Balsalazide

Limits on what this shows

• Key null / negative: None for balsalazide; no balsalazide cellular mitochondrial assay was located.
• At-risk subgroups: None identified.

Regulatory status

No mitochondrial statement in the label sections read [1][2][3].

Population evidence

No human data. Tier B, this drug: Glas 2020 [7] reports balsalazide as a subtype-selective Sirt5 inhibitor with an IC50 of 3.9 µM in a fluorometric assay on recombinant enzyme, selective over Sirt1 to 3 and Sirt6 according to the abstract; the page read contained no cellular data (abstract read through a summarizing tool). Wirawan 2025 [8] states that balsalazide emerged as a Sirt5 inhibitor in a high-throughput screen and that its gut-bacteria-labile azo bond and pharmacokinetics are suboptimal for that use; it gives no cellular or mitochondrial data for balsalazide itself. SIRT5 is described as acting within mitochondria on the urea cycle, TCA cycle and fatty acid oxidation enzymes and on antioxidant capacity [9] (narrative review).

Mechanism

Named at enzyme level: inhibition of an NAD+-dependent lysine deacylase [7][8]. Whether it occurs in tissue is not shown. For scale, a review abstract reports a median plasma Cmax of 0.324 µmol/L for balsalazide [6] (dose not stated in the text read), about 12-fold below the 3.9 µM IC50, and the parent is at least 99% protein bound [2]. Luminal and colonic mucosal exposure to intact balsalazide were not found in the sources read.

CLASS EXTRAPOLATION

Mesalazine in isolated rat heart mitochondria produced concentration- and time-dependent reactive oxygen species, loss of enzyme activity, membrane destabilization and cytochrome c release [12]. In the opposite direction, pure 5-ASA increased spare mitochondrial respiratory capacity in cultured epithelial cells in a DSS colitis study [15]. Cohort test: balsalazide was not in either study (the second used pure 5-ASA; the first, mesalazine). Both are Tier C and cannot be graded above yellow. Concentrations used in [12] were not in the summary read.

Counter-evidence held on record

Counter-evidence and confounding The IC50 comes from a purified enzyme and its authors describe balsalazide as a screening hit, not a tissue-active agent [8]. The two class studies point in opposite directions and neither used balsalazide. Framing caution Not a human mitochondrial toxicity finding and not a deficiency. Do not use it as a basis for CoQ10 or other mitochondrial supplement advice.

Limits on what this shows

• Key null / negative: No study located measured blood or tissue antioxidant capacity (glutathione, superoxide dismutase, malondialdehyde) in balsalazide-treated patients against untreated controls.
• At-risk subgroups: None identified.

Regulatory status

No oxidative-stress or antioxidant statement in the label sections read [1][2][3].

Population evidence

Tier B, this drug. Liu 2009 [10]: C57BL/6J mice with 5% DSS colitis given intragastric balsalazine at 42, 141 and 423 mg/kg. Treatment decreased malondialdehyde and myeloperoxidase and increased superoxide dismutase and glutathione peroxidase activity, and reduced Evans blue permeation and TNF-alpha and IFN-gamma. Group sizes were not in the sections read, and the sections read did not describe a non-colitic, drug-only group. Simmonds 1999 [11]: in cell-free systems and inflamed human colorectal biopsies, "balsalazide and N-acetyl-5-aminosalicylic acid inhibited rectal biopsy chemiluminescence by 93% and 100%, respectively" at therapeutic concentrations (reconstructed OpenAlex abstract read through a summarizing tool; biopsy numbers and the cell-free results not read).

Mechanism

Named: radical scavenging and suppression of oxidant generation by the 5-ASA moiety and its N-acetyl metabolite, part of the drug's intended anti-inflammatory action [11]. In the mouse study the marker changes may also reflect reduced inflammation rather than a direct antioxidant effect [10].

CLASS EXTRAPOLATION

Pro-oxidant direction: 5-ASA with Fe3+ at 20 µM each generated hydroxyl radical and lipid peroxidation in solution [13]; aminophenols including mesalamine drove copper-dependent reactive oxygen species in permeabilized yeast cells [14]. Cohort test: balsalazide was not tested in either; both are Tier C, in vitro, and relevant only to the 5-ASA released in the colon.

Counter-evidence held on record

Counter-evidence and confounding The protective signal is the drug's intended pharmacology and is confounded by disease remission in the colitis model; Hard Rule 2 excludes it from deficiency grading. The pro-oxidant results are solution or yeast chemistry at micromolar concentrations of a different molecule. Framing caution Reverse-direction finding. Do not present as an antioxidant deficiency or as a reason to add antioxidant supplements.

