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.

In vitro and in vivo evaluations of buccal tablet formulations of ritodrine hydrochloride.

Buccal tablets of ritodrine (RD) hydrochloride (HCl), called RD-HCl, were prepared using the direct compression method with alginate (AL), lactose (LC), magnesium stearate (ST), and microcrystalline cellulose (MC) as excipients. The tablets were evaluated based on hardness, and tablets weighing 80 mg and with hardness of greater than 30 N were chosen as appropriate ones. As a result, tablets composed of RD-HCl (4 mg)/LC (38.5 mg)/ST (0.5 mg)/MC (37 mg) and RD-HCl (4 mg)/AL(7 mg)/LC (28.5 mg)/ST (0.5 mg)/MC (37 mg), called D9 and D10, respectively, were selected. These tablets were further evaluated based on in vitro dissolution and in vivo absorption studies in rats. D9 rapidly released RD, achieved an effective plasma concentration from 15 min to 7 h after its buccal administration, and did not exceed the toxic plasma level of 80 ng/mL. D10 gradually released RD, and maintained an effective concentration from 1 h to 7 h after its buccal administration, without exceeding the toxic plasma level. The absorption was more prolonged in D10 than D9. Their in vivo release was considered to be caused gradually from the amount of RD remaining in the oral cavity at 7 h, in particular D10. The superior retention of D10 in plasma and oral cavity appeared to be related to its higher mucoadhesive properties. Although these results were obtained using rats, they suggest that the chosen tablets should have adequate characteristics from the viewpoints of plasma levels.

In vivo absorption study of ritodrine hydrochloride in the buccal administration to rats.

BACKGROUND: Although ritodrine (RD)-hydrochloride (HCl), named RD-HCl, is widely used in the treatment of premature labor by intravenous prolonged infusion or frequent oral dosing of tablets, those administrations often lower patients' quality of life (QOL) or cause undesirable side effects, such as tachycardia; therefore, in this study, the potential usefulness of buccal administration as a novel administration method was examined in vivo. METHOD: First, the HPLC method was assessed for the determination of plasma RD concentration. Then, after RD-HCl solution in saline was administered intravenously (1 mg/kg), intragastrically (10 mg/kg) or buccally (10 mg/kg) in rats, the plasma concentration-time profiles were investigated, and the absorption extent and rate compared. RESULTS: The present modified determination method by HPLC with fluorescence detection (Ex. 278 nm, Em. 306 nm) was suitable to analyze the plasma level at 8-200 ng/mL. Buccal administration gave the best plasma concentration-time profile for maintenance of an effective plasma level and fewer side effects. Absorption rates calculated by deconvolution also supported better sustained absorption in buccal dosing. CONCLUSION: Buccal application of RD-HCl was demonstrated to be a potentially useful dosing method in the treatment of premature labor with RD-HCl.

Pharmacokinetics of ritodrine diastereomers in patients pregnant with singletons and twins.

OBJECTIVE: The chiral pharmacokinetics and pharmacodynamics of ritodrine in patients pregnant with singletons and twins were investigated to determine the optimal use of ritodrine. METHODS: Eight and 20 patients with threatened preterm delivery of singletons and twins, respectively, were infused with ritodrine diastereomers. Serum concentrations of the drug were then measured using a newly developed method of chiral high-performance liquid chromatography. RESULTS: Almost double the dosage of racemic ritodrine was required to prolong pregnancies with twins compared with those of singletons (2.20 +/- 1.06 vs. 1.24 +/- 0.36 microg/min per kilogram; p < 0.0001). The mean ratios of (-)-ritodrine to (+)-ritodrine in singleton and twin pregnancies were 1.17 +/- 0.10 and 1.16 +/- 0.10, respectively. However, the serum concentration and dosage ratio (C/D ratio) of (-)-ritodrine as significantly higher than that of (+)-ritodrine (p < 0.0001), whereas the clearance of (-)-ritodrine was significantly lower than that of (+)-ritodrine (p < 0.0001). A comparison of the gestation period (weeks) and diastereomer clearance did not reveal significant regression in the total analysis of the data obtained from singleton and twin pregnancies. CONCLUSION: 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.

Determination of ritodrine in human plasma by high-performance liquid chromatography coupled with electrospray ionization tandem mass spectrometry.

