Determination of Cytochrome P450 Isoenzyme 2D6 (CYP2D6) Genotypes and Pharmacogenomic Impact on Primaquine Metabolism in an Active-Duty US Military Population

Michele D. Spring*, Jason C. Sousa, Qigui Li, Christian A. Darko, Meshell N. Morrison, Sean R. Marcsisin, Kristin T. Mills, Brittney M. Potter, Kristopher M. Paolino, Patrick S. Twomey, James E. Moon, Donna M. Tosh, Susan B. Cicatelli, Jeffrey W. Froude, Brandon S. Pybus, Thomas G. Oliver, William F. McCarthy, Norman C. Waters, Philip L. Smith, Gregory A. ReichardJason W. Bennett

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

26 Scopus citations

Abstract

Background: Plasmodium vivax malaria requires a 2-week course of primaquine (PQ) for radical cure. Evidence suggests that the hepatic isoenzyme cytochrome P450 2D6 (CYP2D6) is the key enzyme required to convert PQ into its active metabolite. Methods: CYP2D6 genotypes and phenotypes of 550 service personnel were determined, and the pharmacokinetics (PK) of a 30-mg oral dose of PQ was measured in 45 volunteers. Blood and urine samples were collected, with PQ and metabolites were measured using ultraperformance liquid chromatography with mass spectrometry. Results: Seventy-six CYP2D6 genotypes were characterized for 530 service personnel. Of the 515 personnel for whom a single phenotype was predicted, 58% had a normal metabolizer (NM) phenotype, 35% had an intermediate metabolizer (IM) phenotype, 5% had a poor metabolizer (PM) phenotype, and 2% had an ultrametabolizer phenotype. The median PQ area under the concentration time curve from 0 to ∞ was lower for the NM phenotype as compared to the IM or PM phenotypes. The novel 5,6-ortho-quinone was detected in urine but not plasma from all personnel with the NM phenotype. Conclusion: The plasma PK profile suggests PQ metabolism is decreased in personnel with the IM or PM phenotypes as compared to those with the NM phenotype. The finding of 5,6-ortho-quinone, the stable surrogate for the unstable 5-hydroxyprimaquine metabolite, almost exclusively in personnel with the NM phenotype, compared with sporadic or no production in those with the IM or PM phenotypes, provides further evidence for the role of CYP2D6 in radical cure. Clinical Trials Registration: NCT02960568.

Original languageEnglish
Pages (from-to)1761-1770
Number of pages10
JournalJournal of Infectious Diseases
Volume220
Issue number11
DOIs
StatePublished - 22 Oct 2019
Externally publishedYes

Keywords

  • 5,6-ortho-quinone
  • CYP2D6
  • Genotype
  • Metabolism
  • Military
  • Pharmacokinetics
  • Phenotype
  • Primaquine

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