Skip to main content

Advertisement

SpringerLink
Log in

Prediction of Drug Transfer into Milk Considering Breast Cancer Resistance Protein (BCRP)-Mediated Transport

  • Research Paper
  • Published:
Pharmaceutical Research Aims and scope Submit manuscript

ABSTRACT

Purpose

Drug transfer into milk is of concern due to the unnecessary exposure of infants to drugs. Proposed prediction methods for such transfer assume only passive drug diffusion across the mammary epithelium. This study reorganized data from the literature to assess the contribution of carrier-mediated transport to drug transfer into milk, and to improve the predictability thereof.

Methods

Milk-to-plasma drug concentration ratios (M/Ps) in humans were exhaustively collected from the literature and converted into observed unbound concentration ratios (M/Punbound,obs). The ratios were also predicted based on passive diffusion across the mammary epithelium (M/Punbound,pred). An in vitro transport assay was performed for selected drugs in breast cancer resistance protein (BCRP)-expressing cell monolayers.

Results

M/Punbound,obs and M/Punbound,pred values were compared for 166 drugs. M/Punbound,obs values were 1.5 times or more higher than M/Punbound,pred values for as many as 13 out of 16 known BCRP substrates, reconfirming BCRP as the predominant transporter contributing to secretory transfer of drugs into milk. Predictability of M/P values for selected BCRP substrates and non-substrates was improved by considering in vitro-evaluated BCRP-mediated transport relative to passive diffusion alone.

Conclusions

The current analysis improved the predictability of drug transfer into milk, particularly for BCRP substrates, based on an exhaustive data overhaul followed by focused in vitro transport experimentation.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3

Similar content being viewed by others

Abbreviations

ABCG2:

ATP-binding cassette transporter G2

BCRP:

Breast cancer resistance protein

CNT:

Concentrative nucleoside transporter

f m,protein :

Fraction of drug free from binding to milk protein

f m,total :

Unbound drug fraction in milk

f p :

Unbound drug fraction in plasma

GFP:

Green fluorescent protein

HBSS:

Hank’s balanced salt solution

LC-MS/MS:

Liquid chromatography-tandem mass spectroscopy

logD 7.2 :

Octanol/water partition coefficient at pH 7.2

M/P:

Milk-to-plasma concentration ratio

M/P(AUC):

M/P area-under-the-curve ratio

M/Punbound :

Unbound M/P

M/Punbound,obs :

Observed unbound M/P

M/Punbound,pred :

Predicted unbound M/P

MDCK:

Madin-Darby canine kidney

MEM:

Minimum Essential Medium

OCT:

Organic cation transporter

P app :

Partition coefficient between milk lipids and water

PEPT:

Peptide transporter

Robs/pred :

Ratio of M/Punbound,obs to M/Punbound,pred

SEM:

Standard error of the mean

SLC:

Solute carrier

UPLC:

Ultra-performance liquid chromatography

REFERENCES

  1. Flacking R, Ewald U, Starrin B. “I wanted to do a good job”: experiences of ‘becoming a mother’ and breastfeeding in mothers of very preterm infants after discharge from a neonatal unit. Soc Sci Med. 2007;64:2405–16.

    Article  PubMed  Google Scholar 

  2. Jones G, Steketee RW, Black RE, Bhutta ZA, Morris SS. How many child deaths can we prevent this year? Lancet. 2003;362:65–71.

    Article  PubMed  Google Scholar 

  3. Kramer MS. “Breast is best”: the evidence. Early Hum Dev. 2010;86:729–32.

    Article  PubMed  Google Scholar 

  4. Anderson PO. Drug use during breast-feeding. Clin Pharm. 1991;10:594–624.

    CAS  PubMed  Google Scholar 

  5. Matheson I. Drugs taken by mothers in the puerperium. Br Med J (Clin Res Ed). 1985;290:1588–9.

    Article  CAS  Google Scholar 

  6. Atkinson HC, Begg EJ. Prediction of drug distribution into human milk from physicochemical characteristics. Clin Pharmacokinet. 1990;18:151–67.

