Component

Clozapine

Clozapine. Species, exposure and limitations are retained in each linked claim.

7 recorded relationships. Experimental role, claim status and evidence remain attached to each record.

Read recorded mechanisms Open recursive mind map

How nutrients influence it

Every nutrient with a recorded effect on this component, credited to the nutrient that acted rather than the chapter that recorded it. Open a nutrient to see the findings and the conditions they were measured under.

How nutrients reach it in more than one step

Chains of two or more recorded steps that end here, grouped by the nutrient they start from. Each step is a separate finding, so a chain is a route a mechanism could take, not proof that it does.

Tracing routes…

What it does

Every recorded relationship this component is part of, grouped by its role. Plain wording comes first; the technical statement follows.

Recorded relationships

What acts on it

  1. CYP1A2 contributed to clozapine demethylation.

    Human cytochrome P450 1A2 → Clozapine source_derived_draftungraded
    Experimental context and source evidence
    evidence_span
    {"source_cache": "artifacts/dim-research/9384460.abstract.txt", "locator": "Primary indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "eb481193bb0d7564d728a25a9ddd63678e8234e628edca3f13ece910770279b6", "start_char": 0, "end_char": 1794, "text_sha256": "eb481193bb0d7564d728a25a9ddd63678e8234e628edca3f13ece910770279b6"}
    experimental_model
    Recombinant enzymes, antibodies and human liver microsomes
    exposure
    Enzyme-specific inhibition and metabolite formation
    limitations
    Identifies metabolic routes, not a trial of DIM with clozapine. Do not infer a dose change or magnitude of interaction.
    nutrient_topic
    Diindolylmethane (DIM) research collection; topical membership is not evidence of a direct dietary effect. · 3,3'-Diindolylmethane / DIM
    organism
    Human CYP enzymes
    plain_language
    Clozapine shares an enzyme that DIM can induce in laboratory systems; its response to DIM was not measured.
    primary_references
    [dim-p9384460] The involvement of CYP1A2 and CYP3A4 in the metabolism of clozapine. (1997). https://pubmed.ncbi.nlm.nih.gov/9384460/ DOI: 10.1046/j.1365-2125.1997.t01-1-00605.x
    tissue_or_cell_type
    Clozapine oxidation

    Diindolylmethane (DIM): formation, receptor signaling, metabolism and drug interactions (2026-09-17) · lines 662–673

    AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Recombinant enzymes, antibodies and human liver microsomes · source_derived_draft · unverified_draft

    ### dim-clozapine-1a2 CYP1A2 contributed to clozapine demethylation. Condition category: normal nutrient_topic: Diindolylmethane (DIM) research collection; topical membership is not evidence of a direct dietary effect. plain_language: Clozapine shares an enzyme that DIM can induce in laboratory systems; its response to DIM was not measured. organism: Human CYP enzymes tissue_or_cell_type: Clozapine oxidation experimental_model: Recombinant enzymes, antibodies and human liver microsomes limitations: Identifies metabolic routes, not a trial of DIM with clozapine. Do not infer a dose change or magnitude of interaction. exposure: Enzyme-specific inhibition and metabolite formation evidence_span: {"source_cache": "artifacts/dim-research/9384460.abstract.txt", "locator": "Primary indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "eb481193bb0d7564d728a25a9ddd63678e8234e628edca3f13ece910770279b6", "start_char": 0, "end_char": 1794, "text_sha256": "eb481193bb0d7564d728a25a9ddd63678e8234e628edca3f13ece910770279b6"} [dim-p9384460] The involvement of CYP1A2 and CYP3A4 in the metabolism of clozapine. (1997). https://pubmed.ncbi.nlm.nih.gov/9384460/ DOI: 10.1046/j.1365-2125.1997.t01-1-00605.x
    Complete structured claim and evidence

