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.

These results indicate that the clinical effectiveness of ritodrine diastereomers should be evaluated and that administration guidelines should be established based upon serum concentrations so that ritodrine can be more effectively administered to pregnant patients carrying either singletons or twins.

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...