A simple and sensitive HPLC/MS/MS method was developed and evaluated to determine the concentration of ritodrine (RTD) in human plasma. Liquid-liquid extraction with ethyl acetate was employed as the sample preparation method. The structural analogue salbutamol was selected as the internal standard (IS). The liquid chromatography was performed on a Hanbon Sci. & Tech. Lichrospher CN (150 mm x 4.6 mm, i.d., 5 microm) column (Hanbon, China) at 20 degrees C. A mixture of 0.03% acetic acid and methanol (50:50, v/v) was used as isocratic mobile phase to give the retention time 3.60 min for ritodrine and 2.94 min for salbutamol. Selected reaction monitoring (SRM) in positive ionization mode was employed for mass detection. The calibration functions were linear over the concentration range 0.39-100 ng mL(-1). The intra- and inter-day precision of the method were less than 15%. The lower limit of quantification was 0.39 ng mL(-1). The method had been found to be suitable for application to a pharmacokinetic study after oral administration of 20mg ritodrine hydrochloride tablet to 18 healthy female volunteers. The half-life is 2.54+/-0.67 h.

Ritodrine pharmacokinetics.

The purpose of this study was to add to the limited information available regarding the pharmacology of ritodrine in the peripartum period when treatment fails and labor is not inhibited. Plasma or urine samples from eight parturients and 13 infants were studied; in addition plasma samples at delivery were obtained from a total of 26 mothers and infants. All the mothers received ritodrine in the 24 hours before delivery. Plasma and urine ritodrine (free and conjugated) were determined with HPLC by electrochemical detection. In maternal plasma, an apparent rapid distribution phase with a t1/2 of 32 +/- 21 minutes was followed by a prolonged equilibrium phase with a t1/2 of 17 +/- 10 hours. Seventy-six percent of the ritodrine excreted by the mother was in the form of a conjugate. Ninety percent of the ritodrine excreted by the neonate was also excreted in the form of a conjugate.

Maternal and fetal plasma concentrations of ritodrine.

Previous studies using other beta-adrenergic drugs for tocolysis suggest that if treatment fails and the patient delivers shortly after the therapy is discontinued, there is a direct correlation between neonatal drug concentration and major neonatal complications. In the present study, the disposition of ritodrine was studied in 28 maternal-infant pairs in whom intravenous ritodrine had been administered for clinical indications. The fetal to maternal ratio of ritodrine was 1.17 +/- 0.48. The concentration of ritodrine in both maternal and umbilical vein was found to vary inversely with the length of time the drug was discontinued before delivery. A stepwise multilinear regression revealed that the maternal ritodrine dose in the 24 hours before delivery and the drug discontinuance to delivery interval were both independently related to umbilical vein ritodrine concentrations. When combined, the two variables explained 52% of the variance in umbilical vein ritodrine levels. The frequency of respiratory distress syndrome was increased in the neonates in whom umbilical vein ritodrine was greater than 10 ng/mL, compared with the groups with umbilical vein levels ranging from 3.0 to 10.0 ng/mL. However, neonates with the highest ritodrine concentration were also of lower gestational age (29.4 versus 33.5 weeks, P less than .05) and thus, had greater inherent risk of prematurity-related complications.

Analysis of ritodrine in serum by high-performance liquid chromatography with electrochemical detection.

A sensitive and specific assay for ritodrine in serum was developed using high-performance liquid chromatography (HPLC) with electrochemical detection. Serum samples were alkalinized to pH 9.4 by the addition of a sodium carbonate buffer and extracted with ethyl acetate. The extracts were evaporated to dryness and the residues were reconstituted in the HPLC mobile phase and chromatographed on a octadecylsilane reverse-phase column. The detection of ritodrine was achieved by an electrochemical detector with a glassy carbon electrode. The sensitivity was 0.2 ng for on-column injection. The extraction efficiency was 80%.

Levels of ritodrine hydrochloride in fetal blood and amniotic fluid following long-term continuous administration in late pregnancy.