    Article  CAS  PubMed  Google Scholar 

  7. Begg EJ, Atkinson HC, Duffull SB. Prospective evaluation of a model for the prediction of milk: plasma drug concentrations from physicochemical characteristics. Br J Clin Pharmacol. 1992;33:501–5.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  8. Fleishaker JC. Models and methods for predicting drug transfer into human milk. Adv Drug Deliv Rev. 2003;55:643–52.

    Article  CAS  PubMed  Google Scholar 

  9. Rasmussen F. Mammary excretion of benzylpenicillin, erythromycin, and penethamate hydroiodide. Acta Pharmacol Toxicol (Copenh). 1959;16:194–200.

  10. Notarianni LJ, Belk D, Aird SA, Bennett PN. An in vitro technique for the rapid determination of drug entry into breast milk. Br J Clin Pharmacol. 1995;40:333–7.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  11. Fleishaker JC, Desai N, McNamara PJ. Factors affecting the milk-to-plasma drug concentration ratio in lactating women: physical interactions with protein and fat. J Pharm Sci. 1987;76:189–93.

    Article  CAS  PubMed  Google Scholar 

  12. Gerk PM, Kuhn RJ, Desai NS, McNamara PJ. Active transport of nitrofurantoin into human milk. Pharmacotherapy. 2001;21:669–75.

    Article  CAS  PubMed  Google Scholar 

  13. Lau RJ, Emery MG, Galinsky RE. Unexpected accumulation of acyclovir in breast milk with estimation of infant exposure. Obstet Gynecol. 1987;69:468–71.

    CAS  PubMed  Google Scholar 

  14. Oo CY, Kuhn RJ, Desai N, McNamara PJ. Active transport of cimetidine into human milk. Clin Pharmacol Ther. 1995;58:548–55.

    Article  CAS  PubMed  Google Scholar 

  15. Meskin MS, Lien EJ. QSAR analysis of drug excretion into human breast milk. J Clin Hosp Pharm. 1985;10:269–78.

  16. Agatonovic-Kustrin S, Ling LH, Tham SY, Alany RG. Molecular descriptors that influence the amount of drugs transfer into human breast milk. J Pharm Biomed Anal. 2002;29:103–19.

  17. Katritzky AR, Dobchev DA, Hur E, Fara DC, Karelson M. QSAR treatment of drugs transfer into human breast milk. Bioorg Med Chem. 2005;13:1623–32.

    Article  CAS  PubMed  Google Scholar 

  18. Zhao C, Zhang H, Zhang X, et al. Prediction of milk/plasma drug concentration (M/P) ratio using support vector machine (SVM) method. Pharm Res. 2006;23:41–8.

    Article  CAS  PubMed  Google Scholar 

  19. Dostal LA, Weaver RP, Schwetz BA. Excretion of high concentrations of cimetidine and ranitidine into rat milk and their effects on milk composition and mammary gland nucleic acid content. Toxicol Appl Pharmacol. 1990;102:430–42.

    Article  CAS  PubMed  Google Scholar 

  20. Gerk PM, Oo CY, Paxton EW, Moscow JA, McNamara PJ. Interactions between cimetidine, nitrofurantoin, and probenecid active transport into rat milk. J Pharmacol Exp Ther. 2001;296:175–80.

    CAS  PubMed  Google Scholar 

  21. McNamara PJ, Burgio D, Yoo SD. Pharmacokinetics of cimetidine during lactation: species differences in cimetidine transport into rat and rabbit milk. J Pharmacol Exp Ther. 1992;261:918–23.

    CAS  PubMed  Google Scholar 

  22. Jonker JW, Merino G, Musters S, et al. The breast cancer resistance protein BCRP (ABCG2) concentrates drugs and carcinogenic xenotoxins into milk. Nat Med. 2005;11:127–9.

