QSAR treatment of drugs transfer into human breast milk Alan R. Katritzky, a, * Dimitar A. Dobchev, a,c Evrim Hu ¨r, a,b Dan C. Fara a and Mati Karelson c a Center for Heterocyclic Compounds, Department of Chemistry, University of Florida, Gainesville, FL 32611, USA b Department of Chemistry, Faculty of Arts and Science, Osmangazi University, 26020 Eskisehir, Turkey c Institute of Chemistry, Tallinn University of Technology, Ehitajate tee 5, Tallinn 19086, Estonia Received 12 October 2004; revised 8 December 2004; accepted 8 December 2004 Available online 20 January 2005 Abstract—A satisfactory model is developed using CODESSA PRO CODESSA PRO for the correlation and prediction of milk to plasma concentration ratios (M/P ratio) for diverse pharmaceuticals. A set of experimentally derived M/P ratio values were collected from the literature for 115 widely used pharmaceuticals. The experimental logarithmic M/P ratios were tested with more than 850 theoretical molecular descriptors including constitutional, topological, geometrical, quantum chemical, thermodynamic, and electrostatic types. Based on the data set, for 100 commonly used drugs, a seven-parameter QSAR model was derived that shows a satisfactory (R 2 = 0.791) correlation between predicted and observed values of log (M/P) ratio. 1. Introduction Breast feeding is highly beneficial to the health of both mothers and infants: breast milk is the ideal food source for infants providing, among other important benefits, enhanced protection to the infants against many com- mon infectious diseases. 1 Human milk reduces exposure to contaminated food sources, enhances nutritional sta- tus and prevents infections. 2 Breast feeding has psycho- logical and physiological benefits for the mother; thus the incidence of pre-menopausal breast cancer is decreased for women with a longer duration of breast feeding. Breast feeding has been shown to enhance mother–infant bonding and may enhance both maternal self-esteem and self-efficacy by allowing a mother to provide very personal and optimal nourishment to her infant. 3 Because of the significant role of breast milk, the investigation of contamination from motherÕs medi- cation in her breast milk is important. Many women need to take medication while breast feed- ing. The accumulation of a specific medication in milk is associated with a risk to the infant that can exceed the benefits of breast feeding. 4 Several factors such as molecular weight, lipid–water solubility, ionization of the drug, protein bonding and pH of the milk or drug are concerned in the accumulation of a drug in breast milk and its absorption by the baby. 5 The milk to plasma concentration ratio (M/P ratio) of a drug is generally used to estimate the infantÕs exposure to drugs through breast milk. The M/P ratio is an attempt to quantify the equilibrium concentration between breast milk and blood. It is equivalent to the drug concentration in the breast milk (BM) divided by its concentration in the maternal plasma (MP). 6 Theoretically, the M/P ratio can be expressed by Eq. 1 M =P ¼ c d BM c d MP ð1Þ where M/P: the milk to plasma concentration ratio, c d BM : the drug concentration in human breast milk, c d MP : the drug concentration in human maternal plasma. Due to the complex nature of milk, there are several fac- tors that can affect the evaluation of the concentration ratio between milk and plasma. Rasmussen 7–9 observed the influence of pH differential between milk and plasma and assumed that only the unbound, unionized form of a molecule may traverse the membranes in the Keywords: QSAR; Human breast milk; CODESSA-PRO; Multilinear regression. * Corresponding author. Tel.: +1 352 392 0554; fax: +1 352 392 9199; e-mail: katritzky@chem.ufl.edu