Placental transfer of ritodrine hydrochloride (ritodrine) was investigated in late-pregnant women following continuous infusion. Five volunteer women undergoing cesarean section received a total dose of 650-5970 mg of ritodrine for 8-49 days. After the infusion was discontinued at cesarean section, maternal and fetal blood and amniotic fluid were collected for later determinations of ritodrine by radioimmunoassay. Maternal serum concentrations of ritodrine were between 99.0-332.4 ng/ml. Serum levels of ritodrine in cord artery and vein were 75.9-250.5 ng/ml and 74.7-213.0 ng/ml, respectively. Ritodrine levels in amniotic fluid ranged from 126.0 to 424.0 ng/ml. The concentration of ritodrine in cord vein to maternal vein (CV/MV) was 0.695 +/- 0.066 (m +/- SE), while the concentration ratio of the amniotic fluid to maternal vein (AF/MV) was 1.719 +/- 0.211. In the present study of continuous administration of ritodrine, remarkably higher concentrations in fetal circulation and amniotic fluid were observed compared to those in cases of short-term infusion.

Concentrations of ritodrine hydrochloride in maternal and fetal serum and amniotic fluid following intravenous administration in late pregnancy.

Seven healthy pregnant volunteers undergoing elective cesarean section at 39-40 weeks of gestation were studied for transplacental passage of ritodrine hydrochloride, which was administered by intravenous infusion at the rate of 72-149 micrograms/min for 161-335 min. The concentrations of ritodrine in the collected maternal and fetal blood and the amniotic fluid were radioimmunoassayed. The levels of ritodrine in maternal serum were between 22.5 and 51.0 ng/ml one hour after the initiation of infusion, 33.7-66.4 ng/ml after 2 h, 18.2-73.6 ng/ml after 4 h and 45.7-189.6 ng/ml at delivery, respectively. The umbilical blood and amniotic fluid concentrations of ritodrine at delivery were between 15.6 and 35.1 ng/ml in arterial blood, 12.5-29.6 ng/ml in venous blood and 10.0-49.1 ng/ml in amniotic fluid. The ratio of umbilical venous blood concentrations to maternal venous concentrations (CV/MV) ranged from 0.066 to 0.544 with the mean of 0.263 +/- 0.063 (M +/- S.E.). The results obtained substantiate the rapid and appreciable transfer of ritodrine to the fetus and amniotic fluid.

A loading-dose infusion scheme for intravenous tocolysis with ritodrine: a pilot study.

A loading-dose infusion scheme for intravenous ritodrine therapy was tested in twelve patients with preterm labour. We started with a rather high (386 micrograms/min) infusion rate, but the moment tocolysis was reached this infusion rate was reduced to a level needed to maintain the plasma concentration then found. Plasma samples of ritodrine were taken the moment tocolysis was reached and in the steady state, and compared with each other and with expected and calculated plasma concentrations. In the dynamic loading phase we found a half-life for ritodrine of 1 h. This half-life of 1 h can be explained by cumulation of ritodrine in the central compartment and is therefore called cumulation t1/2. In developing an infusion scheme with a loading dose for ritodrine, this cumulation t1/2 of 1 h should be taken into account.

Preparation and evaluation of ritodrine buccal tablets for rational therapeutic use.

Ritodrine hydrochloride (RD-HCl) tablets containing alginate (AL) and lactose (LC) with or without microcrystalline cellulose (MC) as excipients were produced as a buccal dosage form. The RD-HCl (2 mg) tablets with AL/LC but no MC swelled and dissolved gradually in the in vitro dissolution test. The tablet showing the fastest dissolution and highest drug release rate, called Tablet A1, was selected as a tablet to show rapid and prolonged absorption. However, in the in vivo buccal absorption test using rats, it could not give a plasma concentration over the human minimal effective level (15 ng/mL). The modified tablet containing AL, LC, MC and RD-HCl (4 mg), named Tablet B/MC, showed better hardness and faster drug release. Tablet B/MC gave a plasma concentration over the human effective level within 15 min, and the plasma concentration was maintained at >15 ng/mL over 4 h. Moreover, the deconvolution analyses demonstrated that a prolonged high absorption rate could be achieved in vivo best with Tablet B/MC. Tablet B/MC improved the pharmacokinetic profile in comparison with Tablet A1 and the solution dosage form. The RD-HCl buccal tablets with AL, LC and MC as excipients are suggested to be possibly useful for the treatment of premature labor.

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.

A loading model for ritodrine administration in preterm labour.

