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. The study comprised 11 pregnant women who visited the obstetrics department of Hokkaido University Hospital and Tenshi Hospital 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. For all drugs, the M/P ratios were <1 and remained constant over time. For drugs other than ethyl loflazepate, the RID values were less than 10%, which are considered safe; however, even with ethyl loflazepate, it was only slightly over 10%. No abnormalities were found in breastfeeding infants whose mothers were receiving these medications. The RID results of this study suggest that drug exposure through breast milk is small; thus, maternal drug treatment and breastfeeding are compatible. Good Good Clonazepam Flunitrazepam 1 No change Breast milk & formula milk Breast milk Good Good Etizolam 1 1.5 Breast milk Breast milk Good Worsening Lorazepam 0.5 No change Breast milk & formula milk Breast milk & formula milk Good Worsening Lorazepam Ethyl loflazepate 0.5 No change Breast milk Breast milk & formula milk Good Good Flunitrazepam 1 No change Breast milk Breast milk Good Good 10 Lorazepam 0.5 No change Breast milk & formula milk Breast milk & formula milk Good Good 11 Brotizolam 0.25 0.125 Breast milk & formula milk Formula milk (main) Good Good

Due to a decrease in total body clearance in three of the 14 patients, overall serum concentration of ritodrine increased at the end of the pregnancies. To further characterize ritodrine kinetics, additional studies are needed to determine an effective and safe therapy for ritodrine use in twin pregnancy patients.

Aim : To determine the pharmacokinetics of ritodrine in singleton and twin pregnancies. Methods : We treated 105 pregnant women(with singletons, n＝67 ; with twins, n＝38)with continuous infusion of ritodrine and then measured steady-state serum ritodrine concentrations using HPLC. Results : Ritodrine clearance(mean±SD)was significantly lower in women who delivered twins than in those who delivered singletons(1.59±0.30 vs. 1.75±0.43 L／h／kg ; p＜0.001). Serum ritodrine concentration did not differ significantly between women who delivered preterm singletons and those who delivered preterm twins (97.5±61.1 vs. 89.6±50.4 ng／mL ; p＝NS), but was significantly higher in women who delivered twins at term than in those who delivered singletons at term(85.8±39.7 vs. 65.7±38.7 ng／mL ; p＜0.001). Conclusion : Ritodrine clearance was lower in twin pregnancies than in singleton pregnancies. The dose of ritodrine administered to maintain pregnancy should be controlled taking into account singleton or twin pregnancy. (Jpn J Clin Pharmacol Ther 2013 ; 44(5) : 389-394)

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-tonoise = 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. IntroductionRitodrine itself contains two asymmetric carbons. For clinical use, one of its asymmetric centers is fixed in one configuration, thus, there are two diastereomers of (1RS, 2SR)-erythro-1-(4-hydroxyphenyl)-2-[2-(4-hydroxyphenyl)ethylamino]propanol-1-ol) and for which the racemate is administered as a hydrochloride salt treatment in pregnancies that are threatened by abortion (Figure 1). The effectiveness correlation and pharmacodynamics for the treatment of threatened abortion and the measured serum concentration of racemic ritodrine has been previously demonstrated (1,2). Linear pharmacokinetic behavior and decreased clearance of retodrine diastereomers that are commercially available have been found in the late gestation period in twin pregnancy patients (3).Among the numerous pharmaceuticals that have chiral centers, it has been reported that the different enantiomers and/or diastereomers may have different in vivo pharmacokinetics and clinical effects (4-6). Separation of the reference standards of ritodrine diastereomers have been reported employing capillary electrophoresis, but their sensitivity was not enough to measure the concentrations of ritodrine diastereomers in biological fluids including serum or plasma, and no data of chiral ritodrines has been demonstrated after extraction from biological fluids (7,8).Yamasaki et al. have a U.S. patent for therapeutic compositions and use and method of preparation of (-)-ritodrine (9). They have established to resolve ritodrine diastereomers by the selective crystallization method as well as by chromatography, employing optical active columns including Chiralcel OJ and AJ (Daicel Chemical, Tokyo, Japan) at normal phase mode, but detailed procedures are not presented in their patents.They have also demonstrated that suppressing 50% of the contraction of an isolated myometrium caused by oxytocin (IC 50 ) of (-)-ritodrine had an intensity of about 2.6-times that of racemic ritodrine in rats whereas that of (+)-ritodrine had 1/15 activity of racemic ritodrine (9). On comparing the relaxation effects on the isolated tracheal muscle via IC 50 , (-)-ritodrine had the highest activity, of which intensity was about 2.3-times that of racemic ritodrine. (+)-Ritodrine has the lowest activity in the tracheal muscle and the i...

No abstract