Limits on what this shows

• Key null / negative: The balsalazide label lists no iron interaction and no separation interval [1][2][3].
• At-risk subgroups: People with active UC, children, and anyone with chronic blood loss. These are disease groups, not drug-attributable groups.

Regulatory status

No iron statement or iron interaction in the label sections read. Anemia appears in the label only as a disease presentation, according to the summarizing tool [1][2][3].

Population evidence

No iron-status study stratified by balsalazide located. Disease context: the ECCO consensus [24] states that anemia affects about two-thirds of IBD patients at diagnosis, roughly 30 to 40% of adults and about 70% of children during follow-up, driven by ulcer blood loss, impaired uptake and hepcidin-mediated functional deficiency. A 2025 cross-sectional study of 216 UC patients in clinical remission found iron deficiency common; the percentages relayed by the summarizing tool were internally inconsistent, so none is relied on here [25].

Mechanism

CLASS EXTRAPOLATION. Grisham 1992 [13]: "5-ASA was very effective at chelating ferric iron (Fe3+), and it rapidly reduced Fe3+ to the ferrous form," with maximal hydroxyl radical formation at 20 µM 5-ASA and 20 µM Fe3+. Cohort test: pure 5-ASA was tested; balsalazide was not, so this is Tier C and shows chemistry in a tube, not reduced intestinal iron absorption. A drug-interaction checker lists no interaction between iron sulfate and mesalamine (Tier D, mesalamine not balsalazide) [28].

Counter-evidence held on record

Counter-evidence and confounding Confounding by indication is presumed (Hard Rule 6). Anemia or iron deficiency in a person with UC is not an iron-deficiency finding caused by balsalazide. Framing caution Do not tell patients balsalazide causes iron deficiency. Iron decisions belong to the IBD care team; this dossier recommends no iron dose and kept Copper as a separate entry.

Limits on what this shows

• Key null / negative: None for balsalazide. A search for balsalazide with copper, zinc, trace elements or chelation returned only generic chelation pages.
• At-risk subgroups: None identified.

Regulatory status

No copper statement in the label sections read [1][2][3].

Population evidence

No copper-status study stratified by balsalazide located.

Mechanism

CLASS EXTRAPOLATION. Murakami and Yoshino 2022 [14]: ortho- and para-aminophenols, with mesalamine among the para derivatives, showed prooxidant activity in permeabilized yeast cells, measured as aconitase inactivation; concentrations were not in the abstract. Cohort test: mesalamine was studied, balsalazide was not mentioned; Tier C, in vitro. No mechanism for copper loss, malabsorption or retention was found.

Counter-evidence held on record

Counter-evidence and confounding A redox interaction in permeabilized yeast is neither depletion nor excess, and it concerns a different molecule than the one given to patients. Framing caution Kept separate from Iron. Not a copper deficiency or excess claim; no copper supplementation is supported.

Limits on what this shows

• Key null / negative: No balsalazide microbiome study located; alpha diversity results of [16] were not read in detail.
• At-risk subgroups: People on concurrent antibiotics or with marked dysbiosis might alter activation; this is a hypothesis from mechanism, not tested for balsalazide in any source read.

Regulatory status

The label states activation by bacterial azoreduction and delayed colonic release with upper GI obstruction [1][2]. In the text read it says nothing about antibiotics or about effects on microbiome composition.

Population evidence

Direction 1, microbiome to drug (Hard Rule 4, filed as an efficacy dependence, not a depletion): Sousa 2014 [17] states that sulfasalazine, balsalazide and olsalazine rely on colonic bacteria to cleave the azo bond (first 300 characters of the abstract only). Crouwel 2020 [19], a systematic review (1,018 records screened, 89 articles reviewed in full), lists mesalazine-releasing azo drugs among IBD drugs whose efficacy depends on microbial activity. Sousa 2025 [18] compared sulfasalazine, balsalazide and olsalazine degradation in rat faecal, rat caecal and dog samples against human data; the balsalazide rates were not in the summary read. No balsalazide-specific clinical test of antibiotic or dysbiosis effects on efficacy was located. Direction 2, drug to microbiome: no balsalazide study located. A 2026 narrative review of probiotics and UC drugs mentions balsalazide once in a list and reports no microbiota findings for it [20].

Mechanism

Dependence: named (azoreductase cleavage) [1]. Drug effect on microbiota: no balsalazide-specific mechanism found. The unabsorbed carrier and unabsorbed prodrug reach the colon [1], but no study of their effect on bacteria was located.

