PMID- 36726785 OWN - NLM STAT- PubMed-not-MEDLINE LR - 20230203 IS - 1663-9812 (Print) IS - 1663-9812 (Electronic) IS - 1663-9812 (Linking) VI - 13 DP - 2022 TI - Comparative metabolism and tolerability of racemic primaquine and its enantiomers in human volunteers during 7-day administration. PG - 1104735 LID - 10.3389/fphar.2022.1104735 [doi] LID - 1104735 AB - Primaquine (PQ) is an 8-aminoquinoline antimalarial, active against dormant Plasmodium vivax hypnozoites and P. falciparum mature gametocytes. PQ is currently used for P. vivax radical cure and prevention of malaria transmission. PQ is a racemic drug and since the metabolism and pharmacology of PQ's enantiomers have been shown to be divergent, the objectives of this study were to evaluate the comparative tolerability and metabolism of PQ with respect to its two enantiomers in human volunteers in a 7 days' treatment schedule. Fifteen subjects with normal glucose-6-phosphate dehydrogenase (G6PDn) completed four arms, receiving each of the treatments, once daily for 7 days, in a crossover fashion, with a 7-14 days washout period in between: R-(-) enantiomer (RPQ) 22.5 mg; S-(+) enantiomer (SPQ) 22.5 mg; racemic PQ (RSPQ) 45 mg, and placebo. Volunteers were monitored for any adverse events (AEs) during the study period. PQ and metabolites were quantified in plasma and red blood cells (RBCs) by UHPLC-UV-MS/MS. Plasma PQ was significantly higher in SPQ treatment group than for RPQ. Carboxy-primaquine, a major plasma metabolite, was much higher in the RPQ treated group than SPQ; primaquine carbamoyl glucuronide, another major plasma metabolite, was derived only from SPQ. The ortho-quinone metabolites were also detected and showed differences for the two enantiomers in a similar pattern to the parent drugs. Both enantiomers and racemic PQ were well tolerated in G6PDn subjects with the 7 days regimen; three subjects showed mild AEs which did not require any intervention or discontinuation of the drug. The most consistent changes in G6PDn subjects were a gradual increase in methemoglobin and bilirubin, but these were not clinically important. However, the bilirubin increase suggests mild progressive damage to a small fraction of red cells. PQ enantiomers were also individually administered to two G6PD deficient (G6PDd) subjects, one heterozygous female and one hemizygous male. These G6PDd subjects showed similar results with the two enantiomers, but the responses in the hemizygous male were more pronounced. These studies suggest that although the metabolism profiles of individual PQ enantiomers are markedly different, they did not show significant differences in the safety and tolerability in G6PDn subjects. CI - Copyright (c) 2023 Khan, Wang, Chaurasiya, Nanayakkara, Bandara Herath, Harrison, Dale, Stanford, Dahl, McChesney, Gul, ElSohly, Jollow, Tekwani and Walker. FAU - Khan, Washim AU - Khan W AD - National Center for Natural Products Research, The University of Mississippi, University, MS, United States. FAU - Wang, Yan-Hong AU - Wang YH AD - National Center for Natural Products Research, The University of Mississippi, University, MS, United States. FAU - Chaurasiya, Narayan D AU - Chaurasiya ND AD - Department of Infectious Diseases, Division of Drug Discovery, Southern Research Institute, Birmingham, AL, United States. FAU - Nanayakkara, N P Dhammika AU - Nanayakkara NPD AD - National Center for Natural Products Research, The University of Mississippi, University, MS, United States. FAU - Bandara Herath, H M AU - Bandara Herath HM AD - National Center for Natural Products Research, The University of Mississippi, University, MS, United States. FAU - Harrison, Kerri A AU - Harrison KA AD - National Center for Natural Products Research, The University of Mississippi, University, MS, United States. FAU - Dale, Gray AU - Dale G AD - National Center for Natural Products Research, The University of Mississippi, University, MS, United States. FAU - Stanford, Donald A AU - Stanford DA AD - National Center for Natural Products Research, The University of Mississippi, University, MS, United States. FAU - Dahl, Eric P AU - Dahl EP AD - National Center for Natural Products Research, The University of Mississippi, University, MS, United States. FAU - McChesney, James D AU - McChesney JD AD - Ironstone Separations Inc., Etta, MS, United States. FAU - Gul, Waseem AU - Gul W AD - ElSohly Laboratories Inc., Oxford, MS, United States. FAU - ElSohly, Mahmoud A AU - ElSohly MA AD - National Center for Natural Products Research, The University of Mississippi, University, MS, United States. AD - ElSohly Laboratories Inc., Oxford, MS, United States. AD - Pharmaceutics and Drug Delivery, School of Pharmacy, The University of Mississippi, University, MS, United States. FAU - Jollow, David AU - Jollow D AD - Professor Emeritus, Department Cell and Molecular Pharmacology and Experimental Therapeutics, Medical University of South Carolina, Charleston, SC, United States. FAU - Tekwani, Babu L AU - Tekwani BL AD - Department of Infectious Diseases, Division of Drug Discovery, Southern Research Institute, Birmingham, AL, United States. FAU - Walker, Larry A AU - Walker LA AD - National Center for Natural Products Research, The University of Mississippi, University, MS, United States. LA - eng PT - Journal Article DEP - 20230116 PL - Switzerland TA - Front Pharmacol JT - Frontiers in pharmacology JID - 101548923 PMC - PMC9885159 OTO - NOTNLM OT - clinical pharmacokinetics OT - enantiomers OT - metabolism OT - primaquine OT - racemate OT - safety COIS- JM was employed by Ironstone Separations Inc. WG and ME were employed by ElSohly Laboratories, Inc. Neither these commercial entities nor these authors have any financial interest in the drugs tested or study outcome. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. EDAT- 2023/02/03 06:00 MHDA- 2023/02/03 06:01 PMCR- 2023/01/16 CRDT- 2023/02/02 02:02 PHST- 2022/11/22 00:00 [received] PHST- 2022/12/30 00:00 [accepted] PHST- 2023/02/02 02:02 [entrez] PHST- 2023/02/03 06:00 [pubmed] PHST- 2023/02/03 06:01 [medline] PHST- 2023/01/16 00:00 [pmc-release] AID - 1104735 [pii] AID - 10.3389/fphar.2022.1104735 [doi] PST - epublish SO - Front Pharmacol. 2023 Jan 16;13:1104735. doi: 10.3389/fphar.2022.1104735. eCollection 2022.