{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,4]],"date-time":"2026-08-04T13:46:42Z","timestamp":1785851202486,"version":"3.56.0"},"reference-count":32,"publisher":"American Society for Microbiology","issue":"8","license":[{"start":{"date-parts":[[2026,8,5]],"date-time":"2026-08-05T00:00:00Z","timestamp":1785888000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"},{"start":{"date-parts":[[2026,8,5]],"date-time":"2026-08-05T00:00:00Z","timestamp":1785888000000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/journals.asm.org\/non-commercial-tdm-license"}],"funder":[{"DOI":"10.13039\/100010269","name":"Wellcome Trust","doi-asserted-by":"publisher","award":["B9R05430"],"award-info":[{"award-number":["B9R05430"]}],"id":[{"id":"10.13039\/100010269","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["journals.asm.org"],"crossmark-restriction":true},"short-container-title":["Antimicrob Agents Chemother"],"published-print":{"date-parts":[[2026,8,5]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:sec>\n                    <jats:title\/>\n                    <jats:p>\n                      Cytochrome P450 isotype 2D6 (CYP2D6) enzyme metabolizes the 8-aminoquinoline primaquine into its active form, 5-hydroxyprimaquine. Highly polymorphic CYP2D6 produces different enzyme activity levels among individuals. This diversity influences the therapeutic efficacy of primaquine in preventing\n                      <jats:italic toggle=\"yes\">Plasmodium vivax<\/jats:italic>\n                      malaria relapses. Urinary 5,6-orthoquinone primaquine concentrations in Indonesian patients treated with primaquine for malaria were analyzed in relation to CYP2D6 genotype-predicted phenotypes and blood methemoglobin levels. We genotyped samples from 48 patients and classified them into three CYP2D6 metabolic activity groups: intermediate, normal, and ultra-rapid metabolizers. Methemoglobin levels were measured repeatedly up to 27 times over 72 h, including one pre-dose measurement and eight post-dose measurements per day at approximately 30-min intervals following primaquine administration. Intermediate metabolizers exhibited significantly lower urinary concentrations of 5,6-orthoquinone primaquine compared to normal and ultra-rapid metabolizers (geometric mean ratio: 2.24, 95% CI: 1.26\u20133.98,\n                      <jats:italic toggle=\"yes\">P<\/jats:italic>\n                      = 0.01), indicative of reduced drug bioactivation. Methemoglobin concentrations gradually increased from Day 0 to Day 2, particularly in normal metabolizers. Day 2 methemoglobin levels were higher in normal\/ultra-rapid metabolizers in our study sample (geometric mean ratio = 1.51; 95% CI: 0.84\u20132.70;\n                      <jats:italic toggle=\"yes\">P<\/jats:italic>\n                      = 0.15). There was a strong positive relationship between urinary 5,6-orthoquinone primaquine and Day 2 methemoglobin levels (geometric mean ratio per 1,000 ng\/mL increase = 1.90; 95% CI: 1.37\u20132.63;\n                      <jats:italic toggle=\"yes\">P<\/jats:italic>\n                      = 0.0007). Our findings accord with the hypothesized utility of urinary 5,6-orthoquinone primaquine concentrations and methemoglobin levels as pharmacodynamic markers of primaquine bioactivation. Understanding and measuring the impacts of CYP2D6 polymorphisms will aid in interpreting clinical trials and optimizing primaquine dosing strategies.\n                    <\/jats:p>\n                    <jats:sec>\n                      <jats:title>CLINICAL TRIALS<\/jats:title>\n                      <jats:p>\n                        This study is registered with ClinicalTrials.gov as\n                        <jats:related-object xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" document-id=\"NCT03916003\" document-id-type=\"clinical-trial-number\" source-id=\"ClinicalTrials.gov\" source-id-type=\"registry-name\" source-type=\"clinical-trials-registry\" xlink:href=\"https:\/\/clinicaltrials.gov\/study\/NCT03916003\">NCT03916003<\/jats:related-object>\n                        .\n                      <\/jats:p>\n                    <\/jats:sec>\n                  <\/jats:sec>","DOI":"10.1128\/aac.00539-26","type":"journal-article","created":{"date-parts":[[2026,7,13]],"date-time":"2026-07-13T13:56:58Z","timestamp":1783951018000},"update-policy":"https:\/\/doi.org\/10.1128\/asmj-crossmark-policy-page","source":"Crossref","is-referenced-by-count":0,"title":["Primaquine-derived 5,6-orthoquinone concentrations in urine associated with CYP2D6 genotype-predicted phenotype and blood methemoglobin levels"],"prefix":"10.1128","volume":"70","author":[{"ORCID":"https:\/\/orcid.org\/0009-0004-2268-536X","authenticated-orcid":true,"given":"Mario","family":"Vernandes","sequence":"first","affiliation":[{"id":[{"id":"https:\/\/ror.org\/0116zj450","id-type":"ROR","asserted-by":"publisher"}],"name":"Faculty of Medicine, Oxford University Clinical Research Unit Indonesia, Universitas Indonesia","place":["Jakarta, Indonesia"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Willy","family":"Agustine","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/0116zj450","id-type":"ROR","asserted-by":"publisher"}],"name":"Faculty of Medicine, Oxford University Clinical Research Unit Indonesia, Universitas Indonesia","place":["Jakarta, Indonesia"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ihsan","family":"Fadilah","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/0116zj450","id-type":"ROR","asserted-by":"publisher"}],"name":"Faculty of Medicine, Oxford University Clinical Research Unit Indonesia, Universitas Indonesia","place":["Jakarta, Indonesia"]},{"id":[{"id":"https:\/\/ror.org\/052gg0110","id-type":"ROR","asserted-by":"publisher"}],"name":"Centre for Tropical Medicine and Global Health, Nuffield Department of Medicine, University of Oxford","place":["Oxford, United 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Kevin","family":"Baird","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/0116zj450","id-type":"ROR","asserted-by":"publisher"}],"name":"Faculty of Medicine, Oxford University Clinical Research Unit Indonesia, Universitas Indonesia","place":["Jakarta, Indonesia"]},{"id":[{"id":"https:\/\/ror.org\/052gg0110","id-type":"ROR","asserted-by":"publisher"}],"name":"Centre for Tropical Medicine and Global Health, Nuffield Department of Medicine, University of Oxford","place":["Oxford, United Kingdom"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"235","reference":[{"key":"e_1_3_3_2_2","doi-asserted-by":"publisher","DOI":"10.1002\/14651858.CD008152.pub4"},{"key":"e_1_3_3_3_2","doi-asserted-by":"publisher","DOI":"10.4269\/ajtmh.20-0186"},{"key":"e_1_3_3_4_2","doi-asserted-by":"publisher","DOI":"10.1186\/s12916-020-1497-0"},{"key":"e_1_3_3_5_2","doi-asserted-by":"publisher","DOI":"10.4269\/ajtmh.16-0171"},{"key":"e_1_3_3_6_2","doi-asserted-by":"publisher","DOI":"10.1093\/cid\/cis615"},{"key":"e_1_3_3_7_2","doi-asserted-by":"publisher","DOI":"10.1186\/1475-2875-12-212"},{"key":"e_1_3_3_8_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.pharmthera.2016.03.011"},{"key":"e_1_3_3_9_2","volume-title":"Medical genetics summaries","author":"Kane M","year":"2021","unstructured":"Kane M. 2021. 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