title: Enantioselective pharmacokinetics of primaquine in healthy human volunteers.
abstract: Primaquine (PQ), a racemic drug, is the only treatment available for radical cure of relapsing Plasmodium vivax malaria and blocking transmission of P. falciparum malaria. Recent studies have shown differential pharmacologic and toxicologic profiles of individual PQ enantiomers in rodent, dog, and primate animal models. This study was conducted in six healthy adult human volunteers to determine the plasma pharmacokinetic profile of enantiomers of PQ and carboxyprimaquine (cPQ), the major plasma metabolite. The individuals were orally administered PQ diphosphate, equivalent to 45-mg base, 30 minutes after a normal breakfast. Blood samples were collected at different time intervals, and plasma samples were analyzed for enantiomers of PQ and cPQ. Plasma PQ concentrations were low and variable for both parent enantiomers and peaked around 2-4 hours. Peak (-)-(R)-PQ concentrations ranged from 121 ng/ml to 221 ng/ml, and peak (+)-(S)-PQ concentrations ranged from 168 ng/ml to 299 ng/ml. The cPQ concentrations were much higher and were surprisingly consistent from subject to subject. Essentially all the cPQ detected in plasma was (-)-cPQ. The peak concentrations of (-)-cPQ were observed at 8 hours (range: 1104-1756 ng/ml); however, very high concentrations were sustained through 24 hours. (+)-cPQ was two orders of magnitude lower than (-)-cPQ, and in a few subjects it was detected but only under the limit of quantification. In vitro studies with primary human hepatocytes also suggested more rapid metabolism of (-)-PQ compared with (+)-PQ. The results suggest more rapid metabolism of (-)-PQ to (-) cPQ compared with (+)-PQ. Alternatively, (+)-PQ or (+)-cPQ could be rapidly converted to another metabolite(s) or distributed to tissues. This is the first clinical report on enantioselective pharmacokinetic profiles of PQ and cPQ and supports further clinical evaluation of individual PQ enantiomers.
authors: National Center for Natural Products Research (B.L.T., B.A., R.S., N.D.C., S.I.K., S.J., P.S.F., H.M.T.B.H., D.S., N.P.D.N., M.A.E., I.A.K., L.A.W.), Departments of BioMolecular Sciences (B.L.T., S.I.K., S.J., I.A.K., L.A.W.) and Pharmaceutics (M.A.E.), School of Pharmacy, and Department of Student Health Services (T.W.Y.), University of Mississippi, University; Ironstone Separations, Inc., Etta (J.D.M.); ElSohly Laboratories, Inc., Oxford (M.A.E.), Mississippi btekwani@olemiss.edu.
authors: Babu L
authors: BL
authors: Tekwani
authors: National Center for Natural Products Research (B.L.T., B.A., R.S., N.D.C., S.I.K., S.J., P.S.F., H.M.T.B.H., D.S., N.P.D.N., M.A.E., I.A.K., L.A.W.), Departments of BioMolecular Sciences (B.L.T., S.I.K., S.J., I.A.K., L.A.W.) and Pharmaceutics (M.A.E.), School of Pharmacy, and Department of Student Health Services (T.W.Y.), University of Mississippi, University; Ironstone Separations, Inc., Etta (J.D.M.); ElSohly Laboratories, Inc., Oxford (M.A.E.), Mississippi.
authors: Bharathi
authors: B
authors: Avula
authors: National Center for Natural Products Research (B.L.T., B.A., R.S., N.D.C., S.I.K., S.J., P.S.F., H.M.T.B.H., D.S., N.P.D.N., M.A.E., I.A.K., L.A.W.), Departments of BioMolecular Sciences (B.L.T., S.I.K., S.J., I.A.K., L.A.W.) and Pharmaceutics (M.A.E.), School of Pharmacy, and Department of Student Health Services (T.W.Y.), University of Mississippi, University; Ironstone Separations, Inc., Etta (J.D.M.); ElSohly Laboratories, Inc., Oxford (M.A.E.), Mississippi.
authors: Rajnish
authors: R
authors: Sahu
authors: National Center for Natural Products Research (B.L.T., B.A., R.S., N.D.C., S.I.K., S.J., P.S.F., H.M.T.B.H., D.S., N.P.D.N., M.A.E., I.A.K., L.A.W.), Departments of BioMolecular Sciences (B.L.T., S.I.K., S.J., I.A.K., L.A.W.) and Pharmaceutics (M.A.E.), School of Pharmacy, and Department of Student Health Services (T.W.Y.), University of Mississippi, University; Ironstone Separations, Inc., Etta (J.D.M.); ElSohly Laboratories, Inc., Oxford (M.A.E.), Mississippi.
