Primaquine

Limits on what this shows

• Null findings: None located for primaquine itself; a figure page for a hepatocyte infection study with primaquine-quinoxaline hybrids was seen but its caption did not state a primaquine-alone mitochondrial result, so it is not used.

Regulatory status

The label does not describe a mitochondrial effect [1].

Population evidence

No human data. Tier B: (a) Rabiablok 2023 [12], 25 male Wistar rats in 5 groups of 5, 100 to 250 mg/kg for 3 days; at 200 mg/kg, kidney and liver had significantly fewer normal mitochondria (electron microscopy), Drp-1 and caspase-3 rose in kidney, liver and ventricle, Bax mRNA rose, with hemolytic anemia (lower RBC, hemoglobin and hematocrit) and proximal tubular and ventricular lesions; LD50 about 200 mg/kg (198.4, 95% CI 74.4 to 217.7); numeric effect sizes were not given in the text read (PubMed abstract plus MDPI page via a summarizing fetch tool). (b) Katewa and Katyare 2004 [13], rats treated in vivo with chloroquine, primaquine or quinine: state 3 and state 4 respiration fell sharply, uncoupling at phosphorylation sites II and III, with doses and quantitative values not available in the abstract record. (c) Yeast [14]: primaquine's growth inhibition was confined to respiration-dependent cells and aconitase and Fe-S cluster proteins were damaged. A 1986 report titled as showing uncoupling and inhibitory effects of a primaquine metabolite on mitochondrial energetics and ATP synthase [15] was seen as title and keywords only (no abstract) and is not used.

Mechanism

Present as a Tier B mechanism: oxidant-mediated damage to respiratory and Fe-S cluster proteins and mitochondria-linked apoptosis [12][13][14].

Class cohort test

Not a class extrapolation. Primaquine was in the cohort in [12][13][14]. The antimalarial comparators in [13] (chloroquine, quinine) are not used to extend anything to primaquine.

Counter-evidence held on record

Counter-evidence and gaps Doses in [12] (100 to 250 mg/kg) are far above human exposure (15 mg/day, about 0.25 mg/kg), and the yeast data are respiratory-growth assays. Whether any of this occurs in humans at therapeutic doses is unknown. Framing caution Animal and yeast mechanistic signal only. Do not present as a human mitochondrial deficiency or a reason to take mitochondrial supplements.

Limits on what this shows

• Null findings: Glutathione reductase and glutathione peroxidase were reported resistant to primaquine-derived reactive oxygen species in vitro [11].

Regulatory status

The label describes hemolysis and methemoglobin but no antioxidant-nutrient effect [1].

Population evidence

No human antioxidant-marker study isolating primaquine was opened. Repair-pass addition: in the Fabbri cohort [29], all 42 vivax patients received chloroquine plus primaquine (0.5 mg/kg/day for 7 days); malondialdehyde, glutathione reductase and ceruloplasmin activity were higher than in 28 controls before treatment, thioredoxin reductase was lower, and the markers were similar to controls by day 14. This tracks the infection and its clearance, has no non-primaquine comparator, and does not measure a primaquine effect. In rats, primaquine was used as an in vivo pro-oxidant model that lowered sciatic nerve growth factor to 64% and neuropeptide Y to 67% of control [32] (abstract only; dose, route and group sizes not retrieved). Tier B: (a) Muftuoglu and Ozer 1999 [11], in vitro, primaquine 1 mM incubated with human erythrocyte hemolysates for 30 minutes inhibited G6PD 57% at time zero and 78% at 30 minutes (attributed to NADP-site binding then reactive oxygen species), catalase 33% to 39%, superoxide dismutase 11% to 27%, glutathione-S-transferase 0% to 4%; glutathione reductase and glutathione peroxidase were described as resistant (abstract page read through a summarizing fetch tool). (b) Primaquine-5,6-orthoquinone raised superoxide generation in red cells in vitro in a humanized mouse study [9]. (c) Yeast: reactive oxygen species from respiratory activity were implicated in primaquine's growth effect, and deleting mitochondrial superoxide dismutase (SOD2) greatly increased it [14]. A 2025 plasma metabolomics study of vivax patients on four regimens including 14-day primaquine mentions glutathione and redox pathway changes, but the abstract does not give sample size or primaquine-specific attribution and is not used for a grade [17].

