Despite the prevalence of depression in lactating mothers, there is a lack of knowledge about the excretion of antidepressants into breast milk and its potential adverse effects on infants. This creates concern, making depressed lactating mothers more likely to avoid pharmacological treatment. Clinical lactation studies are the most accurate and direct method to predict and demonstrate the excretion of antidepressants into human breast milk, and results from clinical studies can be included in drug labels to help physicians and patients make decisions on antidepressant use during lactation. However, there are limited clinical trials and studies on the pharmacokinetics of antidepressants in lactating women because of a lack of enrollment and ethical and confounding factors, creating a lack of knowledge in this area. To bridge this gap in knowledge, alternative methods should be sought to help estimate the antidepressant concentration in breast milk, which is used to assess the safety and transfer of antidepressants into breast milk. We provide a comprehensive review of the usage of these cost-effective, time-efficient, and ethically feasible methods that serve to provide a valuable estimation of the safety and transfer of antidepressants into breast milk before conducting clinical studies.

The two most extensively studied cannabinoids, cannabidiol (CBD) and delta‐9‐tetrahydrocannabinol (THC), are used for myriad conditions. THC is predominantly eliminated via the cytochromes P450 (CYPs), whereas CBD is eliminated through both CYPs and UDP‐glucuronosyltransferases (UGTs). The fractional contributions of these enzymes to cannabinoid metabolism have shown conflicting results among studies. Physiologically based pharmacokinetic (PBPK) models for CBD and THC and for drug–drug interaction studies involving CBD or THC as object drugs were developed and verified to improve estimates of these contributions. First, physicochemical and pharmacokinetic parameters for CBD, THC, and their metabolites (7‐OH‐CBD, 11‐OH‐THC, and 11‐COOH‐THC) were obtained from the literature or optimized. Second, PBPK base models were developed for CBD and THC after intravenous administration. Third, beginning with the intravenous models, absorption models were developed for CBD after oral and oromucosal spray administration and for THC after oral, inhalation, and oromucosal spray administration. The full models well‐captured the area under the concentration–time curve (AUC) and peak concentration (C_max) of CBD and THC from the verification dataset. Predicted AUC and C_max for CBD and 7‐OH‐CBD were within two‐fold of the observed data. For THC, 11‐OH‐THC, and 11‐COOH‐THC, 100%, 100%, and 83% of the predicted AUC values were within two‐fold, respectively, of the observed values; 100%, 92%, and 94% of the predicted C_max values, respectively, were within two‐fold of the observed values. The verified models could be used to help address critical public health needs, including assessing potential drug interaction risks involving CBD and THC.

Determining the amount of a drug transferred into breast milk is critical for benefit-risk analysis of breastfeeding when a lactating mother takes medications. In this study, we developed a human mammary epithelial cell (MEC)-based permeability assay to assess drug permeability across the mammary epithelium. Human MEC cell MCF10F formed tight junctions when cultured on Transwells with culture medium containing insulin, hydrocortisone and epidermal growth factor (EGF). Formation of integral cell barrier and morphology of the cells were confirmed by assessing trans-epithelial electrical resistance (TEER), flux of fluorescent tracers and imaging with transmission electron microscopy (TEM). MCF10F cells showed consistent P-glycoprotein (P-gp) transporter expression when culturing on Transwell inserts versus on petri dish. A few P-gp transporter drug substrates were used to estimate the permeability from this assay. Human plasma and breast milk were used as incubation medium in basolateral and apical chambers respectively to mimic physiological conditions. The predicted milk to plasma (M/P) ratios were reasonably good. The current effort to develop the MEC-based permeability assay to facilitate M/P ratio prediction showed promising results. This assay may have a potential to be developed as a useful in vitro technique for determining the transfer of small-molecule therapeutic drugs into breast milk.