Plasma metformin exposure

evidence_span

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experimental_model

Clinical transporter-probe cocktail with in-vitro prediction

exposure

Characterized goldenseal botanical product, not purified berberine

limitations

Goldenseal contains multiple alkaloids. This result must not be attributed exclusively to berberine; unchanged renal clearance favors an absorption-related explanation.

nutrient_topic

Berberine research collection; topical membership is not evidence of a direct dietary effect. · Berberine

organism

Sixteen healthy human volunteers

plain_language

The tested botanical mixture changed metformin exposure; purified berberine was not the clinical intervention.

primary_references

[berberine-p33174626] Assessing Transporter-Mediated Natural Product-Drug Interactions Via In vitro-In Vivo Extrapolation: Clinical Evaluation With a Probe Cocktail. (2021). https://pubmed.ncbi.nlm.nih.gov/33174626/ DOI: 10.1002/cpt.2107

tissue_or_cell_type

Oral metformin exposure

Berberine: metabolism, nutrient connections and drug interactions (2026-09-17) · lines 870–881

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Clinical transporter-probe cocktail with in-vitro prediction · source_derived_draft · unverified_draft

### berberine-goldenseal-metformin Goldenseal reduced metformin AUC by 23% without changing its half-life or renal clearance. Condition category: normal nutrient_topic: Berberine research collection; topical membership is not evidence of a direct dietary effect. plain_language: The tested botanical mixture changed metformin exposure; purified berberine was not the clinical intervention. organism: Sixteen healthy human volunteers tissue_or_cell_type: Oral metformin exposure experimental_model: Clinical transporter-probe cocktail with in-vitro prediction limitations: Goldenseal contains multiple alkaloids. This result must not be attributed exclusively to berberine; unchanged renal clearance favors an absorption-related explanation. exposure: Characterized goldenseal botanical product, not purified berberine evidence_span: {"source_cache": "artifacts/berberine-research/33174626.abstract.txt", "locator": "Primary indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "0dbd2401295c8f6e093461899378d5e9b7c2c5757be0bd12d335edf07216afa9", "start_char": 0, "end_char": 1812, "text_sha256": "0dbd2401295c8f6e093461899378d5e9b7c2c5757be0bd12d335edf07216afa9"} [berberine-p33174626] Assessing Transporter-Mediated Natural Product-Drug Interactions Via In vitro-In Vivo Extrapolation: Clinical Evaluation With a Probe Cocktail. (2021). https://pubmed.ncbi.nlm.nih.gov/33174626/ DOI: 10.1002/cpt.2107

evidence_span

{"source_cache": "artifacts/berberine-research/37562957.abstract.txt", "locator": "Primary indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "3d19a5ed2d4ef8f98675f7932f2ea70d6848fc1105362f39681e1c595e204646", "start_char": 0, "end_char": 2598, "text_sha256": "3d19a5ed2d4ef8f98675f7932f2ea70d6848fc1105362f39681e1c595e204646"}

experimental_model

Transporter-expressing cells and oral-versus-intravenous mouse pharmacokinetics

exposure

Goldenseal extract and isolated berberine or hydrastine were tested separately

limitations

Extract potency was normalized to berberine content but does not mean berberine alone caused the effect. Transported probe was metformin, so thiamine depletion was not measured.

nutrient_topic

Berberine research collection; topical membership is not evidence of a direct dietary effect. · Berberine

organism

Human transporters in HEK293 cells; mice

plain_language

The whole botanical product cannot be treated as equivalent to one ingredient.

primary_references

[berberine-p37562957] Goldenseal-Mediated Inhibition of Intestinal Uptake Transporters Decreases Metformin Systemic Exposure in Mice. (2023). https://pubmed.ncbi.nlm.nih.gov/37562957/ DOI: 10.1124/dmd.123.001360

tissue_or_cell_type

Intestinal uptake

Berberine: metabolism, nutrient connections and drug interactions (2026-09-17) · lines 922–933

