Prochlorperazine

Limits on what this shows

• Null / negative: No in vivo or human study of mitochondrial injury at clinical prochlorperazine doses was found. Oral bioavailability is low [6][7], so tissue exposure relative to the in vitro concentrations is unknown.
• At-risk subgroups: None identified; not established for any human subgroup.

Regulatory status

The label makes no mitochondrial statement [1][2].

Population evidence

In vitro study (Vet Hum Toxicol 2000) of fourteen antipsychotic medications across five chemical classes: all tested compounds except haloperidol, including phenothiazine derivatives and prochlorperazine, inhibited succinate oxidation, and the apparent inhibition constant for phenothiazine-type agents fell as lipophilicity rose [9]. Prochlorperazine was in the cohort (named in the retrieved reconstructed abstract). The per-drug inhibition constant for prochlorperazine, the mitochondrial source and the drug concentrations were not in the retrieved text, and no confidence interval exists. Tier C context only: haloperidol, chlorpromazine, thiothixene and clozapine inhibited complex I in rat brain mitochondria, and treated patients had lower platelet complex I activity, but prochlorperazine was not among the in vitro drugs and the drugs taken by the patients were not stated in the retrieved text [11]. A PubMed listing for prochlorperazine and mitochondria returned nine records, none a human or in vivo study of prochlorperazine [26]. A 1974 record on hydroxylated phenothiazine metabolites and rat brain mitochondria names chlorpromazine and perphenazine and has no abstract; no result is claimed [21].

Mechanism

Named: inhibition of mitochondrial succinate oxidation, correlated with lipophilicity [9]. Not tied to a clinical dose or plasma concentration.

Counter-evidence held on record

Counter-evidence on record In vitro respiratory inhibition does not show clinical mitochondrial dysfunction. Evidence is shared with ATP production and the class context with Oxidative stress; see the Overlap map. The reconstructed abstract is thin and was read through a summarizing fetch tool. Framing caution This is not a mitochondrial toxicity claim and not a nutrient deficiency. Do not imply that CoQ10, L-carnitine or antioxidant supplements are needed or protective.

Limits on what this shows

• Null / negative: No clinical study shows a redox deficit or antioxidant-capacity loss in prochlorperazine users.
• At-risk subgroups: None identified.

Regulatory status

The label makes no redox statement [1][2].

Population evidence

In vitro study (Biochem Pharmacol 1995) of chlorpromazine, prochlorperazine, metoclopramide, methotrimeprazine, haloperidol and promethazine in several systems (hydroxyl radical and superoxide scavenging; lipid peroxidation in liposomes; DNA damage; interactions with hemoglobin and myoglobin; hydrogen peroxide and hypochlorous acid). The retrieved text concludes that these agents act as antioxidants under some conditions and pro-oxidants under others [10]. Prochlorperazine was in the cohort. Per-drug results, concentrations and effect sizes were not in the retrieved text, so the direction for prochlorperazine alone is not stated here. A PubMed listing for prochlorperazine and oxidative stress returned ten records; the other titles seen were unrelated (cholestasis, a melanin-binding paper, parasite enzyme chemistry) and were not opened [27]. No human glutathione, malondialdehyde or total antioxidant capacity measurement in prochlorperazine users was found.

Mechanism

Radical-scavenging and pro-oxidant chemistry of phenothiazines, as described at the class level in [10]; not specified for prochlorperazine in the retrieved text.

Counter-evidence held on record

Counter-evidence on record The mixed direction means this cannot be read as a depletion signal; the retrieved summary does not isolate prochlorperazine. Shares the in vitro mitochondrial literature context with Mitochondrial burden; see the Overlap map. Framing caution This is not an antioxidant deficiency. Do not imply that vitamin C, vitamin E or other antioxidant supplements are needed or protective.

