Benzodiazepine Concentrations in the Breast Milk and Plasma of Nursing Mothers: Estimation of Relative Infant Dose.

Objective: Benzodiazepines are common therapies for mental illness and insomnia, and are used during pregnancy and lactation. Although benzodiazepines have been shown to be transferred into breast milk, the amount transferred is small and compatible with breastfeeding. However, information is not available for all drugs. Therefore, we aimed to determine the milk to plasma (M/P) ratio and relative infant dose (RID), which are used as indicators of drug transfer to breast milk, to determine the safety of such drugs for lactating women and breastfeeding infants. Methods: The study comprised of 11 pregnant women who visited the obstetrics department of Hokkaido University Hospital (approval number: 017-0131) and Tenshi Hospital (approval number: 103) for childbirth. The samples were analyzed using liquid chromatography-tandem mass spectrometry, and the M/P ratio and RID were calculated. The condition of the mother and baby at 1 month after delivery was determined from the clinical information. The target benzodiazepines were alprazolam, brotizolam, clonazepam, clotiazepam, etizolam, ethyl loflazepate, flunitrazepam, and lorazepam. Results: For all drugs, the M/P ratios were <1 and remained constant over time. For drugs other than ethyl loflazepate, the RID values were <10%, which are considered safe; however, even with ethyl loflazepate, it was only slightly >10%. No abnormalities were found in breastfeeding infants whose mothers were receiving these medications. Conclusions: The RID results of this study suggest that drug exposure through breast milk is small; thus, maternal drug treatment and breastfeeding are compatible.

Concentration of Sulfate and Glucuronide Conjugates of Ritodrine in Twin Pregnancy.

Ritodrine, a drug for the treatment of threatened premature labor, is a highly selective beta-2 agonist with the major metabolites of sulfate and glucuronide conjugates. This study investigated the continuous evaluation of the concentration of ritodrine conjugates in relation to the clinical course in twin pregnancy. The subjects were 9 twin-pregnancy mothers who delivered after receiving ritodrine treatment between April 2012 and December 2013. Serum ritodrine sulfate and glucuronide conjugates were deconjugated using their specific enzymes. Ritodrine concentration was measured by liquid chromatography-tandem mass spectrometry. The continuous infusion rate of ritodrine was 2.66±0.67 (0.8-3.54) µg/min/kg, and the average concentration of unchanged ritodrine was 118.8±33.2 (63.8-194.0) ng/mL. During the study period between week 32 and week 36 of gestation, the average ratio of unchanged ritodrine concentration and sulfate ritodrine conjugate concentration for weeks 32, 33, 34, 35, and 36 were 1.7, 1.9, 1.5, 1.7, and 1.7 not significant (N.S.), respectively. The average ratio of unchanged ritodrine concentration and glucuronide ritodrine conjugate concentration were 1.8, 2.2, 1.9, 1.8, and 2.1 (N.S.), respectively. No statistical difference was identified in the ratios of unchanged ritodrine concentration and sulfate or glucuronide ritodrine conjugate concentrations. Large individual differences were shown in the concentration of sulfate and glucuronide during the gestational period. No change in the ratio of the formation of ritodrine metabolites was identified as the gestational age progressed.

Stereoselective analysis of ritodrine diastereomers in human serum using HPLC.

A sensitive and selective method has been developed for the determination of ritodrine diastereomers in human serum using high-performance liquid chromatography with a chiral stationary phase column and a fluorescence detector. No interfering peaks from endogenous substances were observed. The method showed good reproducibility and accuracy, and the standard curve was linear up to 100 ng/mL with a correlation coefficient of 0.999. Limit of detection (signal-to-noise = 3) and quantitation (signal-to-noise = 10) were found to be 2 and 5 ng/mL, respectively. This method is suitable for chiral pharmacological and pharmacokinetic studies as well as the therapeutic drug monitoring of ritodrine diastereomers for which no information currently exists.