  2. CYP3A4 contributed to clozapine demethylation and N-oxidation.

    Human cytochrome P450 3A4 → Clozapine source_derived_draftungraded
    Experimental context and source evidence
    evidence_span
    {"source_cache": "artifacts/dim-research/9384460.abstract.txt", "locator": "Primary indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "eb481193bb0d7564d728a25a9ddd63678e8234e628edca3f13ece910770279b6", "start_char": 0, "end_char": 1794, "text_sha256": "eb481193bb0d7564d728a25a9ddd63678e8234e628edca3f13ece910770279b6"}
    experimental_model
    Recombinant enzymes, antibodies and human liver microsomes
    exposure
    Enzyme-specific inhibition and metabolite formation
    limitations
    Identifies metabolic routes, not a trial of DIM with clozapine. Do not infer a dose change or magnitude of interaction.
    nutrient_topic
    Diindolylmethane (DIM) research collection; topical membership is not evidence of a direct dietary effect. · 3,3'-Diindolylmethane / DIM
    organism
    Human CYP enzymes
    plain_language
    Clozapine has more than one relevant route.
    primary_references
    [dim-p9384460] The involvement of CYP1A2 and CYP3A4 in the metabolism of clozapine. (1997). https://pubmed.ncbi.nlm.nih.gov/9384460/ DOI: 10.1046/j.1365-2125.1997.t01-1-00605.x
    tissue_or_cell_type
    Clozapine oxidation

    Diindolylmethane (DIM): formation, receptor signaling, metabolism and drug interactions (2026-09-17) · lines 675–686

    AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Recombinant enzymes, antibodies and human liver microsomes · source_derived_draft · unverified_draft

    ### dim-clozapine-3a4 CYP3A4 contributed to clozapine demethylation and N-oxidation. Condition category: normal nutrient_topic: Diindolylmethane (DIM) research collection; topical membership is not evidence of a direct dietary effect. plain_language: Clozapine has more than one relevant route. organism: Human CYP enzymes tissue_or_cell_type: Clozapine oxidation experimental_model: Recombinant enzymes, antibodies and human liver microsomes limitations: Identifies metabolic routes, not a trial of DIM with clozapine. Do not infer a dose change or magnitude of interaction. exposure: Enzyme-specific inhibition and metabolite formation evidence_span: {"source_cache": "artifacts/dim-research/9384460.abstract.txt", "locator": "Primary indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "eb481193bb0d7564d728a25a9ddd63678e8234e628edca3f13ece910770279b6", "start_char": 0, "end_char": 1794, "text_sha256": "eb481193bb0d7564d728a25a9ddd63678e8234e628edca3f13ece910770279b6"} [dim-p9384460] The involvement of CYP1A2 and CYP3A4 in the metabolism of clozapine. (1997). https://pubmed.ncbi.nlm.nih.gov/9384460/ DOI: 10.1046/j.1365-2125.1997.t01-1-00605.x
    Complete structured claim and evidence

Where it participates (unsigned role)

  1. Caffeine-derived CYP1A2 indices correlated with clozapine clearance in the 14-person study.

    CYP1A2 catalytic activity → Plasma clozapine exposure source_derived_draftungraded
    Experimental context and source evidence
    evidence_span
    {"source_cache": "artifacts/dim-research/7893591.abstract.txt", "locator": "Primary indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "d568c4f2cdf1fc2d58f2ea22e395a7d7813cef2b1433fe25da51a2c40df5c545", "start_char": 0, "end_char": 849, "text_sha256": "d568c4f2cdf1fc2d58f2ea22e395a7d7813cef2b1433fe25da51a2c40df5c545"}
    experimental_model
    Clinical caffeine phenotyping and prior clozapine exposure
    exposure
    Caffeine test related to single-dose clozapine kinetics
    limitations
    Correlation supports enzyme relevance; no DIM administration or prediction of an individual clinical effect.
    nutrient_topic
    Diindolylmethane (DIM) research collection; topical membership is not evidence of a direct dietary effect. · 3,3'-Diindolylmethane / DIM
    organism
    14 healthy adults
    plain_language
    Enzyme activity was linked to drug handling in people, separately from any DIM exposure.
    primary_references
    [dim-p7893591] Clozapine disposition covaries with CYP1A2 activity determined by a caffeine test. (1994). https://pubmed.ncbi.nlm.nih.gov/7893591/ DOI: 10.1111/j.1365-2125.1994.tb04385.x
    tissue_or_cell_type
    CYP1A2 phenotype and clozapine disposition

    Diindolylmethane (DIM): formation, receptor signaling, metabolism and drug interactions (2026-09-17) · lines 688–699

    AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Clinical caffeine phenotyping and prior clozapine exposure · source_derived_draft · unverified_draft

