Comparative single dose pharmacokinetics and metabolism of racemic primaquine and its enantiomers in human volunteers.
| Title: | Comparative single dose pharmacokinetics and metabolism of racemic primaquine and its enantiomers in human volunteers. |
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| Authors: | Khan W; National Center for Natural Products Research, The University of Mississippi, University, MS, 38677, USA.; Wang YH; National Center for Natural Products Research, The University of Mississippi, University, MS, 38677, USA.; Chaurasiya ND; Department of Infectious Diseases, Division of Drug Discovery, Southern Research Institute, Birmingham, AL, 35205, USA.; Nanayakkara ND; National Center for Natural Products Research, The University of Mississippi, University, MS, 38677, USA.; Herath HB; National Center for Natural Products Research, The University of Mississippi, University, MS, 38677, USA.; Harrison KA; National Center for Natural Products Research, The University of Mississippi, University, MS, 38677, USA.; Dale G; National Center for Natural Products Research, The University of Mississippi, University, MS, 38677, USA.; Stanford DA; National Center for Natural Products Research, The University of Mississippi, University, MS, 38677, USA.; Dahl EP; National Center for Natural Products Research, The University of Mississippi, University, MS, 38677, USA.; McChesney JD; Ironstone Separations, Inc., Etta, MS, 38627, USA.; Gul W; ElSohly Laboratories, Inc., Oxford, MS, 38655, USA.; ElSohly MA; National Center for Natural Products Research, The University of Mississippi, University, MS, 38677, USA; Pharmaceutics and Drug Delivery, School of Pharmacy, The University of Mississippi, University, MS, 38677, USA; ElSohly Laboratories, Inc., Oxford, MS, 38655, USA.; Khan SI; National Center for Natural Products Research, The University of Mississippi, University, MS, 38677, USA.; Fasinu PS; Department of Pharmacology & Toxicology, University of Alabama at Birmingham, Birmingham, AL, 35294, USA.; Khan IA; National Center for Natural Products Research, The University of Mississippi, University, MS, 38677, USA; Departments of BioMolecular Sciences, School of Pharmacy, The University of Mississippi, University, MS, 38677, USA.; Tekwani BL; Department of Infectious Diseases, Division of Drug Discovery, Southern Research Institute, Birmingham, AL, 35205, USA. Electronic address: btekwani@southernresearch.org.; Walker LA; National Center for Natural Products Research, The University of Mississippi, University, MS, 38677, USA. Electronic address: lwalker@olemiss.edu. |
| Source: | Drug metabolism and pharmacokinetics [Drug Metab Pharmacokinet] 2022 Aug; Vol. 45, pp. 100463. Date of Electronic Publication: 2022 May 02. |
| Publication Type: | Journal Article |
| Language: | English |
| Journal Info: | Publisher: Elsevier Country of Publication: England NLM ID: 101164773 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1880-0920 (Electronic) Linking ISSN: 13474367 NLM ISO Abbreviation: Drug Metab Pharmacokinet Subsets: MEDLINE |
| Imprint Name(s): | Publication: 2015- : London : Elsevier; Original Publication: Tokyo, Japan : Japanese Society for the Study of Xenobiotics, c2002- |
| MeSH Terms: | Antimalarials*/metabolism ; Antimalarials*/pharmacology ; Primaquine*/metabolism; Animals ; Healthy Volunteers ; Humans ; Stereoisomerism |