Limits on what this shows

• Why no grade: Dual condition met: no Tier B or C evidence of a copper-status effect, and no circulating copper claim for prochlorperazine was located. The PubMed listing "prochlorperazine copper" returned three records, all unrelated (desferrioxamine ocular toxicity, taste aversion in rats, stomach-mucosa enzyme activity) [23]. A phenothiazine and ceruloplasmin listing returned ten records, mostly 1970s to 1980s in vitro biochemistry on phenothiazine oxidation by ceruloplasmin (by title only, not opened) [25]; the one record opened, Lovstad 1974, names chlorpromazine, promazine, triflupromazine and levomepromazine, not prochlorperazine, and has no abstract [19]. That biochemistry concerns the drug acting as an oxidation substrate, not copper status or ceruloplasmin depletion, so it was not treated as supporting a grade.
• Access caveat: Predominantly a genuine gap on the channels that could be read, with partial tooling limitation: only the first ten records of the ceruloplasmin listing were visible, most titles were not opened, and no consumer-site sampling was possible. Kept as a fully independent entry; never merged with Iron.

Channels tried

PubMed HTML listings: prochlorperazine copper [23]; combined micronutrient query (5 results, none a copper-status study) [22]; phenothiazine ceruloplasmin [25]. OpenAlex single-record lookup for [19]. DailyMed label text [1][2]: no copper mention. WebSearch: budget exhausted before the review began. PubMed eutils, Crossref search, Europe PMC, Semantic Scholar and Unpaywall were not attempted by curl, per the environment policy.

Limits on what this shows

• Why no grade: Dual condition met on what could be read: no Tier B or C source for an iron-status effect, and no circulating iron claim located. The combined micronutrient listing returned five records, none measuring iron status (a desferrioxamine toxicity report, a ferric gluconate hypersensitivity report in a premedicated patient, and unrelated items) [22]. A phenothiazine and iron deficiency listing returned nine records, including a 2000 observational study of serum iron and ferritin in acute neuroleptic akathisia; its record has no abstract, so the drugs, sample size and direction of any iron finding could not be read and nothing is claimed from it [20][24]. If low iron were found to predispose to akathisia, that would be the nutrient affecting the drug's effect (Hard Rule 4), not a depletion; this is not established. Restless-legs items in the same listing were not opened.
• Access caveat: Tooling-limited. The most direct query was rate-limited and the one potentially relevant study [20] could not be read beyond its record. Re-check this category when access is restored. Kept independent from Copper.

Channels tried

PubMed HTML listings: combined query [22]; phenothiazine iron deficiency [24]. The direct "prochlorperazine iron" listing returned HTTP 429 twice and was not read; "prochlorperazine ferritin" returned HTTP 404 (probable zero, unconfirmed). OpenAlex record for [20]. DailyMed label text [1][2]: no iron mention. WebSearch: budget exhausted.

Limits on what this shows

• Null / negative: No fecal metagenomic, diversity or short-chain fatty acid measurement in prochlorperazine users was found. Concentrations used are high relative to what is known of systemic exposure, and luminal concentration after oral dosing was not addressed in the retrieved text. A PubMed query pairing prochlorperazine with microbiome terms returned HTTP 404 and was not read; it is treated as a probable zero, not a confirmed one (see access note).
• At-risk subgroups: None identified.

Regulatory status

No microbiome statement in the label extractions [1][2].

Population evidence

In vitro susceptibility study (Basic Clin Pharmacol Toxicol 2005): thioridazine and prochlorperazine tested against 11 E. faecalis and 9 E. faecium strains from human infections and animal reservoirs; both showed activity against all strains, with inhibitory concentrations of 16 to 32 micrograms per mL for thioridazine and 32 to 64 micrograms per mL for prochlorperazine; subinhibitory phenothiazine concentrations restored susceptibility to vancomycin or ampicillin in resistant strains [15]. Prochlorperazine was in the cohort. Class context (Tier C): in a screen of the Prestwick library, over 1,000 marketed drugs against 40 gut strains, antipsychotics were overrepresented among drugs with anticommensal activity [16]. The retrieved page did not name prochlorperazine and the supplementary drug-level table was not opened, so prochlorperazine cohort membership is unverified and [16] is context only.