    ### dim-clozapine-phenotype Caffeine-derived CYP1A2 indices correlated with clozapine clearance in the 14-person study. Condition category: normal nutrient_topic: Diindolylmethane (DIM) research collection; topical membership is not evidence of a direct dietary effect. plain_language: Enzyme activity was linked to drug handling in people, separately from any DIM exposure. organism: 14 healthy adults tissue_or_cell_type: CYP1A2 phenotype and clozapine disposition experimental_model: Clinical caffeine phenotyping and prior clozapine exposure limitations: Correlation supports enzyme relevance; no DIM administration or prediction of an individual clinical effect. exposure: Caffeine test related to single-dose clozapine kinetics evidence_span: {"source_cache": "artifacts/dim-research/7893591.abstract.txt", "locator": "Primary indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "d568c4f2cdf1fc2d58f2ea22e395a7d7813cef2b1433fe25da51a2c40df5c545", "start_char": 0, "end_char": 849, "text_sha256": "d568c4f2cdf1fc2d58f2ea22e395a7d7813cef2b1433fe25da51a2c40df5c545"} [dim-p7893591] Clozapine disposition covaries with CYP1A2 activity determined by a caffeine test. (1994). https://pubmed.ncbi.nlm.nih.gov/7893591/ DOI: 10.1111/j.1365-2125.1994.tb04385.x
    Complete structured claim and evidence

  2. Olanzapine inhibited recombinant human DDO at an IC50 near 23 micromolar under both 4 and 100 micromolar FAD conditions; clozapine did not inhibit the tested enzyme.

    Olanzapine → Human D-aspartate oxidase / DDO source_derived_draftungraded
    Experimental context and source evidence
    evidence_access
    Primary full text
    experimental_model
    Purified human DDO drug concentration-response assay.
    limitations
    Biochemical potency is not proof of clinically relevant brain inhibition or a reason to change treatment.
    nutrient_topic
    D-Aspartate collection; species, compartment, exposure, co-substrates and manipulation remain explicit. · D-Aspartate
    plain_language
    Two drugs differed at a D-aspartate-clearing enzyme.
    primary_references
    Olanzapine, but not clozapine, increases glutamate release in the prefrontal cortex of freely moving mice by inhibiting D-aspartate oxidase activity. · 2017 · https://pubmed.ncbi.nlm.nih.gov/28393897/ · DOI 10.1038/srep46288

    D-Aspartate: synthesis, clearance, neural and endocrine mechanisms (2026-09-19) · lines 264–270

    AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Purified human DDO drug concentration-response assay. · source_derived_draft · unverified_draft

    ## d-aspartate-olanzapine-human-ddo Two drugs differed at a D-aspartate-clearing enzyme. Olanzapine inhibited recombinant human DDO at an IC50 near 23 micromolar under both 4 and 100 micromolar FAD conditions; clozapine did not inhibit the tested enzyme. Model: Purified human DDO drug concentration-response assay. Limitations: Biochemical potency is not proof of clinically relevant brain inhibition or a reason to change treatment. Evidence access: Primary full text Olanzapine, but not clozapine, increases glutamate release in the prefrontal cortex of freely moving mice by inhibiting D-aspartate oxidase activity. · 2017 · https://pubmed.ncbi.nlm.nih.gov/28393897/ · DOI 10.1038/srep46288
    Complete structured claim and evidence

  3. Four weeks of olanzapine at 5 mg/kg/day intraperitoneally increased prefrontal extracellular D-aspartate and glutamate in wild-type mice; the increments were absent in Ddo-knockout mice.

    Olanzapine → Extracellular D-aspartate in mouse prefrontal cortex source_derived_draftungraded
    Experimental context and source evidence
    evidence_access
    Primary full text
    experimental_model
    Mouse microdialysis 24 hours after the final injection.
    limitations
    Knockouts already differ at baseline. This does not prove the pathway mediates clinical antipsychotic efficacy.
    nutrient_topic
    D-Aspartate collection; species, compartment, exposure, co-substrates and manipulation remain explicit. · D-Aspartate
    plain_language
    Removing the enzyme removed this drug-associated increment in the mouse experiment.
    primary_references
    Olanzapine, but not clozapine, increases glutamate release in the prefrontal cortex of freely moving mice by inhibiting D-aspartate oxidase activity. · 2017 · https://pubmed.ncbi.nlm.nih.gov/28393897/ · DOI 10.1038/srep46288

    D-Aspartate: synthesis, clearance, neural and endocrine mechanisms (2026-09-19) · lines 280–286

    AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Mouse microdialysis 24 hours after the final injection. · source_derived_draft · unverified_draft

