BCRP, Drugs in Breast Milk, Lactation, Mammary Drug Transporters, OCT1, Postpartum
Conditions
Keywords
breast milk, lactation, cimetidine, proteomics, OCT1, BCRP, OCTN2, PEPT2, ENT1, CNT3, MRP1, OATP2B1, OATP3A1, OCT2, postpartum, pharmacokinetics
Brief summary
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.
Detailed description
Each woman will receive a single oral dose of cimetidine 200 mg on each of 3 study days (3-5 weeks, 3-4 months, and 6-8 months postpartum) followed by serial collection of blood, urine and breast milk samples over 12-hours. Cimetidine concentrations will be assay using a validated LC/MS/MS assay. Subjects will be genotyped for OCT1 and BCRP. Mammary epithelial cells will be isolated from breast milk and transporter expression will be quantified. Each woman will serve as her own control.
Interventions
DRUGCimetidine 200 MG
Cimetidine will serve as the probe drug
Sponsors
Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)
University of Washington
Study design
Allocation
NA
Intervention model
SEQUENTIAL
Primary purpose
BASIC_SCIENCE
Masking
NONE
Intervention model description
This is a phase 1 study design of an approved drug to evaluate the time-course for the expression and activity of OCT1 and BCRP in the mammary gland 3-5 weeks, 3-4 months and 6-8 months postpartum.
Eligibility
Sex/Gender
ALL
Age
14 Days to 50 Years
Healthy volunteers
Yes
Inclusion criteria
1. Healthy postpartum women 2. 18-50 years of age and their infants 3. Able to provide written informed consent
Exclusion criteria
1. Receiving cimetidine within the 3 days prior to each study day. Concomitant administration of cimetidine will confound interpretation of study results. 2. Hypersensitivity to cimetidine Patients with known allergic reactions to cimetidine will be excluded for safety reasons 3. Receiving medication known to interact with cimetidine: OCT, BCRP, CYP3A4, CYP2D6, CYP1A2 and CYP2C9 substrates (e.g. amiodarone, clopidogrel, diazepam, ketoconazole, metformin, nifedipine, phenytoin, procainamide, theophylline,tricyclic antidepressants and warfarin) Patients with drug interactions will be excluded for safety reasons. 4. Receiving BCRP inhibitors/inducers (afatinib, aripipraxole, axitinib, cimetidine, cyclosporine, curcumin/tumeric, delavirdine, efavirenz, elacridar, elvitegravir, etravirine, FTC, 5-fluorouracil, fluvastatin, imatinib, lanzoprazole, lapatinib, lopinavir, maraviroc, nelfinavir, nebicapone, nilotinib, novobiocin, oltipraz, omeprazole, pantoprazole, phenobarbital, promazine, rabeprazole, riboflavin, rifampicin, risperidone, saquinavir, sirolimus, sorafenib, sulfasalazine, sunitinib, tacrolimus, tariquidar, telaprevir, telatinib, teriflunomide, tolcapone, triflunomide, trametinib, trifluoperazine, venlafaxine, zidonuvir), OCT1 inhibitors/inducers (acyclovir, amantadine, amiloride, amitriptyline, bucindolol, carvedilol, chlorpheniramine, chlorpromazine, cimetidine, citalopram, clonidine, clopidogrel, clotrimazole, clozapine, cocaine, corticosterone, cyclosporine, daclatasvir, darunavir, desipramine, dextromethorphan, diltiazem, disopyramide, dronedarone, efavirenz, famotidine, fentanyl, fluvoxamine, formoterol, fuloxetine, griseofulvin, doxazosine, ganciclovir, guanfacine, imipramine, indinavir, isavuconazole, itraconazole, ketoconazole, lamotrigine, lasmiditan, levofloxacin, levomepromazine, lidocaine, maprotiline, methylnicotinamide, morphine, moxifloxacin, nefazodone, nelfinavir, nevirapine, nicotine, nomifensine, ondansetron, oxybutynin, paroxetine, pentamidine, phenoxybenzamine, prazosin, probenecid, procainamide, propafenone, pyrazinamide, quetiapine,quinidine, quinine, reboxetine, remoxidpride, reseripine, rifampicin, ritonavir, salmeterol, saquinavir, tramadol, trimethoprim, trimipramine, verapamil) Inhibitors and inducers of the drug transporters will confound data analysis and interpretation. 5. Kidney disease could confound data analysis and interpretation. Therefore, patients with known kidney disease with documented renal function impairment will be excluded from the study. Current serum creatinine \> 1.2 mg/dL in their medical record will be excluded. 6. Known liver disease Liver disease will confound data analysis and interpretation. Therefore, patients with known significant liver disease will be excluded from the study. Current ALT exceeding 2-times the upper limit of normal in their medical record will be excluded. 7. Inability to fast for 4 hours prior to the study. To limit PK variability across study days, subjects will be requested to fast for 4 hours prior to each study day. 8. Smokers (tobacco or other nicotine containing products Nicotine interacts with OCT1 and will confound data analysis and interpretation
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Mammary clearance of cimetidine | 3-5 weeks, 3-4 months and 6-8 months postpartum | Cimetidine excretion into breast milk at three postpartum stages |
| Mammary epithelial cell expression of BCRP | 3-5 weeks, 3-4 months and 6-8 months postpartum | BCRP protein expression in MECs at three postpartum stages |
| Mammary epithelial cell expression of OCT1 | 3-5 weeks, 3-4 months and 6-8 months postpartum | OCT1 protein expression in MECs at three postpartum stages |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Relationship between OCT1 expression and activity | 3-5 weeks, 3-4 months and 6-8 months postpartum | Effect of time postpartum on OCT1 protein expression in MECs and correlation with cimetidine mammary CL |
| Relationship between BCRP expression and activity | 3-5 weeks, 3-4 months and 6-8 months postpartum | Effect of time postpartum on BCRP protein expression in MECs and correlation with cimetidine mammary CL |
| Cimetidine relative infant dose and infant concentration | 3-5 weeks, 3-4 months and 6-8 months postpartum | cimetidine relative infant dose (RID) and infant concentration |
| Maternal cimetidine PK | 3-5 weeks, 3-4 months and 6-8 months postpartum | Effects of time postpartum on cimetidine CL/F |
Countries
United States
Contacts
Primary ContactMary Hebert, PharmD, FCCP
Outcome results
None listed