Mechanism

Direct growth inhibition in monoculture; resistance modification independent of efflux-pump inhibition per the authors [15]. No mechanism for in vivo gut community change is established.

Counter-evidence held on record

Counter-evidence on record In vitro monoculture susceptibility with clinical isolates is not evidence of dysbiosis in people. Isolates were infection or animal derived, not commensal community samples. Framing caution This is not a dysbiosis claim. Do not imply that probiotics, prebiotics or dietary changes are needed because of this drug.

Limits on what this shows

• Null / negative: No cohort or interventional study measuring hemoglobin, hematocrit or arterial oxygenation in prochlorperazine users was found. No nutrient (iron, B12, folate) was measured in the case report as retrieved.
• At-risk subgroups: Not defined. Confounding by indication (vomiting, poor intake, underlying illness, concurrent marrow-toxic drugs) is presumed (Hard Rule 6).

Regulatory status

Label adverse-reaction text lists "blood dyscrasias (pancytopenia, thrombocytopenic purpura, leukopenia, agranulocytosis, eosinophilia, hemolytic anemia, aplastic anemia)" [1]. No frequency, mechanism or red-cell data appeared in the extraction. The label does not mention methemoglobin or G6PD [1][2].

Population evidence

One case report (Am J Psychiatry 1960): a single patient developed anemia attributed to prochlorperazine without leukopenia or other peripheral blood abnormality, and later tolerated triflupromazine and trifluoperazine [14]. No hemoglobin values, onset, or mechanism were in the retrieved record. A PubMed listing for prochlorperazine and methemoglobinemia returned one record, an unrelated tongue-discoloration review [30]; a listing for prochlorperazine and anemia returned five records, of which one is the case report above and the rest are unrelated [31].

Mechanism

Not established. Idiosyncratic hematologic toxicity is stated by the label without a named mechanism; nothing in the sources opened links it to a nutrient.

Counter-evidence held on record

Counter-evidence on record This is a drug toxicity and a clinical outcome, not an oxygen-delivery deficiency and not iron, B12 or folate deficiency (Hard Rule 2). A single 1960 case and an unquantified label listing do not establish a rate. Shares its label source with the label-toxicity facts in the pharmacokinetic block; see the Overlap map. Framing caution Do not imply that anemia on this drug is nutritional or that iron or other supplements are indicated. Unexplained fatigue, pallor, fever, sore throat or bruising on prochlorperazine warrants clinical review of a complete blood count by a prescriber.

Limits on what this shows

• Null / negative: No ATP, phosphocreatine or lactate measurement in prochlorperazine-exposed tissue or people was found. Sedation or fatigue from the drug is intended pharmacology and is not an ATP deficiency.
• At-risk subgroups: None identified.

Regulatory status

The label makes no energy-metabolism statement [1][2].

Population evidence

The only prochlorperazine-specific source bearing on energy metabolism is the succinate-oxidation study [9], which measured substrate oxidation, not ATP. A PubMed listing for prochlorperazine and ATP returned ten records, including purinergic P2X7 receptor modulation and cell-migration papers; none was opened and none is relied on [28]. Class context (Tier C): complex I inhibition by chlorpromazine and others [11]; prochlorperazine absent from the in vitro cohort.

Mechanism

Plausible through respiratory-chain inhibition [9]; conversion to an ATP deficit is not shown for prochlorperazine.

Counter-evidence held on record

Counter-evidence on record Graded yellow on mechanistic plausibility only, and it depends on the same single source as Mitochondrial burden; do not count the two as independent lines of evidence (see the Overlap map). Kept as its own entry per Hard Rule 7. Framing caution This is not an energy-deficiency claim. Do not equate drug-related sedation or tiredness with low ATP, and do not imply that energy supplements are indicated.