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Contribution of Protein Binding, Lipid Partitioning, and Asymmetrical Transport to Drug Transfer into Milk in Mouse Versus Human

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Abstract

Purpose

Drug transfer into milk is a general concern during lactation. Because data are limited in human subjects, particularly for new drugs, experimental animal models of lactational drug transfer are critical. This study analyzed drug transfer into milk in a mouse model, as well as the contribution of similar and dissimilar host factors.

Methods

Milk/plasma drug concentration ratios (M/P) in humans were obtained from the literature, while those in mice were determined experimentally after intraperitoneal implantation of osmotic pumps containing drugs of interest. Unbound drug fractions in plasma and milk were determined in vitro for both species.

Results

M/P values were determined for 27 drugs in mice and compared with those in human. These values were increased in mice for 21 drugs; the geometric mean ratio of M/P between mice and humans was 2.03 (95% CI, 1.42–2.89) for all 27 drugs. These results were reasonably explained by the relatively high protein and lipid content in mouse milk. Moreover, species-specific asymmetrical transport systems were suggested for 9 drugs.

Conclusions

In addition to species-specific differences in milk protein and lipid content, variances in asymmetrical drug transport across the mammary epithelium may yield discordant M/P values in humans and mice.

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Abbreviations

ABC:

ATP-binding cassette

AUC:

area under the drug concentration-time curve

BCRP:

breast cancer resistance protein/ABC transporter G2

BEH:

bridged ethyl hybrid

C m :

drug concentration in milk

C m,lipid :

drug concentration in lipid fraction of milk

C m,skim :

drug concentration in skim milk

C m,unbound :

unbound drug concentration in skim milk

C p :

drug concentration in plasma

C p,unbound :

unbound drug concentration in plasma

DMSO:

dimethyl sulfoxide

f m :

unbound drug fraction in skim milk

f m,total :

fraction of drug free from binding to milk protein and lipid

f p :

unbound drug fraction in plasma

K f :

milk lipid-to-water partition coefficient

LC-MS/MS:

liquid chromatography-tandem mass spectroscopy

M/P:

ratio of drug concentration in milk to that in plasma

M/Punbound :

ratio of unbound drug concentration in milk to that in plasma

M/Punbound,pred :

M/Punbound ratio predicted based on pH partition theory

OCT:

organic cation transporter

SDS:

sodium dodecyl sulfate

SLC:

solute carrier

UPLC:

ultra-performance liquid chromatography

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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 [Grant 22136015] from the Ministry of Education, Science and Culture of Japan.

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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

  2. 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

    Kousei Ito, Hiroki Koshimichi, Masashi Honma & Hiroshi Suzuki

  3. Pharmacology & Pharmacokinetics, The University of Tokyo Hospital Faculty of Medicine, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo, 113-8655, Japan

    Akihiro Hisaka

  4. National Center for Child Health & Development, 2-10-1 Okura, Setagaya-ku, Tokyo, 157-8535, Japan

    Takashi Igarashi

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  1. Naoki Ito
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Correspondence to Kousei Ito.

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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 30, 2410–2422 (2013). https://doi.org/10.1007/s11095-013-1085-5

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  • DOI: https://doi.org/10.1007/s11095-013-1085-5

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