authors: Narayan D
authors: ND
authors: Chaurasiya
authors: National Center for Natural Products Research (B.L.T., B.A., R.S., N.D.C., S.I.K., S.J., P.S.F., H.M.T.B.H., D.S., N.P.D.N., M.A.E., I.A.K., L.A.W.), Departments of BioMolecular Sciences (B.L.T., S.I.K., S.J., I.A.K., L.A.W.) and Pharmaceutics (M.A.E.), School of Pharmacy, and Department of Student Health Services (T.W.Y.), University of Mississippi, University; Ironstone Separations, Inc., Etta (J.D.M.); ElSohly Laboratories, Inc., Oxford (M.A.E.), Mississippi.
authors: Shabana I
authors: SI
authors: Khan
authors: National Center for Natural Products Research (B.L.T., B.A., R.S., N.D.C., S.I.K., S.J., P.S.F., H.M.T.B.H., D.S., N.P.D.N., M.A.E., I.A.K., L.A.W.), Departments of BioMolecular Sciences (B.L.T., S.I.K., S.J., I.A.K., L.A.W.) and Pharmaceutics (M.A.E.), School of Pharmacy, and Department of Student Health Services (T.W.Y.), University of Mississippi, University; Ironstone Separations, Inc., Etta (J.D.M.); ElSohly Laboratories, Inc., Oxford (M.A.E.), Mississippi.
authors: Surendra
authors: S
authors: Jain
authors: National Center for Natural Products Research (B.L.T., B.A., R.S., N.D.C., S.I.K., S.J., P.S.F., H.M.T.B.H., D.S., N.P.D.N., M.A.E., I.A.K., L.A.W.), Departments of BioMolecular Sciences (B.L.T., S.I.K., S.J., I.A.K., L.A.W.) and Pharmaceutics (M.A.E.), School of Pharmacy, and Department of Student Health Services (T.W.Y.), University of Mississippi, University; Ironstone Separations, Inc., Etta (J.D.M.); ElSohly Laboratories, Inc., Oxford (M.A.E.), Mississippi.
authors: Pius S
authors: PS
authors: Fasinu
authors: National Center for Natural Products Research (B.L.T., B.A., R.S., N.D.C., S.I.K., S.J., P.S.F., H.M.T.B.H., D.S., N.P.D.N., M.A.E., I.A.K., L.A.W.), Departments of BioMolecular Sciences (B.L.T., S.I.K., S.J., I.A.K., L.A.W.) and Pharmaceutics (M.A.E.), School of Pharmacy, and Department of Student Health Services (T.W.Y.), University of Mississippi, University; Ironstone Separations, Inc., Etta (J.D.M.); ElSohly Laboratories, Inc., Oxford (M.A.E.), Mississippi.
authors: H M T Bandara
authors: HM
authors: Herath
authors: National Center for Natural Products Research (B.L.T., B.A., R.S., N.D.C., S.I.K., S.J., P.S.F., H.M.T.B.H., D.S., N.P.D.N., M.A.E., I.A.K., L.A.W.), Departments of BioMolecular Sciences (B.L.T., S.I.K., S.J., I.A.K., L.A.W.) and Pharmaceutics (M.A.E.), School of Pharmacy, and Department of Student Health Services (T.W.Y.), University of Mississippi, University; Ironstone Separations, Inc., Etta (J.D.M.); ElSohly Laboratories, Inc., Oxford (M.A.E.), Mississippi.
authors: Donald
authors: D
authors: Stanford
authors: National Center for Natural Products Research (B.L.T., B.A., R.S., N.D.C., S.I.K., S.J., P.S.F., H.M.T.B.H., D.S., N.P.D.N., M.A.E., I.A.K., L.A.W.), Departments of BioMolecular Sciences (B.L.T., S.I.K., S.J., I.A.K., L.A.W.) and Pharmaceutics (M.A.E.), School of Pharmacy, and Department of Student Health Services (T.W.Y.), University of Mississippi, University; Ironstone Separations, Inc., Etta (J.D.M.); ElSohly Laboratories, Inc., Oxford (M.A.E.), Mississippi.