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Transporter-expressing cells and oral-versus-intravenous mouse pharmacokinetics · source_derived_draft · unverified_draft

### berberine-isolated-berberine-mouse-null Isolated berberine did not alter metformin pharmacokinetics in the mouse experiment, whereas goldenseal extract reduced metformin Cmax. Condition category: normal nutrient_topic: Berberine research collection; topical membership is not evidence of a direct dietary effect. plain_language: The whole botanical product cannot be treated as equivalent to one ingredient. organism: Human transporters in HEK293 cells; mice tissue_or_cell_type: Intestinal uptake experimental_model: Transporter-expressing cells and oral-versus-intravenous mouse pharmacokinetics limitations: Extract potency was normalized to berberine content but does not mean berberine alone caused the effect. Transported probe was metformin, so thiamine depletion was not measured. exposure: Goldenseal extract and isolated berberine or hydrastine were tested separately evidence_span: {"source_cache": "artifacts/berberine-research/37562957.abstract.txt", "locator": "Primary indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "3d19a5ed2d4ef8f98675f7932f2ea70d6848fc1105362f39681e1c595e204646", "start_char": 0, "end_char": 2598, "text_sha256": "3d19a5ed2d4ef8f98675f7932f2ea70d6848fc1105362f39681e1c595e204646"} [berberine-p37562957] Goldenseal-Mediated Inhibition of Intestinal Uptake Transporters Decreases Metformin Systemic Exposure in Mice. (2023). https://pubmed.ncbi.nlm.nih.gov/37562957/ DOI: 10.1124/dmd.123.001360

evidence_span

{"source_cache": "artifacts/berberine-research/25359200.abstract.txt", "locator": "Primary indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "e46385d733a3c5fc9c39b89a27ef7ca62d228258ae47bb605c6a86eca68ee8db", "start_char": 0, "end_char": 1353, "text_sha256": "e46385d733a3c5fc9c39b89a27ef7ca62d228258ae47bb605c6a86eca68ee8db"}

experimental_model

Transporter-expressing cells and intravenous rat pharmacokinetics

exposure

Intravenous metformin 2 mg/kg and berberine 10 mg/kg in rats; in-vitro concentration-response

limitations

HEK293 is the host cell, not proof that the expressed transporter is human; the indexed proteins are rat Slc22a1/Slc22a2. Intravenous rat results cannot determine an oral human interaction. Assayed substrate was metformin, not thiamine.

nutrient_topic

Berberine research collection; topical membership is not evidence of a direct dietary effect. · Berberine

organism

Rat OCT1/2 in HEK293 cells and rats; rat protein identity indexed in primary-publication chemical records

plain_language

Blocking uptake or elimination can increase circulating drug after intravenous dosing.

primary_references

[berberine-p25359200] Organic cation transporter-mediated drug-drug interaction potential between berberine and metformin. (2015). https://pubmed.ncbi.nlm.nih.gov/25359200/ DOI: 10.1007/s12272-014-0510-6

tissue_or_cell_type

Metformin uptake and disposition

Berberine: metabolism, nutrient connections and drug interactions (2026-09-17) · lines 792–803

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Transporter-expressing cells and intravenous rat pharmacokinetics · source_derived_draft · unverified_draft

