Abstract
Medication use during lactation is a matter of concern due to unnecessary exposure of infants to drugs. Although some studies have predicted the extent of drug transfer into milk from physicochemical parameters, drug concentration-time profiles in milk have not been predicted or even analyzed yet. In the present study, a drug transfer model was constructed by defining secretion and reuptake clearances (CLsec and CLre, respectively) between milk and plasma based on unbound drug concentrations. Through the use of this model, drug concentration-time profiles were analyzed in human milk and plasma based on data collected from the literature. CLsec and CLre values were obtained successfully for 49 drugs. Because the CLsec and CLre values were in general similar for each drug, transport across the mammary epithelia was mediated by passive diffusion in most cases. This study demonstrated that the logarithmically transformed values of CLsec and CLre can be predicted from physicochemical parameters with adjusted R2 values of 0.705 and 0.472, respectively. Moreover, 66.7 and 77.8% of predicted CLsec and CLre values were within 3-fold error ranges of the observed values for 45 and 27 drugs, respectively. Finally, time profiles of drug concentrations in milk were simulated from physicochemical parameters. The milk-to-plasma area under the concentration-time curve ratios also were predicted successfully within 3-fold error ranges of the observed values for 71.9% of the drugs analyzed. The method described herein therefore may be useful in predicting drug concentration-time profiles in human milk for newly developed drugs.
Footnotes
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.
Article, publication date, and citation information can be found at http://dmd.aspetjournals.org.
doi:10.1124/dmd.111.040972.
↵ The online version of this article (available at http://dmd.aspetjournals.org) contains supplemental material.
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ABBREVIATIONS:
- CLsec
- secretion clearance
- CLre
- reuptake clearance
- M/P (AUC)
- milk-to-plasma area under the concentration-time curve ratio
- MW
- molecular weight
- Vm
- milk volume
- Cp(t)
- drug concentration in plasma
- Cm(t)
- drug concentration in milk
- fp
- unbound fraction of drug in plasma
- fm,total
- unbound fraction of drug in milk
- fm,protein
- protein binding in milk
- Papp
- partition coefficient between milk lipid and water
- Tmax
- time of maximum concentration
- log D
- common logarithm of octanol-water distribution coefficient
- log P
- common logarithm of octanol-water partition coefficient
- PSA
- polar surface area
- HBA
- hydrogen bond acceptor
- HBD
- hydrogen bond donor
- BCRP/ABCG2
- breast cancer resistance protein/ATP-binding cassette transporter G2.
- Received May 31, 2011.
- Accepted September 21, 2011.
- Copyright © 2011 by The American Society for Pharmacology and Experimental Therapeutics
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