authors: N P Dhammika
authors: NP
authors: Nanayakkara
authors: National Center for Natural Products Research (B.L.T., B.A., R.S., N.D.C., S.I.K., S.J., P.S.F., H.M.T.B.H., D.S., N.P.D.N., M.A.E., I.A.K., L.A.W.), Departments of BioMolecular Sciences (B.L.T., S.I.K., S.J., I.A.K., L.A.W.) and Pharmaceutics (M.A.E.), School of Pharmacy, and Department of Student Health Services (T.W.Y.), University of Mississippi, University; Ironstone Separations, Inc., Etta (J.D.M.); ElSohly Laboratories, Inc., Oxford (M.A.E.), Mississippi.
authors: James D
authors: JD
authors: McChesney
authors: National Center for Natural Products Research (B.L.T., B.A., R.S., N.D.C., S.I.K., S.J., P.S.F., H.M.T.B.H., D.S., N.P.D.N., M.A.E., I.A.K., L.A.W.), Departments of BioMolecular Sciences (B.L.T., S.I.K., S.J., I.A.K., L.A.W.) and Pharmaceutics (M.A.E.), School of Pharmacy, and Department of Student Health Services (T.W.Y.), University of Mississippi, University; Ironstone Separations, Inc., Etta (J.D.M.); ElSohly Laboratories, Inc., Oxford (M.A.E.), Mississippi.
authors: Travis W
authors: TW
authors: Yates
authors: National Center for Natural Products Research (B.L.T., B.A., R.S., N.D.C., S.I.K., S.J., P.S.F., H.M.T.B.H., D.S., N.P.D.N., M.A.E., I.A.K., L.A.W.), Departments of BioMolecular Sciences (B.L.T., S.I.K., S.J., I.A.K., L.A.W.) and Pharmaceutics (M.A.E.), School of Pharmacy, and Department of Student Health Services (T.W.Y.), University of Mississippi, University; Ironstone Separations, Inc., Etta (J.D.M.); ElSohly Laboratories, Inc., Oxford (M.A.E.), Mississippi.
authors: Mahmoud A
authors: MA
authors: ElSohly
authors: National Center for Natural Products Research (B.L.T., B.A., R.S., N.D.C., S.I.K., S.J., P.S.F., H.M.T.B.H., D.S., N.P.D.N., M.A.E., I.A.K., L.A.W.), Departments of BioMolecular Sciences (B.L.T., S.I.K., S.J., I.A.K., L.A.W.) and Pharmaceutics (M.A.E.), School of Pharmacy, and Department of Student Health Services (T.W.Y.), University of Mississippi, University; Ironstone Separations, Inc., Etta (J.D.M.); ElSohly Laboratories, Inc., Oxford (M.A.E.), Mississippi.
authors: Ikhlas A
authors: IA
authors: Khan
authors: National Center for Natural Products Research (B.L.T., B.A., R.S., N.D.C., S.I.K., S.J., P.S.F., H.M.T.B.H., D.S., N.P.D.N., M.A.E., I.A.K., L.A.W.), Departments of BioMolecular Sciences (B.L.T., S.I.K., S.J., I.A.K., L.A.W.) and Pharmaceutics (M.A.E.), School of Pharmacy, and Department of Student Health Services (T.W.Y.), University of Mississippi, University; Ironstone Separations, Inc., Etta (J.D.M.); ElSohly Laboratories, Inc., Oxford (M.A.E.), Mississippi.
authors: Larry A
authors: LA
authors: Walker
mesh_terms: D000284:Administration, Oral; D000328:Adult; D000962:Antimalarials / Q000097:blood / Q000737:chemistry* / Q000493:pharmacokinetics*; D002478:Cells, Cultured; D002851:Chromatography, High Pressure Liquid; D064368:Healthy Volunteers; D022781:Hepatocytes / Q000378:metabolism*; D006801:Humans; D008875:Middle Aged; D015394:Molecular Structure; D011319:Primaquine / Q000031:analogs & derivatives* / Q000097:blood / Q000737:chemistry / Q000493:pharmacokinetics; D061251:Primary Cell Culture; D021241:Spectrometry, Mass, Electrospray Ionization; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
chemical_list: D000962:Antimalarials; C035150:8-(3-carboxy-1-methylpropylamino)-6-methoxyquinoline; D011319:Primaquine