Mechanism

Present: oxidant metabolites, NADPH-dependent recovery limited by G6PD [9][11]. G6PD activity is an enzyme, not a nutrient.

Class cohort test

Not a class extrapolation. Primaquine was the studied drug in [9][10][11][14].

Counter-evidence held on record

Counter-evidence and gaps The in vitro concentration (1 mM) is far above plasma concentrations in the label (about 50 ng/mL, roughly 0.2 micromolar) [1]. The oxidative hematologic effect is the same mechanism as the oxygen-delivery entry; see the Overlap map. Framing caution Redox injury is a drug toxicity mechanism, not an antioxidant-vitamin deficiency. Do not use this entry to recommend antioxidant supplements.

Limits on what this shows

• Null findings: None located; no human iron study was found, so there is no null either.

Regulatory status

The label does not mention iron [1].

Population evidence

None in humans. Tier B: Flaherty 2022 [10]: primaquine- and tafenoquine-treated G6PD-deficient humanized mice showed loss of splenic CD169+ macrophages by days 5 to 7, and liver F4/80+ macrophages and iron deposits increased as the liver became the main site of red-cell clearance (abstract read via summarizing fetch tool; doses and numbers not given). Lalevé 2015 [14]: yeast, primaquine impaired purified aconitase and accelerated turnover of the Fe-S cluster of Rli1; the record does not discuss iron status. A PubMed search combining primaquine, iron and ferritin returned only two unrelated 1987 and 1994 records.

Mechanism

Present: extravascular clearance of damaged red cells loads reticuloendothelial iron (redistribution) [10]; oxidant damage to Fe-S clusters [14]. Neither reduces body iron.

Counter-evidence held on record

Counter-evidence and gaps Hemoglobin loss in G6PD deficiency is a toxicity outcome and is not iron deficiency (Hard Rule 2); iron recovery after a hemolytic episode is physiology, not a drug effect on iron. Mouse tissue iron staining is not a body-iron measure. Framing caution Excess or retention direction in a mouse model; it must not be read as a reason to take iron. Iron supplementation after hemolysis is a clinical decision for the prescriber.

Limits on what this shows

• Null findings: By day 14, after parasite clearance, the oxidative markers measured (which included ceruloplasmin activity) were reported as not different from healthy controls [29]. No source measured serum copper or ceruloplasmin in primaquine users against patients treated without primaquine.

Regulatory status

The label does not mention copper or ceruloplasmin [1].

Population evidence

Fabbri 2013 [29], observational cohort in the Brazilian Amazon: 34 P. vivax patients without jaundice, 8 with cholestatic jaundice and 28 healthy controls; every patient received the national regimen of chloroquine 25 mg/kg over 3 days plus primaquine 0.5 mg/kg/day for 7 days; G6PD-deficient patients were excluded. Ceruloplasmin was measured as plasma oxidase activity (not as protein mass and not as serum copper) on day 1 before treatment and on day 14 (18 of the 34 non-jaundiced and 7 of the 8 jaundiced patients returned). Ceruloplasmin was significantly higher than in controls on day 1 in both patient groups; the paper states that by day 14 the oxidative stress markers "were not different" from the healthy group but does not single out ceruloplasmin, and the numeric values are in figures that were not readable in the text opened. A disease-level meta-analysis of 16 studies [30] found copper in malaria patients versus uninfected controls not significantly different overall (Hedges g 0.38, 95% CI -0.48 to 1.25, I2 98.73%) with no stratification by treatment; primaquine appears there only in a reference title. A small Iranian-journal study of 12 vivax patients versus 12 controls reported serum copper of 2.69 versus 2.05 ppm [31] without stating the treatment given, so it says nothing about the drug.