OBJECTIVE: To develop a ritodrine infusion scheme for preterm labour that avoids plasma levels above those needed for tocolysis, requires only one rate adjustment, and is easy to apply in practice. DESIGN: Prospective study of tocolytic effect and plasma ritodrine concentrations during application of the infusion scheme. SETTING: High risk labour ward. SUBJECTS: Consecutive series of 31 women in labour at less than 36 weeks' gestation. INTERVENTION: Loading dose ritodrine infusion followed, as soon as tocolysis is reached, by a decrease in the infusion rate calculated on the basis of the interval between start of treatment and tocolysis. RESULTS: Overall, steady state ritodrine levels were nearly identical to those at the time of tocolysis and correlated well with levels anticipated on the basis of our calculation (n = 30; r = 0.91; P < 0.001). Adjustments during steady state were made in 12 women (40%), but in only two of them within 12 h after tocolysis had been reached. Delivery was postponed for more than 48 h in 29 women (93.5%) and beyond 37 weeks' gestation in 19 (61.3%). CONCLUSION: The loading model is easy to apply, avoids relative overdoses, requires few adjustments, is well tolerated, uses smaller quantities of ritodrine, and results in lower plasma ritodrine concentrations than the conventional infusion scheme.

Intramuscular versus intravenous ritodrine hydrochloride for preterm labor management.

A prospective, interinstitutional comparative trial was undertaken to examine the efficacy, safety, and pharmacodynamics of different administration routes of ritodrine hydrochloride for the management of preterm labor. Forty-five subjects between 20 and 36 weeks' gestation received either intravenous (n = 24) or intramuscular (n = 21) therapy. Successful tocolysis occurred in 14 of 21 (67%) patients in the group treated intramuscularly and in 16 of 24 (67%) patients in the group treated intravenously. A greater mean dose (8.6 versus 3.3 mg/hour) and a higher mean serum concentration (38.9 versus 24.7 micrograms/ml) were needed to achieve successful tocolysis in the intravenous group as compared with the intramuscular group. Patients who did not respond to tocolytic therapy in both groups had levels of ritodrine in the blood either equivalent to or greater than those of subjects who were successfully treated. Analysis of ritodrine levels in the successfully treated intramuscular group demonstrated significant differences in blood levels depending on muscle group used. These differences can be at least partially attributed to higher mean doses administered to patients receiving vastus lateralis injections as compared with those receiving gluteal muscle injections. The results suggest that intramuscular administration of ritodrine is an efficacious and safe route of drug delivery. Additional studies are needed to better define dose-response curves for the intramuscular administration of ritodrine hydrochloride.

Pharmacokinetics of orally administered ritodrine.

The oral dosing regimen for ritodrine was based in large part on kinetic data obtained in nonpregnant subjects. There are limited kinetic data after oral administration of ritodrine in pregnancy. The purpose of the present study was to compare ritodrine kinetics in pregnant and nonpregnant women, evaluate the effect of feeding on ritodrine absorption in pregnant women, and determine if the plasma concentration of ritodrine is proportional to the dose administered in nonpregnant women. Plasma concentrations after a single 20 mg dose of ritodrine were significantly greater in fasting nonpregnant women than in fasting pregnant women. The area under the concentration time curve was 1372 +/- 385 and 1001 +/- 257 ng/ml/min, respectively. In pregnant women ingesting 20 mg of ritodrine, plasma concentrations were not significantly different in the fed or fasted state; plasma concentrations peaked at 11 ng/ml and were less than 3 ng/ml within 4 hours. In nonpregnant subjects the concentration of ritodrine in plasma was proportional to the dose. After ingestion of 10, 20, or 30 mg of ritodrine, the area under the curve was 751 +/- 253, 1372 +/- 385, and 2148 +/- 571 ng/ml/min, respectively. These data indicate that ritodrine concentrations in pregnant women after a 20 mg oral dose are low. Increases in dosage will probably result in proportional increases in plasma concentration. The maximal dose of ritodrine recommended for prevention of recurrent preterm labor should be increased.

Ritodrine serum levels: influence of dose and route of administration.

