research, University of Mississippi, Oxford, Mississippi, USA Department of Pharmacology, School of Pharmacy, University of Mississippi, Oxford, Mississippi, USA.
authors.forename: Babu L
authors.initials: BL
authors.lastname: Tekwani
authors.affiliation: National Center for Natural Products Research, University of Mississippi, Oxford, Mississippi, USA.
authors.forename: Aruna
authors.initials: A
authors.lastname: Sampath
authors.affiliation: National Center for Natural Products Research, University of Mississippi, Oxford, Mississippi, USA.
authors.forename: N P Dhammika
authors.initials: NP
authors.lastname: Nanayakkara
authors.affiliation: Walter Reed Army Institute of Research, Div. Experimental Therapeutics, Silver Spring, Maryland, USA.
authors.forename: Colin
authors.initials: C
authors.lastname: Ohrt
authors.affiliation: Department of Immunology and Medicine, Armed Forces Research Institute of Medical Science, Bangkok, Thailand.
authors.forename: Charlotte
authors.initials: C
authors.lastname: Lanteri
authors.affiliation: Department of Veterinary Medicine, Armed Forces Research Institute of Medical Science, Bangkok, Thailand.
authors.forename: Montip
authors.initials: M
authors.lastname: Gettyacamin
authors.affiliation: Department of Immunology and Medicine, Armed Forces Research Institute of Medical Science, Bangkok, Thailand.
authors.forename: Paktiya
authors.initials: P
authors.lastname: Teja-Isavadharm
authors.affiliation: National Center for Natural Products Research, University of Mississippi, Oxford, Mississippi, USA Department of Pharmacology, School of Pharmacy, University of Mississippi, Oxford, Mississippi, USA.
authors.forename: Larry
authors.initials: L
authors.lastname: Walker
mesh_terms: D000818:Animals; D000962:Antimalarials / Q000097:blood / Q000737:chemistry / Q000493:pharmacokinetics* / Q000494:pharmacology; D002738:Chloroquine / Q000494:pharmacology*; D004195:Disease Models, Animal; D004334:Drug Administration Schedule; D004359:Drug Therapy, Combination; D006801:Humans; D007668:Kidney / Q000187:drug effects; D008099:Liver / Q000187:drug effects; D008253:Macaca mulatta; D008288:Malaria / Q000097:blood / Q000188:drug therapy* / Q000469:parasitology; D016780:Malaria, Vivax; D008297:Male; D008706:Methemoglobin / Q000378:metabolism; D018384:Oxidative Stress; D016789:Plasmodium cynomolgi / Q000187:drug effects* / Q000254:growth & development; D010966:Plasmodium vivax; D011319:Primaquine / Q000097:blood / Q000737:chemistry / Q000493:pharmacokinetics* / Q000494:pharmacology; D012008:Recurrence; D013237:Stereoisomerism
chemical_list: D000962:Antimalarials; D002738:Chloroquine; D008706:Methemoglobin; D011319:Primaquine