### berberine-metformin-iv-rat Intravenous berberine coadministration increased metformin AUC and reduced systemic clearance in rats. Condition category: normal nutrient_topic: Berberine research collection; topical membership is not evidence of a direct dietary effect. plain_language: Blocking uptake or elimination can increase circulating drug after intravenous dosing. organism: Rat OCT1/2 in HEK293 cells and rats; rat protein identity indexed in primary-publication chemical records tissue_or_cell_type: Metformin uptake and disposition experimental_model: Transporter-expressing cells and intravenous rat pharmacokinetics limitations: HEK293 is the host cell, not proof that the expressed transporter is human; the indexed proteins are rat Slc22a1/Slc22a2. Intravenous rat results cannot determine an oral human interaction. Assayed substrate was metformin, not thiamine. exposure: Intravenous metformin 2 mg/kg and berberine 10 mg/kg in rats; in-vitro concentration-response evidence_span: {"source_cache": "artifacts/berberine-research/25359200.abstract.txt", "locator": "Primary indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "e46385d733a3c5fc9c39b89a27ef7ca62d228258ae47bb605c6a86eca68ee8db", "start_char": 0, "end_char": 1353, "text_sha256": "e46385d733a3c5fc9c39b89a27ef7ca62d228258ae47bb605c6a86eca68ee8db"} [berberine-p25359200] Organic cation transporter-mediated drug-drug interaction potential between berberine and metformin. (2015). https://pubmed.ncbi.nlm.nih.gov/25359200/ DOI: 10.1007/s12272-014-0510-6

evidence_span

{"source_cache": "artifacts/berberine-research/30428337.abstract.txt", "locator": "Primary indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "d35cfbe70c74323ef13e51af7affae3f13a4ff7b80a1d278620b8ced217346d8", "start_char": 0, "end_char": 1775, "text_sha256": "d35cfbe70c74323ef13e51af7affae3f13a4ff7b80a1d278620b8ced217346d8"}

experimental_model

Oral rat pharmacokinetics, intestinal sacs and rat-transporter-expressing cells

exposure

Oral metformin/berberine coadministration; concentration-dependent transport assays

limitations

Route differs from the intravenous rat study. Changes in plasma, kidney tissue and excretion are separate outcomes; not proof of improved human combination efficacy.

nutrient_topic

Berberine research collection; topical membership is not evidence of a direct dietary effect. · Berberine

organism

Rats and recombinant rat OCT1, OCT2 and MATE1

plain_language

An intestinal effect can reverse the direction seen after intravenous dosing.

primary_references

[berberine-p30428337] Organic cation transporter and multidrug and toxin extrusion 1 co-mediated interaction between metformin and berberine. (2019). https://pubmed.ncbi.nlm.nih.gov/30428337/ DOI: 10.1016/j.ejps.2018.11.010

tissue_or_cell_type

Intestinal uptake, kidney distribution and excretion

Berberine: metabolism, nutrient connections and drug interactions (2026-09-17) · lines 844–855

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Oral rat pharmacokinetics, intestinal sacs and rat-transporter-expressing cells · source_derived_draft · unverified_draft

### berberine-metformin-oral-rat Oral berberine coadministration decreased metformin Cmax and AUC over the first four hours in rats. Condition category: normal nutrient_topic: Berberine research collection; topical membership is not evidence of a direct dietary effect. plain_language: An intestinal effect can reverse the direction seen after intravenous dosing. organism: Rats and recombinant rat OCT1, OCT2 and MATE1 tissue_or_cell_type: Intestinal uptake, kidney distribution and excretion experimental_model: Oral rat pharmacokinetics, intestinal sacs and rat-transporter-expressing cells limitations: Route differs from the intravenous rat study. Changes in plasma, kidney tissue and excretion are separate outcomes; not proof of improved human combination efficacy. exposure: Oral metformin/berberine coadministration; concentration-dependent transport assays evidence_span: {"source_cache": "artifacts/berberine-research/30428337.abstract.txt", "locator": "Primary indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "d35cfbe70c74323ef13e51af7affae3f13a4ff7b80a1d278620b8ced217346d8", "start_char": 0, "end_char": 1775, "text_sha256": "d35cfbe70c74323ef13e51af7affae3f13a4ff7b80a1d278620b8ced217346d8"} [berberine-p30428337] Organic cation transporter and multidrug and toxin extrusion 1 co-mediated interaction between metformin and berberine. (2019). https://pubmed.ncbi.nlm.nih.gov/30428337/ DOI: 10.1016/j.ejps.2018.11.010

availability_state

machinery_impairment Imported condition classification; unverified.