    Article  CAS  PubMed  Google Scholar 

  23. Merino G, Jonker JW, Wagenaar E, van Herwaarden AE, Schinkel AH. The breast cancer resistance protein (BCRP/ABCG2) affects pharmacokinetics, hepatobiliary excretion, and milk secretion of the antibiotic nitrofurantoin. Mol Pharmacol. 2005;67:1758–64.

    Article  CAS  PubMed  Google Scholar 

  24. van Herwaarden AE, Schinkel AH. The function of breast cancer resistance protein in epithelial barriers, stem cells and milk secretion of drugs and xenotoxins. Trends Pharmacol Sci. 2006;27:10–6.

    Article  PubMed  Google Scholar 

  25. Ito N, Ito K, Ikebuchi Y, et al. Organic cation transporter/solute carrier family 22a is involved in drug transfer into milk in mice. J Pharm Sci. 2014;(in press).

  26. Alcorn J, Lu X, Moscow JA, McNamara PJ. Transporter gene expression in lactating and nonlactating human mammary epithelial cells using real-time reverse transcription-polymerase chain reaction. J Pharmacol Exp Ther. 2002;303:487–96.

    Article  CAS  PubMed  Google Scholar 

  27. Farke C, Meyer HH, Bruckmaier RM, Albrecht C. Differential expression of ABC transporters and their regulatory genes during lactation and dry period in bovine mammary tissue. J Dairy Res. 2008;75:406–14.

    Article  CAS  PubMed  Google Scholar 

  28. Gilchrist SE, Alcorn J. Lactation stage-dependent expression of transporters in rat whole mammary gland and primary mammary epithelial organoids. Fundam Clin Pharmacol. 2010;24:205–14.

    CAS  PubMed  Google Scholar 

  29. Groneberg DA, Doring F, Theis S, Nickolaus M, Fischer A, Daniel H. Peptide transport in the mammary gland: expression and distribution of PEPT2 mRNA and protein. Am J Physiol Endocrinol Metab. 2002;282:E1172–9.

    Article  CAS  PubMed  Google Scholar 

  30. Ito S, Alcorn J. Xenobiotic transporter expression and function in the human mammary gland. Adv Drug Deliv Rev. 2003;55:653–65.

    Article  CAS  PubMed  Google Scholar 

  31. Koshimichi H, Ito K, Hisaka A, Honma M, Suzuki H. Analysis and prediction of drug transfer into human milk taking into consideration secretion and reuptake clearances across the mammary epithelia. Drug Metab Dispos. 2011;39:2370–80.

    Article  CAS  PubMed  Google Scholar 

  32. Hale TW. Medications and mother’s milk. 13th ed. TX: Hale Publishing; 2008.

    Google Scholar 

  33. Ito N, Ito K, Koshimichi H, et al. Contribution of protein binding, lipid partitioning, and asymmetrical transport to drug transfer into milk in mouse versus human. Pharm Res. 2013;30:2410–22.

    Article  CAS  PubMed  Google Scholar 

  34. Atkinson HC, Begg EJ. Relationship between human milk lipid-ultrafiltrate and octanol-water partition coefficients. J Pharm Sci. 1988;77:796–8.

    Article  CAS  PubMed  Google Scholar 

  35. Kodaira H, Kusuhara H, Fujita T, Ushiki J, Fuse E, Sugiyama Y. Quantitative evaluation of the impact of active efflux by p-glycoprotein and breast cancer resistance protein at the blood–brain barrier on the predictability of the unbound concentrations of drugs in the brain using cerebrospinal fluid concentration as a surrogate. J Pharmacol Exp Ther. 2011;339:935–44.