Serum levels of ritodrine were measured by radio-immunoassay both after single and during chronic administration. In 50 non-pregnant women, the maximum ritodrine levels found after a single dose of 10 mg p.o. were 7.4 +/- 4.7 (ng/ml, +/- SD, n = 10); after 20 mg p.o.: 23.8 +/- 5; after 10 mg i.m.: 30.7 +/- 8.2; after 9.3 mg i.v.: 34.7 +/- 5.5; and after 18 mg i.v.: 75.1 +/- 20.7. Ritodrine determinations during chronic intravenous infusion in 116 pregnant women, at one of the seven infusion rates, showed that the serum steady-state ritodrine levels were proportional to the infusion rates below 400 micrograms/min; above that rate the ritodrine levels flattened out. In 91 pregnant women the ritodrine serum levels were measured at one of a number of different time intervals during chronic oral administration of 5 mg (n = 52) or 10 mg (n = 39) every 4 h. During the chronic oral administration of 10 mg every 4 h, the mean ritodrine levels ranged between 14.3 ng/ml at the peak and 4.6 ng/ml just prior to the subsequent dose. For rapid and controlled tocolysis, intravenous infusion is the most appropriate method; intramuscular administration has no obvious advantage. In this respect, a daily dose of 60 mg, 6 X 10 mg, administered by oral route is probably too low; moreover, the bioavailability of the drug by this route was quite different in two volunteers. Although the absolute bioavailability of the drug was estimated in only a small group of volunteers, consistent results (around 40%) were obtained with the 20-mg oral formulation.

Determination of ritodrine in biological fluids of the pregnant sheep by fused-silica capillary gas chromatography using electron-capture detection.

A sensitive and selective gas chromatographic assay method employing splitless injection, fused-silica capillary columns and electron-capture detection is reported for the quantitation of the tocolytic drug, ritodrine, in a variety of biological fluids obtained from the pregnant ewe and fetus. This method has improved sensitivity and selectivity over previously published assay procedures. A 25 m x 0.31 mm I.D., cross-linked 5% phenylmethylsilicone, fused-silica capillary column was employed for all analyses. Linearity of response was observed over the range 2.5-75 ng of ritodrine base per 0.05-0.5 ml of biological fluid, representing approximately 1-75 pg at the detector. The coefficient of variation was less than 10% over the range 2.5-75 ng of added ritodrine. The minimum quantifiable amount is approximately 2.5 ng from a 0.5-ml biological fluid sample. Applicability of this method to biological fluids, obtained from ovine subjects, is demonstrated by the analysis of samples obtained during the course of ritodrine placental transfer studies.

Effect of pregnancy on ritodrine pharmacokinetics.

Dosing regimens for ritodrine are based in large part on pharmacokinetic studies performed with nonpregnant subjects. Pregnancy is characterized by changes in renal blood flow, plasma volume, protein concentration, and hepatic function. These physiologic changes frequently alter drug pharmacokinetics. To define the effect of pregnancy on ritodrine kinetics, we compared ritodrine pharmacokinetics in four pregnant and four nonpregnant rhesus monkeys. Significant differences were demonstrated in the distribution phase half-life (0.40 +/- 0.08 hours in the pregnant monkeys and 0.21 +/- 0.03 hours in the nonpregnant animals), volume of distribution (1.99 +/- 0.94 L/kg in the pregnant monkeys and 4.75 +/- 0.90 L/kg in the nonpregnant animals), plasma clearance (18.8 +/- 7.1 ml/min/kg in the pregnant monkeys and 27.2 +/- 5.0 ml/min/kg in the nonpregnant animals), and disposition half-life (1.8 +/- 0.4 hours in the pregnant monkeys and 3.3 +/- 0.4 hours in the nonpregnant animals). Pregnant animals receiving ritodrine had higher steady-state plasma concentrations than nonpregnant animals (104 versus 53 ng/ml at an infusion rate of 2 micrograms/kg/min). These data indicate that dosing regimens for ritodrine based on studies of nonpregnant subjects may be subject to considerable error.

Serum levels of ritodrine during oral maintenance therapy.

In order to elucidate some aspects of the efficacy of orally administered ritodrine, serum concentrations of ritodrine were determined during intravenous and oral therapy. Ritodrine serum concentrations during steady-state intravenous therapy (200 micrograms/min) ranged from 91.0 to 123.0 ng/ml. Serum concentrations during maintenance therapy with 120 mg ritodrine per os fluctuate between 3.2 and 30.5 ng/ml, depending on the moment of tablet intake. During oral maintenance therapy a striking correlation was found between the maternal heart rate and the serum concentration of ritodrine. The findings suggest that efficacy of orally administered ritodrine is doubtful on pharmacological grounds.