What was searched

Original pass: WebSearch "primaquine copper OR ceruloplasmin OR serum copper human" (nothing on primaquine and copper status) and a PubMed "primaquine oxidative stress" listing (one copper(II)-primaquine chemistry paper [18]). Repair pass: WebSearch "primaquine serum copper ceruloplasmin malaria patients" and "serum copper zinc Plasmodium vivax patients before and after treatment chloroquine primaquine"; a PubMed listing for primaquine AND (copper OR ceruloplasmin) returned seven records (copper-complex antimalarial chemistry, a nanoplatform, an electrode method, a 1983 NADPH oxidation mechanism paper, a quinone oxidoreductase kinetics paper, a G6PD rapid-test paper), none measuring copper or ceruloplasmin in primaquine users. A 2024 ceruloplasmin-in-malaria systematic review (Malar J) surfaced in search but its PMC page returned a bot check and was not opened.

Mechanism

Absent for the drug. No copper-specific pharmacology of primaquine was found. A 2026 paper on copper(II)-primaquine coordination chemistry [18] is in vitro chemistry (abstract only, no copper-coordination result stated) and says nothing about copper status. Ceruloplasmin is an acute-phase protein and a copper-binding oxidase; the Fabbri paper itself describes it as proposed to reduce inflammation and the acute-phase response [29].

Class cohort test

Not a class extrapolation. Primaquine was in the regimen in [29], always together with chloroquine, so its contribution cannot be separated. Hard Rule 6 applies: the change in the indication (malaria) is presumed to explain the finding.

Counter-evidence held on record

Counter-evidence and gaps Moved from ungraded to yellow in a repair pass because a human cohort on a primaquine regimen measured a copper-dependent protein, even though the result is a disease effect. Ceruloplasmin activity is not copper status. There is no comparator group without primaquine, the sample at day 14 was partial (25 of 42 patients), and chloroquine was given in the same regimen. The paper also notes that antimalarial drugs are suspected oxidants in red cells but argues both patient groups had the same exposure, so no drug effect can be isolated. Framing caution This is not evidence that primaquine raises or lowers copper. Do not read the infection-related ceruloplasmin rise as a copper excess, and do not use this entry to suggest copper supplementation or restriction. No dose is recommended.

Limits on what this shows

• Why no grade: The dual condition was met: no opened source gave primaquine to a host and measured the microbiome, the opened microbiome data concern other antimalarials or no drug and are not class evidence for an 8-aminoquinoline (Hard Rule 6 cohort test fails), and no circulating claim was found. The wide PubMed listing returning no relevant record, across two passes and several phrasings, makes this most likely a genuine literature gap. The residual tooling-limited item is the supplementary table of [35]; GI adverse reactions in the label are not microbiome data. Re-check if a screen of drugs against gut bacterial strains is shown to include primaquine (that would be Tier B in vitro).

What was searched

Original pass: WebSearch "primaquine gut microbiota human OR mice 16S dysbiosis" and a second phrasing with "gut microbiome antimalarial": results opened were a rhesus macaque malaria microbiome paper (primaquine not mentioned; treatment drugs not named) [20], a 2025 review of microbiota, malaria parasite and mice (abstract only; primaquine not discussed) [28], and a mouse study of artesunate-amodiaquine and artemether-lumefantrine that did not modify the murine gut microbiota (primaquine not included) [19]. Repair pass: two more WebSearch phrasings ("primaquine gut microbiota Plasmodium vivax radical cure patients microbiome"; "primaquine treatment intestinal microbiota mice 16S rRNA") returned a vector-mosquito microbiota paper, malaria reviews and vivax radical-cure reviews, none a primaquine host-microbiome study; two further queries (drug-screen and in vitro gut commensal phrasings) were refused because the search budget was used up. A PubMed listing for primaquine AND (microbiota OR microbiome OR dysbiosis) returned exactly one record, a 2025 Plasmodium falciparum resistance-marker paper in Ecuador that is unrelated to the gut. Pages opened and found not to involve primaquine: a P. yoelii mouse fecal-microbiome paper with no drug given [33]; and a Kenyan infant stool 16S study of artemether-lumefantrine (primaquine not given) [34]. The 2018 Nature screen of non-antibiotic drugs against human gut bacteria [35] was opened as a page and showed no mention of primaquine in the visible text, but its supplementary drug list was not opened, so whether primaquine was among the tested compounds is unresolved.