evidence_span

{"source_cache": "artifacts/metformin-research/7555503.abstract.txt", "locator": "Indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "c960785146be30aa07921ceef25600c044dd421566e708cdc5c45bffccb0e301", "start_char": 0, "end_char": 2221, "text_sha256": "c960785146be30aa07921ceef25600c044dd421566e708cdc5c45bffccb0e301"}

experimental_model

Plasma metformin measurement by HPLC in 14 people with lactic acidosis during metformin treatment

exposure

Chronic metformin with intercurrent renal failure

limitations

A case series in an intensive-care setting. It argues against a simple dose-toxicity relationship; the numbers are small.

nutrient_topic

Metformin research collection; topical membership is not evidence of a direct clinical effect, and pharmacological exposure is not dietary intake. · Metformin

organism

Human

plain_language

When the kidneys fail and the drug is not stopped, it builds up.

primary_references

[metformin-p7555503] Role of metformin accumulation in metformin-associated lactic acidosis. (1995). https://pubmed.ncbi.nlm.nih.gov/7555503/ DOI: 10.2337/diacare.18.6.779

tissue_or_cell_type

Whole body

trigger_kind

machinery_impairment Imported condition classification; unverified.

Metformin: transport, molecular targets, gut mechanisms and nutrient interactions (2026-09-19) · lines 1425–1436

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Plasma metformin measurement by HPLC in 14 people with lactic acidosis during metformin treatment · source_derived_draft · unverified_draft

### metformin-accumulation-lactic-acidosis Ten of fourteen patients with lactic acidosis during metformin treatment had significant metformin accumulation, generally because metformin was not withdrawn despite conditions affecting its renal elimination, and serum creatinine correlated positively with plasma metformin. Condition category: machinery_impairment nutrient_topic: Metformin research collection; topical membership is not evidence of a direct clinical effect, and pharmacological exposure is not dietary intake. plain_language: When the kidneys fail and the drug is not stopped, it builds up. organism: Human tissue_or_cell_type: Whole body experimental_model: Plasma metformin measurement by HPLC in 14 people with lactic acidosis during metformin treatment limitations: A case series in an intensive-care setting. It argues against a simple dose-toxicity relationship; the numbers are small. exposure: Chronic metformin with intercurrent renal failure evidence_span: {"source_cache": "artifacts/metformin-research/7555503.abstract.txt", "locator": "Indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "c960785146be30aa07921ceef25600c044dd421566e708cdc5c45bffccb0e301", "start_char": 0, "end_char": 2221, "text_sha256": "c960785146be30aa07921ceef25600c044dd421566e708cdc5c45bffccb0e301"} [metformin-p7555503] Role of metformin accumulation in metformin-associated lactic acidosis. (1995). https://pubmed.ncbi.nlm.nih.gov/7555503/ DOI: 10.2337/diacare.18.6.779

availability_state

machinery_impairment Imported condition classification; unverified.

evidence_span

{"source_cache": "artifacts/metformin-research/19332510.abstract.txt", "locator": "Indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "79d5ec9a2d5c447e349d0e00742a2f2a05a3c9f9581199c4dde1f9b7910c029c", "start_char": 0, "end_char": 1536, "text_sha256": "79d5ec9a2d5c447e349d0e00742a2f2a05a3c9f9581199c4dde1f9b7910c029c"}

experimental_model

Targeted disruption of the murine Mate1 gene with metformin pharmacokinetics

exposure

Single intravenous metformin 5 mg/kg in Mate1(-/-) and Mate1(+/+) mice

limitations

Mouse pharmacokinetics; it does not establish a human exposure threshold or a clinical toxicity risk.

nutrient_topic

Metformin research collection; topical membership is not evidence of a direct clinical effect, and pharmacological exposure is not dietary intake. · Metformin

organism

Mouse

plain_language

Blood levels rise when the exit route is gone.

primary_references

[metformin-p19332510] Targeted disruption of the multidrug and toxin extrusion 1 (mate1) gene in mice reduces renal secretion of metformin. (2009). https://pubmed.ncbi.nlm.nih.gov/19332510/ DOI: 10.1124/mol.109.056242

tissue_or_cell_type

Kidney and liver

trigger_kind

machinery_impairment Imported condition classification; unverified.

