Analysis and Prediction of Drug Transfer into Human Milk Taking into Consideration Secretion and Reuptake Clearances across the Mammary Epithelia

作者：Koshimichi Hiroki; Ito Kousei^*; Hisaka Akihiro; Honma Masashi; Suzuki Hiroshi

来源：Drug Metabolism and Disposition, 2011, 39(12): 2370-2380.

DOI：10.1124/dmd.111.040972

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 (CL(sec) and CL(re), 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. CL(sec) and CL(re) values were obtained successfully for 49 drugs. Because the CL(sec) and CL(re) 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 CL(sec) and CL(re) can be predicted from physicochemical parameters with adjusted R(2) values of 0.705 and 0.472, respectively. Moreover, 66.7 and 77.8% of predicted CL(sec) and CL(re) 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.

• 出版日期2011-12