    Article  CAS  PubMed  Google Scholar 

  36. Kondo C, Suzuki H, Itoda M, et al. Functional analysis of SNPs variants of BCRP/ABCG2. Pharm Res. 2004;21:1895–903.

    Article  CAS  PubMed  Google Scholar 

  37. Barrera B, Otero JA, Egido E, et al. The anthelmintic triclabendazole and its metabolites inhibit the membrane transporter ABCG2/BCRP. Antimicrob Agents Chemother. 2012;56:3535–43.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  38. Pan G, Giri N, Elmquist WF. Abcg2/Bcrp1 mediates the polarized transport of antiretroviral nucleosides abacavir and zidovudine. Drug Metab Dispos. 2007;35:1165–73.

    Article  CAS  PubMed  Google Scholar 

  39. Wang X, Furukawa T, Nitanda T, et al. Breast cancer resistance protein (BCRP/ABCG2) induces cellular resistance to HIV-1 nucleoside reverse transcriptase inhibitors. Mol Pharmacol. 2003;63:65–72.

    Article  CAS  PubMed  Google Scholar 

  40. Hemauer SJ, Patrikeeva SL, Wang X, et al. Role of transporter-mediated efflux in the placental biodisposition of bupropion and its metabolite, OH-bupropion. Biochem Pharmacol. 2010;80:1080–6.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  41. Marki-Zay J, Tauberne Jakab K, Szeremy P, Krajcsi P. MDR-ABC transporters: biomarkers in rheumatoid arthritis. Clin Exp Rheumatol. 2013;31:779–87.

    PubMed  Google Scholar 

  42. Pavek P, Merino G, Wagenaar E, et al. Human breast cancer resistance protein: interactions with steroid drugs, hormones, the dietary carcinogen 2-amino-1-methyl-6-phenylimidazo(4,5-b)pyridine, and transport of cimetidine. J Pharmacol Exp Ther. 2005;312:144–52.

    Article  CAS  PubMed  Google Scholar 

  43. Merino G, Alvarez AI, Pulido MM, Molina AJ, Schinkel AH, Prieto JG. Breast cancer resistance protein (BCRP/ABCG2) transports fluoroquinolone antibiotics and affects their oral availability, pharmacokinetics, and milk secretion. Drug Metab Dispos. 2006;34:690–5.

    Article  CAS  PubMed  Google Scholar 

  44. Ando T, Kusuhara H, Merino G, Alvarez AI, Schinkel AH, Sugiyama Y. Involvement of breast cancer resistance protein (ABCG2) in the biliary excretion mechanism of fluoroquinolones. Drug Metab Dispos. 2007;35:1873–9.

    Article  CAS  PubMed  Google Scholar 

  45. Kato Y, Takahara S, Kato S, et al. Involvement of multidrug resistance-associated protein 2 (Abcc2) in molecular weight-dependent biliary excretion of beta-lactam antibiotics. Drug Metab Dispos. 2008;36:1088–96.

    Article  CAS  PubMed  Google Scholar 

  46. Gunness P, Aleksa K, Koren G. Acyclovir is a substrate for the human breast cancer resistance protein (BCRP/ABCG2): implications for renal tubular transport and acyclovir-induced nephrotoxicity. Can J Physiol Pharmacol. 2011;89:675–80.

    Article  CAS  PubMed  Google Scholar 

  47. Hasegawa M, Kusuhara H, Adachi M, Schuetz JD, Takeuchi K, Sugiyama Y. Multidrug resistance-associated protein 4 is involved in the urinary excretion of hydrochlorothiazide and furosemide. J Am Soc Nephrol. 2007;18:37–45.

    Article  CAS  PubMed  Google Scholar 

  48. Kim HS, Sunwoo YE, Ryu JY, et al. The effect of ABCG2 V12M, Q141K and Q126X, known functional variants in vitro, on the disposition of lamivudine. Br J Clin Pharmacol. 2007;64:645–54.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  49. Nakanishi H, Yonezawa A, Matsubara K, Yano I. Impact of P-glycoprotein and breast cancer resistance protein on the brain distribution of antiepileptic drugs in knockout mouse models. Eur J Pharmacol. 2013;710:20–8.