Metformin: transport, molecular targets, gut mechanisms and nutrient interactions (2026-09-19) · lines 281–292

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Targeted disruption of the murine Mate1 gene with metformin pharmacokinetics · source_derived_draft · unverified_draft

### metformin-mate1-null-exposure Mate1(-/-) mice showed a two-fold increase in the area under the blood metformin concentration-time curve. Condition category: machinery_impairment nutrient_topic: Metformin research collection; topical membership is not evidence of a direct clinical effect, and pharmacological exposure is not dietary intake. plain_language: Blood levels rise when the exit route is gone. organism: Mouse tissue_or_cell_type: Kidney and liver experimental_model: Targeted disruption of the murine Mate1 gene with metformin pharmacokinetics limitations: Mouse pharmacokinetics; it does not establish a human exposure threshold or a clinical toxicity risk. exposure: Single intravenous metformin 5 mg/kg in Mate1(-/-) and Mate1(+/+) mice evidence_span: {"source_cache": "artifacts/metformin-research/19332510.abstract.txt", "locator": "Indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "79d5ec9a2d5c447e349d0e00742a2f2a05a3c9f9581199c4dde1f9b7910c029c", "start_char": 0, "end_char": 1536, "text_sha256": "79d5ec9a2d5c447e349d0e00742a2f2a05a3c9f9581199c4dde1f9b7910c029c"} [metformin-p19332510] Targeted disruption of the multidrug and toxin extrusion 1 (mate1) gene in mice reduces renal secretion of metformin. (2009). https://pubmed.ncbi.nlm.nih.gov/19332510/ DOI: 10.1124/mol.109.056242

evidence_span

{"source_cache": "artifacts/metformin-research/8165821.abstract.txt", "locator": "Indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "60471d633165552bd5a5c4e9e5ff05686d069ceedfd367ca892828c66d116bbd", "start_char": 0, "end_char": 1265, "text_sha256": "60471d633165552bd5a5c4e9e5ff05686d069ceedfd367ca892828c66d116bbd"}

experimental_model

Radiolabelled metformin tissue distribution in normal and streptozotocin-diabetic mice

exposure

Oral metformin 50 mg/kg with 14C-metformin, and a separate intravenous study

limitations

Mouse tissue concentrations at a single dose level. Metformin is not metabolised, so these are distribution rather than metabolic findings.

nutrient_topic

Metformin research collection; topical membership is not evidence of a direct clinical effect, and pharmacological exposure is not dietary intake. · Metformin

organism

Mouse

plain_language

The liver sees a higher concentration than the rest of the body.

primary_references

[metformin-p8165821] Accumulation of metformin by tissues of the normal and diabetic mouse. (1994). https://pubmed.ncbi.nlm.nih.gov/8165821/ DOI: 10.3109/00498259409043220

tissue_or_cell_type

Small intestine, stomach, colon, salivary gland, kidney, liver, heart and skeletal muscle

Metformin: transport, molecular targets, gut mechanisms and nutrient interactions (2026-09-19) · lines 307–318

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Radiolabelled metformin tissue distribution in normal and streptozotocin-diabetic mice · source_derived_draft · unverified_draft

