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

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  • Additional Information
    • Affiliation:
      Department of Bacterial and Parasitic Diseases, US Army Medical Directorate of the Armed Forces Research Institute of Medical Sciences, Bangkok, Thailand
      The Henry M. Jackson Foundation for the Advancement of Military Medicine, Silver Spring
      Experimental Therapeutics Branch, Silver Spring
      General Dynamics Information Technology, Silver Spring
      Clinical Trials Center, Silver Spring
      Food and Drug Administration, Boston, Massachusetts
      Davita Medical Group, Colorado Springs, Colorado
      Division of Infectious Disease, SUNY Upstate Medical University, Syracuse, New York
      Licensing and Early Development–Oncology, Genentech, South San Francisco, California
      Malaria Vaccine Branch, Silver Spring
      Clinical Operations, Government and Public Health Solutions, ICON, Hinckley, Ohio
      Vaccines/Therapeutics Division, Defense Threat Reduction Agency, Fort Belvoir, Virginia
      Clinical Pharamacology Division, Silver Spring
      U. S. Army Medical Materiel Development Activity, Fort Detrick, Maryland
      Center for Enabling Capabilities, Silver Spring
    • Subject Terms:
    • Subject Terms:
    • 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.
    • Journal Subset:
      Biomedical; Editorial Board Reviewed; Peer Reviewed; USA
    • Instrumentation:
      Profile of Mood States (POMS)
      Clinical Decision Making in Nursing Scale (CDMNS) (Jenkins)
      Impact of Events Scale (IES)
    • ISSN:
      0022-1899
    • MEDLINE Info:
      PMID: NLM31549155 NLM UID: 0413675
    • Publication Date:
      20200515
    • Publication Date:
      20200521
    • DOI:
      10.1093/infdis/jiz386
    • Accession Number:
      139269480
  • Citations
    • ABNT:
      SPRING, M. D. et al. Determination of Cytochrome P450 Isoenzyme 2D6 (CYP2D6) Genotypes and Pharmacogenomic Impact on Primaquine Metabolism in an Active-Duty US Military Population. Journal of Infectious Diseases, [s. l.], v. 220, n. 11, p. 1761–1770, 2019. DOI 10.1093/infdis/jiz386. Disponível em: http://search.ebscohost.com/login.aspx?direct=true&site=eds-live&db=rzh&AN=139269480. Acesso em: 25 set. 2020.
    • AMA:
      Spring MD, Sousa JC, Li Q, et al. Determination of Cytochrome P450 Isoenzyme 2D6 (CYP2D6) Genotypes and Pharmacogenomic Impact on Primaquine Metabolism in an Active-Duty US Military Population. Journal of Infectious Diseases. 2019;220(11):1761-1770. doi:10.1093/infdis/jiz386
    • APA:
      Spring, M. D., Sousa, J. C., Li, Q., Darko, C. A., Morrison, M. N., Marcsisin, S. R., Mills, K. T., Potter, B. M., Paolino, K. M., Twomey, P. S., Moon, J. E., Tosh, D. M., Cicatelli, S. B., Froude, J. W., Pybus, B. S., Oliver, T. G., McCarthy, W. F., Waters, N. C., Smith, P. L., & Reichard, G. A. (2019). Determination of Cytochrome P450 Isoenzyme 2D6 (CYP2D6) Genotypes and Pharmacogenomic Impact on Primaquine Metabolism in an Active-Duty US Military Population. Journal of Infectious Diseases, 220(11), 1761–1770. https://doi.org/10.1093/infdis/jiz386
    • Chicago/Turabian: Author-Date:
      Spring, Michele D, Jason C Sousa, Qigui Li, Christian A Darko, Meshell N Morrison, Sean R Marcsisin, Kristin T Mills, et al. 2019. “Determination of Cytochrome P450 Isoenzyme 2D6 (CYP2D6) Genotypes and Pharmacogenomic Impact on Primaquine Metabolism in an Active-Duty US Military Population.” Journal of Infectious Diseases 220 (11): 1761–70. doi:10.1093/infdis/jiz386.
    • Harvard:
      Spring, M. D. et al. (2019) ‘Determination of Cytochrome P450 Isoenzyme 2D6 (CYP2D6) Genotypes and Pharmacogenomic Impact on Primaquine Metabolism in an Active-Duty US Military Population’, Journal of Infectious Diseases, 220(11), pp. 1761–1770. doi: 10.1093/infdis/jiz386.
    • Harvard: Australian:
      Spring, MD, Sousa, JC, Li, Q, Darko, CA, Morrison, MN, Marcsisin, SR, Mills, KT, Potter, BM, Paolino, KM, Twomey, PS, Moon, JE, Tosh, DM, Cicatelli, SB, Froude, JW, Pybus, BS, Oliver, TG, McCarthy, WF, Waters, NC, Smith, PL & Reichard, GA 2019, ‘Determination of Cytochrome P450 Isoenzyme 2D6 (CYP2D6) Genotypes and Pharmacogenomic Impact on Primaquine Metabolism in an Active-Duty US Military Population’, Journal of Infectious Diseases, vol. 220, no. 11, pp. 1761–1770, viewed 25 September 2020, .
    • MLA:
      Spring, Michele D., et al. “Determination of Cytochrome P450 Isoenzyme 2D6 (CYP2D6) Genotypes and Pharmacogenomic Impact on Primaquine Metabolism in an Active-Duty US Military Population.” Journal of Infectious Diseases, vol. 220, no. 11, Dec. 2019, pp. 1761–1770. EBSCOhost, doi:10.1093/infdis/jiz386.
    • Chicago/Turabian: Humanities:
      Spring, Michele D, Jason C Sousa, Qigui Li, Christian A Darko, Meshell N Morrison, Sean R Marcsisin, Kristin T Mills, et al. “Determination of Cytochrome P450 Isoenzyme 2D6 (CYP2D6) Genotypes and Pharmacogenomic Impact on Primaquine Metabolism in an Active-Duty US Military Population.” Journal of Infectious Diseases 220, no. 11 (December 2019): 1761–70. doi:10.1093/infdis/jiz386.
    • Vancouver/ICMJE:
      Spring MD, Sousa JC, Li Q, Darko CA, Morrison MN, Marcsisin SR, et al. Determination of Cytochrome P450 Isoenzyme 2D6 (CYP2D6) Genotypes and Pharmacogenomic Impact on Primaquine Metabolism in an Active-Duty US Military Population. Journal of Infectious Diseases [Internet]. 2019 Dec [cited 2020 Sep 25];220(11):1761–70. Available from: http://search.ebscohost.com/login.aspx?direct=true&site=eds-live&db=rzh&AN=139269480