Cimetidine Excretion During Lactation

Overseen By Mary Hebert, PharmD, FCCP

Age: < 65

Sex: Any

Trial Phase: Phase 4

Sponsor: University of Washington

Must not be taking: Cimetidine, Antidepressants, Antipsychotics, others

Disqualifiers: Kidney disease, Liver disease, Smokers, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Prior Safety Data This treatment has passed at least one previous human trial

Compensation: Varies

Number of Visits: 3

Duration: 6-8 months

50 Participants Needed

Trial Summary

Will I have to stop taking my current medications?

Yes, you may need to stop taking certain medications. The trial excludes participants taking medications that interact with cimetidine or affect specific drug transporters. It's best to discuss your current medications with the trial team to see if any need to be stopped.

What data supports the effectiveness of the drug cimetidine when excreted in breast milk?

Research shows that cimetidine is actively transported into breast milk at higher concentrations than expected, but it appears safe for infants as the amount they ingest is small. Additionally, studies in animals indicate that high concentrations of cimetidine in milk do not harm the suckling pups or affect milk composition. ^{1 2 3 4 5}

Is cimetidine safe for breastfeeding mothers and their infants?

Cimetidine is excreted into breast milk, but the amount ingested by a breastfeeding infant is estimated to be 6.7% of the maternal dose, which appears to be safe under normal conditions. Studies in rats also showed no harmful effects on suckling pups or milk composition. ^{1 2 6 7 8}

How does the drug cimetidine differ from other treatments for its condition?

Cimetidine is unique because it is actively transported into human milk, unlike most drugs that passively diffuse. This active transport mechanism results in higher concentrations in milk, which may have implications for breastfeeding mothers and their infants. ^{1 2 3 9 10}

What is the purpose of this trial?

This is a prospective, non-randomized, phase I study design evaluating the in vivo activities and expression of OCT1 and BCRP in mammary gland of lactating women at three time points postpartum.

Research Team

Mary Hebert, PharmD, FCCP

Principal Investigator

University of Washington

Eligibility Criteria

This trial is for healthy, lactating or pregnant women planning to breastfeed, aged 18-50, and their nursing infants between 3 weeks to 8 months old. Participants must not be on medications that could interact with the study drug.

Inclusion Criteria

I am a healthy woman aged 18-50, currently breastfeeding or planning to, with a nursing infant aged 3 weeks to 8 months.

Exclusion Criteria

Following multiple gestation (twins, triplets etc.)

You are a smoker.

Pregnancy

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive a single oral dose of cimetidine 200 mg on each of 3 study days at different postpartum stages

6-8 months

3 visits (in-person)

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

Treatment Details

Interventions

• Drug Excretion in Breast Milk

Trial Overview The study is testing how Cimetidine (200 MG), a medication commonly used to treat heartburn and stomach ulcers, is excreted in breast milk at different times after childbirth.

Participant Groups

Group I: Healthy Lactating Women Experimental Treatment 1 Intervention

Healthy Lactating Women will be studied on 3 study days and serve as their own control.

Who Is Running the Clinical Trial?

University of Washington

Lead Sponsor

Trials

1,858

Recruited

2,023,000+

Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)

Collaborator

Trials

2,103

Recruited

2,760,000+

Findings from Research

Cimetidine transfer into human milk is significantly higher than what would be expected from passive diffusion, indicating the presence of an active transport mechanism, with a milk/serum ratio of 5.77 compared to a predicted ratio of 1.05.

The estimated dose of cimetidine that a suckling infant receives is about 6.7% of the maternal dose, which suggests that it may be safe for breastfeeding mothers under normal conditions.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Active transport of cimetidine into human milk. Oo, CY., Kuhn, RJ., Desai, N., et al.[2013]

Cimetidine and ranitidine were found to be excreted in high concentrations into rat milk, with cimetidine levels significantly exceeding plasma concentrations, indicating a strong transfer to milk.

Despite the high levels of these medications in milk, there were no harmful effects observed on the suckling pups or on the overall composition and synthesis of the milk, suggesting safety in this context.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Excretion of high concentrations of cimetidine and ranitidine into rat milk and their effects on milk composition and mammary gland nucleic acid content. Dostal, LA., Weaver, RP., Schwetz, BA.[2019]

Cimetidine transfers into milk in both rabbits and rats, with a higher concentration in milk compared to serum, indicating that nursing offspring may be exposed to significant levels of the drug.

The mechanism of cimetidine transfer differs between species: in rabbits, it appears to be primarily through diffusion, while in rats, it may involve active transport, suggesting species-specific pharmacokinetics.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pharmacokinetics of cimetidine during lactation: species differences in cimetidine transport into rat and rabbit milk. McNamara, PJ., Burgio, D., Yoo, SD.[2013]

Cimetidine is effectively eliminated in neonates through both metabolic and renal pathways, with a half-life ranging from 3.4 to 2.1 hours, indicating that their ability to process the drug improves as they mature.