### metformin-portal-gradient Maximum metformin concentrations in the hepatic portal vein were higher than in the inferior vena cava in both normal and diabetic mice. Condition category: normal nutrient_topic: Metformin research collection; topical membership is not evidence of a direct clinical effect, and pharmacological exposure is not dietary intake. plain_language: The liver sees a higher concentration than the rest of the body. organism: Mouse tissue_or_cell_type: Small intestine, stomach, colon, salivary gland, kidney, liver, heart and skeletal muscle experimental_model: Radiolabelled metformin tissue distribution in normal and streptozotocin-diabetic mice limitations: Mouse tissue concentrations at a single dose level. Metformin is not metabolised, so these are distribution rather than metabolic findings. exposure: Oral metformin 50 mg/kg with 14C-metformin, and a separate intravenous study evidence_span: {"source_cache": "artifacts/metformin-research/8165821.abstract.txt", "locator": "Indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "60471d633165552bd5a5c4e9e5ff05686d069ceedfd367ca892828c66d116bbd", "start_char": 0, "end_char": 1265, "text_sha256": "60471d633165552bd5a5c4e9e5ff05686d069ceedfd367ca892828c66d116bbd"} [metformin-p8165821] Accumulation of metformin by tissues of the normal and diabetic mouse. (1994). https://pubmed.ncbi.nlm.nih.gov/8165821/ DOI: 10.3109/00498259409043220

evidence_span

{"source_cache": "artifacts/metformin-research/27216492.abstract.txt", "locator": "Indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "c874a5c13e2e709b4b36040f281e2b187e7956b4610decddc35403170c0ed45d", "start_char": 0, "end_char": 3863, "text_sha256": "c874a5c13e2e709b4b36040f281e2b187e7956b4610decddc35403170c0ed45d"}

experimental_model

Two randomised crossover trials of delayed-release metformin targeted to the ileum

exposure

Delayed-release versus immediate-release metformin over 5 to 7 day periods

limitations

The dissociation of effect from plasma exposure is the key observation. Funded by the manufacturer of the delayed-release formulation, which the record retains.

nutrient_topic

Metformin research collection; topical membership is not evidence of a direct clinical effect, and pharmacological exposure is not dietary intake. · Metformin

organism

Human

plain_language

The drug can work from inside the gut without much of it entering the blood.

primary_references

[metformin-p27216492] Once-daily delayed-release metformin lowers plasma glucose and enhances fasting and postprandial GLP-1 and PYY: results from two randomised trials. (2016). https://pubmed.ncbi.nlm.nih.gov/27216492/ DOI: 10.1007/s00125-016-3992-6

tissue_or_cell_type

Distal small intestine

Metformin: transport, molecular targets, gut mechanisms and nutrient interactions (2026-09-19) · lines 827–838

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Two randomised crossover trials of delayed-release metformin targeted to the ileum · source_derived_draft · unverified_draft

### metformin-gut-restricted-effect Delayed-release metformin targeted to the ileum produced similar reductions in fasting and postprandial glucose despite an almost 60% reduction in systemic metformin exposure compared with immediate-release metformin. Condition category: normal nutrient_topic: Metformin research collection; topical membership is not evidence of a direct clinical effect, and pharmacological exposure is not dietary intake. plain_language: The drug can work from inside the gut without much of it entering the blood. organism: Human tissue_or_cell_type: Distal small intestine experimental_model: Two randomised crossover trials of delayed-release metformin targeted to the ileum limitations: The dissociation of effect from plasma exposure is the key observation. Funded by the manufacturer of the delayed-release formulation, which the record retains. exposure: Delayed-release versus immediate-release metformin over 5 to 7 day periods evidence_span: {"source_cache": "artifacts/metformin-research/27216492.abstract.txt", "locator": "Indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "c874a5c13e2e709b4b36040f281e2b187e7956b4610decddc35403170c0ed45d", "start_char": 0, "end_char": 3863, "text_sha256": "c874a5c13e2e709b4b36040f281e2b187e7956b4610decddc35403170c0ed45d"} [metformin-p27216492] Once-daily delayed-release metformin lowers plasma glucose and enhances fasting and postprandial GLP-1 and PYY: results from two randomised trials. (2016). https://pubmed.ncbi.nlm.nih.gov/27216492/ DOI: 10.1007/s00125-016-3992-6