| Abstract: | Primaquine (PQ) is a racemic drug used in treatment of malaria for six decades. Recent studies suggest that the two enantiomers of PQ are differentially metabolized in animals, and this results in different pharmacological and toxicological profiles. The current study characterizes the pharmacokinetic (PK) properties, metabolism and tolerability of the individual enantiomers of PQ in healthy human volunteers with normal glucose-6-phosphate dehydrogenase (G6PD) activity. Two cohorts (at two dose levels), each with 18 subjects, participated in three study arms in a crossover fashion: a single dose of the (-)-R enantiomer (RPQ), a single dose of the (+)-S enantiomer (SPQ), and a single dose of racemic PQ (RSPQ). PQ and its key metabolites carboxyprimaquine (cPQ) and PQ-N-carbamoyl glucuronide (PQ-N-CG) were analyzed. Clear differences were observed in PK and metabolism of the two enantiomers. Relative PQ exposure was higher with SPQ as compared to RPQ. PQ maximum plasma concentration (Cmax) and area under the plasma concentration-time curve were higher for SPQ, while the apparent volume of distribution and total body clearance were higher for RPQ. Metabolism of the two enantiomers showed dramatic differences: plasma PQ-N-CG was derived solely from SPQ, while RPQ was much more efficiently converted to cPQ than was SPQ. Cmax of cPQ and PQ-N-CG were 10 and 2 times higher, respectively, than the parent drugs. The study demonstrates that the PK properties of PQ enantiomers show clear differences, and metabolism is highly enantioselective. Such differences in metabolism suggest potentially distinct toxicity profiles in multi-dose regimens, especially in G6PD-deficient subjects.; (Copyright © 2022 The Japanese Society for the Study of Xenobiotics. Published by Elsevier Ltd. All rights reserved.) |
| Competing Interests: | Declaration of competing interest The authors have declared no conflicts of interest. |
| References: | J Pharm Sci. 1988 May;77(5):380-2. (PMID: 3411455); Cochrane Database Syst Rev. 2018 Feb 02;2:CD008152. (PMID: 29393511); Lancet. 2005 Apr 9-15;365(9467):1308. (PMID: 15823379); Curr Opin Infect Dis. 2006 Dec;19(6):623-31. (PMID: 17075340); Exp Toxicol Pathol. 1999 Jul;51(4-5):299-303. (PMID: 10445386); Antimicrob Agents Chemother. 1977 Jul;12(1):51-60. (PMID: 407841); Malar J. 2016 Apr 19;15:224. (PMID: 27093859); Antimicrob Agents Chemother. 1983 Nov;24(5):615-52. (PMID: 6660845); PLoS Negl Trop Dis. 2018 Apr 19;12(4):e0006230. (PMID: 29672516); Antimicrob Agents Chemother. 2008 Jun;52(6):2130-7. (PMID: 18378716); Malar J. 2018 Aug 13;17(1):294. (PMID: 30103751); J Antimicrob Chemother. 2018 Nov 1;73(11):3102-3113. (PMID: 30085149); Drug Metab Dispos. 2015 Apr;43(4):571-7. (PMID: 25637634); Br J Clin Pharmacol. 1980 Oct;10(4):399-404. (PMID: 6934796); Biochem Pharmacol. 1987 Oct 15;36(20):3365-9. (PMID: 3675598); Drug Metab Dispos. 2010 Mar;38(3):361-7. (PMID: 20008038); Antimicrob Agents Chemother. 2014 Dec;58(12):7283-91. (PMID: 25267666); Am J Trop Med Hyg. 1990 Jun;42(6):532-7. (PMID: 2164790); Br J Clin Pharmacol. 1984 Apr;17(4):441-6. (PMID: 6721990); Pharmaceuticals (Basel). 2021 Apr 22;14(5):. (PMID: 33922294); Antimicrob Agents Chemother. 2014 Aug;58(8):4737-44. (PMID: 24913163); Malar J. 2016 Sep 13;15:466. (PMID: 27618912); Malar J. 2012 Aug 02;11:259. (PMID: 22856549); BMC Infect Dis. 2019 Mar 12;19(1):250. (PMID: 30871496); J Lab Clin Med. 1991 Jun;117(6):468-76. (PMID: 2045714); PLoS One. 2016 Mar 24;11(3):e0151898. (PMID: 27010542); Cochrane Database Syst Rev. 2020 Aug 19;8:CD012656. (PMID: 32816320); J Chromatogr B Analyt Technol Biomed Life Sci. 2021 Jan 15;1163:122510. (PMID: 33387859); Malar J. 2014 Dec 17;13:507. (PMID: 25518709); Br J Clin Pharmacol. 1985 Jun;19(6):745-50. (PMID: 4027117); Curr Drug Metab. 2006 Dec;7(8):873-81. (PMID: 17168688) |
| Grant Information: | R01 AI148469 United States AI NIAID NIH HHS |
| Contributed Indexing: | Keywords: Carboxyprimaquine; Enantiomers; Pharmacokinetics; Primaquine; Primaquine-N-Carbamoyl-glucuronide; Racemate; UHPLC-MS/MS |
| Substance Nomenclature: | 0 (Antimalarials); MVR3634GX1 (Primaquine) |
| Entry Date(s): | Date Created: 20220616 Date Completed: 20220726 Latest Revision: 20250728 |
| Update Code: | 20260130 |
| PubMed Central ID: | PMC9789533 |
| DOI: | 10.1016/j.dmpk.2022.100463 |
| PMID: | 35709685 |
| Database: | MEDLINE |
Journal Article