Full-term neonates recover about 90% of the administered cimetidine dose in urine, significantly higher than the 60% seen in adults, suggesting that dosing may need to be adjusted for premature infants or those with renal issues.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The pharmacokinetics and metabolism of cimetidine in neonates. Ziemniak, JA., Wynn, RJ., Aranda, JV., et al.[2019]

Maternal pretreatment with cimetidine during lactation significantly inhibits drug metabolism in both mouse dams and their pups in a dose-dependent manner, with the highest dose (50 mg/kg/day) showing comparable inhibition levels in dams and female pups, but less effect on male pups.

Among the metabolic processes studied, aniline hydroxylase was the least affected by cimetidine, indicating that the impact of maternal drug exposure varies based on the specific metabolic pathway and the sex of the offspring.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Dose-related and other effects of maternal cimetidine pretreatment during lactation on drug metabolism in mouse dams and pups. Osuide, G., Wambebe, C., Ikediobi, CO., et al.[2018]

A new and sensitive method using gas chromatography-mass spectrometry (GC-MS) was developed to measure 11 different antihistamines in breast milk, which is crucial for understanding their safety during breastfeeding.

The method demonstrated high accuracy and precision, making it suitable for clinical investigations and studies on the pharmacokinetics and safety of antihistamines for breastfeeding mothers and their newborns.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A fully validated method for the simultaneous determination of 11 antihistamines in breast milk by gas chromatography-mass spectrometry. Katselou, M., Athanaselis, S., Nikolaou, P., et al.[2018]

A systematic review of seven studies involving 25 mother-infant pairs found that the relative infant dose of various antihistamines in breast milk is low, with all medications showing less than 5% exposure to breastfed infants, indicating a generally low risk of adverse effects.

Despite the low exposure levels, most antihistamine product labels in the EU and the US recommend avoiding use during breastfeeding due to insufficient evidence, highlighting a significant knowledge gap that calls for more research on the safety of antihistamines for breastfeeding women.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Antihistamine use during breastfeeding with focus on breast milk transfer and safety in humans: A systematic literature review. Ngo, E., Spigset, O., Lupattelli, A., et al.[2022]

Drugs taken by nursing mothers typically transfer into breast milk in much smaller amounts than those taken during pregnancy, which is important for assessing infant safety.

A systematic approach to evaluating drug therapy in nursing mothers can help maintain breastfeeding while minimizing risks to the infant, considering factors like drug dosage, infant age, and potential side effects.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Drug use during breast-feeding. Anderson, PO.[2004]

Nitrofurantoin is actively transported into the milk of lactating Sprague Dawley rats, with a milk to serum concentration ratio significantly higher than what would be expected from passive diffusion, indicating a specialized transport mechanism.

The study suggests the existence of at least two different transporter systems in mammary epithelial cells: one for organic cations like cimetidine and another for anions like nitrofurantoin, as evidenced by the varying effects of cimetidine on the clearance of nitrofurantoin.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Active transport of nitrofurantoin into rat milk. Oo, CY., Paxton, EW., McNamara, PJ.[2019]

Cimetidine (CM) shows significant active transport into rat milk, with a milk-to-serum ratio (M/S) of 29.3 compared to 13.0 for ranitidine (RN), indicating a stronger accumulation mechanism for CM.

Both CM and RN can have their milk transfer affected by each other, suggesting that their transport into milk can be saturated and inhibited, which supports the idea of an active transport process across mammary epithelial cells.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Active transport of cimetidine and ranitidine into the milk of Sprague Dawley rats. McNamara, PJ., Meece, JA., Paxton, E.[2013]

References

1. United States pubmed.ncbi.nlm.nih.gov

Active transport of cimetidine into human milk. [2013]

2. United States pubmed.ncbi.nlm.nih.gov

Excretion of high concentrations of cimetidine and ranitidine into rat milk and their effects on milk composition and mammary gland nucleic acid content. [2019]

3. United States pubmed.ncbi.nlm.nih.gov

Pharmacokinetics of cimetidine during lactation: species differences in cimetidine transport into rat and rabbit milk. [2013]

4. Switzerland pubmed.ncbi.nlm.nih.gov

The pharmacokinetics and metabolism of cimetidine in neonates. [2019]

5. Switzerland pubmed.ncbi.nlm.nih.gov

Dose-related and other effects of maternal cimetidine pretreatment during lactation on drug metabolism in mouse dams and pups. [2018]

6. England pubmed.ncbi.nlm.nih.gov

A fully validated method for the simultaneous determination of 11 antihistamines in breast milk by gas chromatography-mass spectrometry. [2018]

7. England pubmed.ncbi.nlm.nih.gov

Antihistamine use during breastfeeding with focus on breast milk transfer and safety in humans: A systematic literature review. [2022]

8. United States pubmed.ncbi.nlm.nih.gov

Drug use during breast-feeding. [2004]

9. United States pubmed.ncbi.nlm.nih.gov

Active transport of nitrofurantoin into rat milk. [2019]

10. United States pubmed.ncbi.nlm.nih.gov

Active transport of cimetidine and ranitidine into the milk of Sprague Dawley rats. [2013]