Limits on what this shows

• Null findings: The 0.4 to 0.5 mg/kg dose in one small trial showed no day-7 hemoglobin difference from placebo, and low doses (0.1 to 0.25 mg/kg) showed no significant change from baseline versus placebo in deficient people [3]. A WorldWide Antimalarial Resistance Network individual-patient-data analysis (29 studies, 3,421 patients) is reported by a secondary Oxford summary to find primaquine not associated with increased anemia in patients without G6PD deficiency and better hemoglobin by day 42, because it prevents relapse; the primary article was not opened [24].
• At-risk subgroups: G6PD deficiency, including heterozygous females with intermediate activity; high daily or weekly dose; NADH methemoglobin reductase deficiency; co-use of dapsone, sulfonamides or other hemolytic or methemoglobin-inducing drugs; established granulocytopenia (leukopenia warning) [1]. Hemoglobin falls above 25% also occurred in G6PD-normal patients in the Ethiopian cohort [7].

Regulatory status

Label [1]: hemolytic reactions, moderate to severe, may occur in G6PD deficiency and "occurs commonly" there, and may be severe or fatal in severe deficiency; severe G6PD deficiency is a contraindication; test G6PD and take baseline hemoglobin and hematocrit; monitor about day 3 and day 8 when status is mild to moderate or unknown. Methemoglobin may rise transiently by up to 10% without risk factors and may be severe with NADH methemoglobin reductase deficiency or co-use of dapsone or sulfonamides; levels are usually below 10%.

Population evidence

(a) Systematic review of prospective studies of primaquine in G6PD-deficient people, Uthman 2017 [3]: 5 randomized trials and 4 controlled cohorts. High dose (0.75 mg/kg), deficient versus placebo: day-7 hemoglobin mean difference -1.45 g/dL (95% CI -2.17 to -0.74; 2 trials) and percentage fall from baseline -10.31% (95% CI -17.69 to -2.92; 3 trials). High dose, deficient versus G6PD-replete: day-7 hemoglobin -1.19 g/dL (95% CI -1.94 to -0.44; 2 trials), change from baseline -9.10% (95% CI -12.55 to -5.65; 5 trials). Low dose (0.1 to 0.25 mg/kg), deficient versus placebo: change from baseline similar (mean difference 1.72%, 95% CI -1.89 to 5.34; 2 trials); low dose, deficient versus replete: day-7 hemoglobin -0.57 g/dL (95% CI -0.97 to -0.17; 1 trial). Certainty was graded low or very low and severe events were "not common." (b) Bancone 2016 [4]: 819 subjects given single low-dose primaquine 0.25 mg base/kg with dihydroartemisinin-piperaquine three times at monthly intervals; mean fractional hemoglobin change in G6PD-deficient subjects -5.0%, -4.2% and -4.7% per round versus 0.3%, -0.8% and -1.7% in normal subjects; a fall above 25% occurred in 1.8% of the population, all asymptomatic. Repair-pass addition from the PLOS One article text: overall mean difference in fractional hemoglobin change, deficient versus normal, after adjustment for age and number of doses, -4.32% (95% CI -6.05 to -2.60, P below 0.001); 124 of 1,400 screened subjects (8.9%) were G6PD deficient by fluorescent spot test; one normal-phenotype Mahidol heterozygote fell from 9.1 to 6.8 g/dL with black urine; no methemoglobin data were reported. Read through a summarizing fetch tool, and the paper's Table 3 (per-round confidence intervals) is an image that was not read. (c) Lek 2019 [5], randomized trial in 109 Cambodians with falciparum malaria: day-7 hemoglobin 10.9 g/dL in G6PD-deficient (n=9) versus 12.05 g/dL in G6PD-normal (n=46) recipients of single low-dose primaquine, difference -1.15 g/dL (95% CI -2.24 to -0.05); no transfusion; the abstract record was fragmentary in places and some figures should be verified. (d) ALTPRIM 2025 [6], randomized trial in 54 G6PD-deficient patients in the Brazilian Amazon: the daily primaquine arm (0.5 mg/kg/day for 7 days) was halted for safety after 2 participants; day-3 hemoglobin change after the first dose was -1.61 for weekly primaquine versus -0.99 for weekly chloroquine (units not stated in the abstract). (e) Prospective Ethiopian cohort [7], 879 patients on the 14-day regimen, none G6PD-deficient by the screen used: median day-3 fractional hemoglobin change -0.9%; 9 patients fell more than 25% (2 below 8 g/dL), none symptomatic; 91.9% had hematologic recovery by day 13. (f) Methemoglobin: an individual-patient-data meta-analysis [8] of 8 randomized trials and 1,747 G6PD-normal patients found day-7 methemoglobin rose with weight-adjusted primaquine dose; each doubling was associated with adjusted hazard ratio 0.70 for recurrence (95% CI 0.57 to 0.86). Absolute methemoglobin values were not in the abstract. Abstracts were read through PubMed and OpenAlex records via a summarizing fetch tool; full texts were not opened.