    ## d-aspartate-olanzapine-mouse-dependence Removing the enzyme removed this drug-associated increment in the mouse experiment. Four weeks of olanzapine at 5 mg/kg/day intraperitoneally increased prefrontal extracellular D-aspartate and glutamate in wild-type mice; the increments were absent in Ddo-knockout mice. Model: Mouse microdialysis 24 hours after the final injection. Limitations: Knockouts already differ at baseline. This does not prove the pathway mediates clinical antipsychotic efficacy. Evidence access: Primary full text Olanzapine, but not clozapine, increases glutamate release in the prefrontal cortex of freely moving mice by inhibiting D-aspartate oxidase activity. · 2017 · https://pubmed.ncbi.nlm.nih.gov/28393897/ · DOI 10.1038/srep46288
    Complete structured claim and evidence

  4. Caffeine coadministration increased mean clozapine AUC by 19% in the crossover experiment.

    Caffeine → Plasma clozapine exposure source_derived_draftungraded
    Experimental context and source evidence
    evidence_access
    Primary abstract
    experimental_model
    12 nonsmoking healthy men; single 12.5 mg clozapine; caffeine 400–1000 mg/day, mean 550.
    limitations
    Small healthy-volunteer study; patient effect size and toxicity cannot be inferred for an individual.
    nutrient_topic
    Caffeine collection; salts, coffee, species and coexposure contexts retain their identities. · Caffeine
    plain_language
    Caffeine changed exposure to a drug sharing its metabolic pathway.
    primary_references
    Effect of caffeine on clozapine pharmacokinetics in healthy volunteers. · 2000 · https://pubmed.ncbi.nlm.nih.gov/10606838/ · DOI 10.1046/j.1365-2125.2000.00111.x

    Caffeine: receptors, metabolism, nutrient interactions, adaptation and discovery questions (2026-09-18) · lines 268–274

    AI-assisted research curation; primary-abstract references and experimental limitations individually identified. Not publisher full text. · supports · 12 nonsmoking healthy men; single 12.5 mg clozapine; caffeine 400–1000 mg/day, mean 550. · source_derived_draft · unverified_draft

    ## caf-clozapine-auc Caffeine changed exposure to a drug sharing its metabolic pathway. Caffeine coadministration increased mean clozapine AUC by 19% in the crossover experiment. Model: 12 nonsmoking healthy men; single 12.5 mg clozapine; caffeine 400–1000 mg/day, mean 550. Limitations: Small healthy-volunteer study; patient effect size and toxicity cannot be inferred for an individual. Evidence access: Primary abstract Effect of caffeine on clozapine pharmacokinetics in healthy volunteers. · 2000 · https://pubmed.ncbi.nlm.nih.gov/10606838/ · DOI 10.1046/j.1365-2125.2000.00111.x
    Complete structured claim and evidence

  5. Mean clozapine oral clearance fell 14%; metabolite-to-parent ratios also fell during caffeine exposure.

    Caffeine → Clozapine oral clearance source_derived_draftungraded
    Experimental context and source evidence
    evidence_access
    Primary abstract
    experimental_model
    Same randomized open-label crossover.
    limitations
    Not a medication-adjustment rule.
    nutrient_topic
    Caffeine collection; salts, coffee, species and coexposure contexts retain their identities. · Caffeine
    plain_language
    The pharmacokinetic pattern supported reduced drug metabolism.
    primary_references
    Effect of caffeine on clozapine pharmacokinetics in healthy volunteers. · 2000 · https://pubmed.ncbi.nlm.nih.gov/10606838/ · DOI 10.1046/j.1365-2125.2000.00111.x

    Caffeine: receptors, metabolism, nutrient interactions, adaptation and discovery questions (2026-09-18) · lines 276–282

    AI-assisted research curation; primary-abstract references and experimental limitations individually identified. Not publisher full text. · supports · Same randomized open-label crossover. · source_derived_draft · unverified_draft

    ## caf-clozapine-clear The pharmacokinetic pattern supported reduced drug metabolism. Mean clozapine oral clearance fell 14%; metabolite-to-parent ratios also fell during caffeine exposure. Model: Same randomized open-label crossover. Limitations: Not a medication-adjustment rule. Evidence access: Primary abstract Effect of caffeine on clozapine pharmacokinetics in healthy volunteers. · 2000 · https://pubmed.ncbi.nlm.nih.gov/10606838/ · DOI 10.1046/j.1365-2125.2000.00111.x
    Complete structured claim and evidence

In the sources

Preserved passages that mention this component, quoted exactly. Open one to read it in context.

    This is a research prototype built from draft material. It is not medical advice, and its statements still await verification against the original studies.

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