    Article  CAS  PubMed  Google Scholar 

  50. Beery E, Rajnai Z, Abonyi T, et al. ABCG2 modulates chlorothiazide permeability–in vitro-characterization of its interactions. Drug Metab Pharmacokinet. 2012;27:349–53.

    CAS  PubMed  Google Scholar 

  51. Werthmann Jr MW, Krees SV. Excretion of chlorothiazide in human breast milk. J Pediatr. 1972;81:781–3.

    Article  CAS  PubMed  Google Scholar 

  52. Miller ME, Cohn RD, Burghart PH. Hydrochlorothiazide disposition in a mother and her breast-fed infant. J Pediatr. 1982;101:789–91.

    Article  CAS  PubMed  Google Scholar 

  53. Lilienblum W, Dekant W, Foth H, et al. Alternative methods to safety studies in experimental animals: role in the risk assessment of chemicals under the new European Chemicals Legislation (REACH). Arch Toxicol. 2008;82:211–36.

    Article  CAS  PubMed  Google Scholar 

  54. Noguchi K, Katayama K, Sugimoto Y. Human ABC transporter ABCG2/BCRP expression in chemoresistance: basic and clinical perspectives for molecular cancer therapeutics. Pharmgenomics Pers Med. 2014;7:53–64.

    PubMed Central  PubMed  Google Scholar 

  55. Lagas JS, van Waterschoot RA, Sparidans RW, Wagenaar E, Beijnen JH, Schinkel AH. Breast cancer resistance protein and P-glycoprotein limit sorafenib brain accumulation. Mol Cancer Ther. 2010;9:319–26.

    Article  CAS  PubMed  Google Scholar 

Download references

ACKNOWLEDGMENTS AND DISCLOSURES

This work was supported by a research scholarship from the Japan Research Foundation for Clinical Pharmacology, and a Grant-in-Aid for Scientific Research on Innovative Areas HD-Physiology from the Ministry of Education, Science and Culture of Japan (Grant No. 22136015).

Author information

Authors and Affiliations

  1. Department of Pediatrics, the University of Tokyo Hospital, Faculty of Medicine, the University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo, 113-8655, Japan

    Naoki Ito & Akira Oka

  2. Laboratory of Biopharmaceutics, Graduate School of Pharmaceutical Sciences, Chiba University, Inohana 1-8-1, Chuo-ku, Chiba, 260-8675, Japan

    Kousei Ito

  3. Department of Pharmacy, the University of Tokyo Hospital, Faculty of Medicine, the University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo, 113-8655, Japan

    Yuki Ikebuchi, Yu Toyoda, Tappei Takada & Hiroshi Suzuki

  4. Laboratory of Geriatric Pharmacology and Therapeutics, Graduate School of Pharmaceutical Sciences, Chiba University, 1-8-1 Inohana, Chuo-ku, Chiba, 263-8675, Japan

    Akihiro Hisaka

Authors
  1. Naoki Ito
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Kousei Ito
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Yuki Ikebuchi
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Yu Toyoda
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Tappei Takada
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Akihiro Hisaka
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Akira Oka
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Hiroshi Suzuki
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Kousei Ito.

Electronic supplementary material

Below is the link to the electronic supplementary material.

Supplementary Fig. 1

(PDF 67.0 kb)

Supplementary Fig. 2

(PDF 146 kb)

Supplementary Table I

(PDF 57.6 kb)

Supplementary Table II

(PDF 102 kb)

Supplementary Table III

(PDF 59.8 kb)

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Ito, N., Ito, K., Ikebuchi, Y. et al. Prediction of Drug Transfer into Milk Considering Breast Cancer Resistance Protein (BCRP)-Mediated Transport. Pharm Res 32, 2527–2537 (2015). https://doi.org/10.1007/s11095-015-1641-2

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11095-015-1641-2

KEY WORDS

Search

Navigation