Mechanism

Present and named. Primaquine metabolites generate oxidant stress in red cells; G6PD-deficient cells have limited NADPH to recover. In a humanized mouse model of G6PD Mediterranean deficiency, the metabolite primaquine-5,6-orthoquinone increased superoxide and methemoglobin formation in vitro and selectively cleared older G6PD-deficient red cells in vivo [9]. In a second humanized mouse model, primaquine and tafenoquine raised eryptosis markers within 24 hours with intravascular and extravascular hemolysis [10].

Hard Rule 2 justification for orange

This entry is graded above yellow on purpose and against the usual caution that a drug toxicity outcome should not exceed yellow unless a nutrient is measured. The justification: the Oxygen delivery/utilization category is defined by hemoglobin, hematocrit, red-cell mass and functional hemoglobin, and those variables were measured directly in more than one independent human source [3][4][5][6][7], with methemoglobin and hemolysis stated by the label [1]. The entry makes no iron, folate or B12 deficiency claim and no supplementation claim; anemia is explicitly not filed as a nutrient deficiency. It is orange (bounded) and not red because the exposure is conditional on G6PD status and dose, no nutrient is measured, and several cohorts combine primaquine with a partner drug or measure malaria-affected patients. This matches how the dapsone oxygen-delivery entry in batch B017 was handled.

Counter-evidence held on record

Counter-evidence and confounding Malaria itself lowers hemoglobin, and partner drugs (chloroquine, dihydroartemisinin-piperaquine) can contribute, so baseline-to-nadir change in [4][5][6][7] is not a pure primaquine effect; trials in [3] compared primaquine with placebo or with G6PD-replete people and are the cleaner contrast. Doses differ widely between sources (single 0.25 mg/kg to 0.75 mg/kg, 14-day 15 mg, weekly regimens), so pooling them would not be valid. Framing caution This is a drug toxicity monitoring signal tied to G6PD status and dose, not an iron, folate or B12 deficiency and not a reason to supplement anything. Anemia is an outcome (Hard Rule 2). Do not infer an oxygen-carrying nutrient gap from this entry.

Limits on what this shows

• Null findings: Site I phosphorylation was unaffected [13].

Regulatory status

Not addressed in the label [1].

Population evidence

None in humans. Tier B: Katewa and Katyare 2004 [13] (rats; primaquine, chloroquine and quinine): ADP phosphorylation rates decreased significantly through uncoupling at sites II and III; basal and Mg2+-stimulated ATPase activities rose and DNP-stimulated ATPase fell by about half; cytochrome content changes differed by drug. ATP levels, ADP/O ratios, respiratory control ratios and doses were not available in the record read. Abstract read as an OpenAlex reconstruction through a summarizing fetch tool.

Mechanism

Present as uncoupling of oxidative phosphorylation (mechanism class E) in an animal study [13].

Class cohort test

Not a class extrapolation; primaquine was a studied drug [13].

Counter-evidence held on record

Counter-evidence and gaps Respiration and ADP phosphorylation rates are surrogates and not a direct ATP measurement. Shares evidence with the Mitochondrial burden entry (Overlap map). Framing caution Not a human energy deficit and not a reason to take energy or mitochondrial supplements.