Ritodrine pharmacokinetics in twin pregnancy patients

Biological & Pharmaceutical Bulletin

Fujieda

et al. 2017

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.

Section: Discussionmentioning

confidence: 99%

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confidence: 99%

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confidence: 99%

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Concentration of Sulfate and Glucuronide Conjugates of Ritodrine in Twin Pregnancy

Biological & Pharmaceutical Bulletin

Fujieda

et al. 2017

“…Ballabh et al 6) reported that the half-life of betamethasone is significantly longer in singleton than in twin pregnancies ( reported that the weekly increase in daily dose of insulin between weeks 14 and 27 is two times higher in twin pregnancies compared with singleton. We previously reported that ritodrine clearance decreases as twin pregnancies progress 8) . However, the effects of ritodrine pharmacokinetics and number of fetuses on delivery outcomes have not been reported.…”

Section: Introductionmentioning

confidence: 99%

Difference in Ritodrine Pharmacokinetics between Singleton and Twin Pregnancies

Jpn. J. Clin. Pharmacol. Ther.

Fujieda

et al. 2013

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)

“…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).…”

Section: Introductionmentioning

confidence: 99%

Stereoselective Analysis of Ritodrine Diastereomers in Human Serum Using HPLC

Journal of Chromatographic Science

Ito

et al. 2010

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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...