CLASS EXTRAPOLATION

Xu 2018 [16]: cross-sectional mucosal 16S study, 57 UC patients (20 untreated, 37 treated with 5-ASA for at least 1 month) plus a 10-patient validation cohort. Treated patients had higher Firmicutes (Enterococcus) and lower Proteobacteria (Escherichia-Shigella); Bacteroides and Prevotella_9 decreased. The paper does not name the 5-ASA formulations, so whether balsalazide was in the cohort cannot be confirmed; treated as Tier C. In DSS colitis mice, pure 5-ASA blunted E. coli expansion through epithelial PPAR-gamma signaling [15]; balsalazide not tested. Sulfasalazine microbiome findings are not borrowed (different molecule, balsalazide not in those cohorts).

Counter-evidence held on record

Counter-evidence and confounding Treated and untreated UC patients differ in disease activity, so [16] cannot separate drug effect from inflammation. The direction reported (less Proteobacteria) is toward a less dysbiotic profile, not a harm signal. Framing caution Not a finding that balsalazide harms the microbiome. Do not suggest probiotics or other supplements on this basis.

Limits on what this shows

• Key null / negative: No hemoglobin, hematocrit or hemolysis study stratified to balsalazide was located. The pediatric laboratory review found no concerning change [4].
• At-risk subgroups: Patients co-treated with azathioprine, 6-mercaptopurine or other myelotoxic drugs [1]. G6PD status is not addressed in the label text read.

Regulatory status

Section 5.3: mesalamine-induced hypersensitivity "may present as internal organ involvement, including myocarditis, pericarditis, nephritis, hepatitis, pneumonitis and hematologic abnormalities." Section 7.2: concurrent azathioprine, 6-mercaptopurine or other myelotoxic drugs "may increase the risk for blood disorders, bone marrow failure, and associated complications"; blood counts and platelets should be monitored [1]. The label text read contained no hemolysis, hemoglobin or G6PD statement.

Population evidence

Tier A, null: FDA pediatric clinical review [4], 68 subjects aged 5 to 17 with mild to moderate UC, randomized high dose (6.75 g/day, n=33) or low dose (2.25 g/day, n=35) for 8 weeks; laboratory testing at screening and week 8 showed "no concerning changes in median values, shifts from normal to abnormal, or panic values" (read through a summarizing tool; hemoglobin not itemized). Small and short.

Mechanism

Idiosyncratic hypersensitivity or marrow suppression; no nutrient mechanism. No oxygen-transport or tissue-oxygen mechanism is named.

CLASS EXTRAPOLATION

Dore 2023 [23]: 453 IBD patients; none of 78 G6PD-deficient patients receiving mesalamine was hospitalized or treated for acute hemolytic anemia, and chronic hemolysis markers did not differ in 30 cases versus 112 controls on mesalamine up to 4,500 mg/day; ex vivo methemoglobin release occurred only above 2.5 mg/mL. Cohort test: mesalamine (and sulfasalazine in 3 patients); balsalazide not mentioned, so Tier C. The ECCO consensus [24] groups sulfasalazine and 5-ASA as minor contributors to hemolysis without drug-level stratification (Tier C). Sulfasalazine's own red-cell toxicity in the sulfasalazine dossier in this series is tied to sulfapyridine exposure (internal cross-reference only, primary sources not opened here); balsalazide releases no sulfapyridine [1][2], so it is not borrowed.

Counter-evidence held on record

Counter-evidence and confounding Anemia in ulcerative colitis is common and disease-driven (see Iron) [24]. A drug's blood-cell toxicity is monitored with a blood count, not corrected with nutrients (Hard Rule 2). Framing caution Recorded as an outcome entry kept separate from ATP production. No nutrient or supplement action is implied.

Limits on what this shows

• Key null / negative: None for balsalazide.
• At-risk subgroups: None identified.

Regulatory status

No energy-metabolism statement in the label sections read [1][2][3].

Population evidence

No human data. No balsalazide study measured ATP, oxygen consumption or fatigue as an energy outcome.

Mechanism

CLASS EXTRAPOLATION. Cevallos 2021 [15]: C57BL/6J mice with 2.5 to 3% DSS colitis fed pure 5-ASA (2.5 g/kg in chow for 9 to 10 days) "restored epithelial ATP levels" and epithelial hypoxia, via epithelial PPAR-gamma signaling; cultured cells showed increased spare mitochondrial respiratory capacity. Cohort test: pure 5-ASA was used; balsalazide was not tested; Tier C, reverse direction. The balsalazide SIRT5 result [7] is filed under Mitochondrial burden; SIRT5 is described as supporting mitochondrial energy production [9], but no study read links balsalazide to any ATP change.

Counter-evidence held on record

Counter-evidence and confounding The mouse finding is tissue restoration during inflammation and may reflect remission. Whether colonic 5-ASA released from balsalazide acts the same way was not tested. Framing caution Kept separate from Mitochondrial burden and Oxygen delivery/utilization. Not an energy-deficit claim; no supplement is supported.