Measurements of 5,6-Orthoquinone, a Surrogate for the Presumed Active Primaquine Metabolite 5-Hydroxyprimaquine, in the Urine of Cambodian Adults

Pattaraporn Vanachayangkul, Darapiseth Sea, Mariusz Wojnarski, Somethy Sok, Chanikarn Kodchakorn, Winita Taaksorn, Sohei Hom, Mali Ittiverakul, Worachet Kuntawunginn, Montri Arsanok, Nillawan Buathong, Thay Kheang Heng, Kong Nareth, Samon Nou, Sok Chandara, Sokna Ly, Pheaktra Oung, Brian Vesely, Jason Bennett, Gregory ReichardBrandon Pybus, Charlotte Lanteri, David Saunders, Mark Fukuda, Philip Smith, Lek Dysoley, Huy Rekol, Norman C. Waters, Michele Spring*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

2 Scopus citations

Abstract

The active metabolites of primaquine, in particular 5-hydroxyprimaquine, likely responsible for the clearance of dormant hypnozoites, are produced through the hepatic CYP450 2D6 (CYP2D6) enzymatic pathway. With the inherent instability of 5- hydroxyprimaquine, a stable surrogate, 5,6-orthoquinone, can now be detected and measured in the urine as part of primaquine pharmacokinetic studies. This study performed CYP450 2D6 genotyping and primaquine pharmacokinetic testing, to include urine 5,6-orthoquinone, in 27 healthy adult Cambodians, as a preliminary step to prepare for future clinical studies assessing primaquine efficacy for Plasmodium vivax infections. The CYP2D6*10 reduced activity allele was found in 57% of volunteers, and the CYP2D6 genotypes were dominated by*1/*10 (33%) and*10/*10 (30%). Predicted phenotypes were evenly split between Normal Metabolizer (NM) and Intermediate Metabolizer (IM) except for one volunteer with a gene duplication and unclear phenotype, classifying as either IM or NM. Median plasma primaquine (PQ) area under the curve (AUC) was lower in the NM group (460 h*ng/mL) compared to the IM group (561 h*ng/mL), although not statistically significant. Similar to what has been found in the US study, no 5,6-orthoquinone was detected in the plasma. The urine creatinine-corrected 5,6-orthoquinone AUC in the NM group was almost three times higher than in the IM group, with peak measurements (Tmax) at 4 h. Although there is variation among individuals, future studies examining the relationship between the levels of urine 5,6- orthoquinone and primaquine radical cure efficacy could result in a metabolism biomarker predictive of radical cure.

Original languageEnglish
Article numbere01821-21
JournalAntimicrobial Agents and Chemotherapy
Volume66
Issue number3
DOIs
StatePublished - Mar 2022
Externally publishedYes

Keywords

  • 5,6-orthoquinone
  • CYP2D6
  • Malaria
  • Metabolism
  • Primaquine
  • Vivax

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