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.

Oral Biodisposition Study of Ritodrine after Its Buccal Administration in Rats.

BACKGROUND: In the previous study, buccal absorption of ritodrine (RD) hydrochloride was reported in vivo. As a result, buccal dosing of RD solution was found to be useful for the maintenance of effective plasma concentration. However, in order to find out the dosing schedule more clearly, it is important to clarify the in vivo drug behavior. OBJECTIVE: The biodistributions of RD in oral cavity and buccal mucosal were investigated in order to understand the in vivo drug behavior after the buccal application. METHOD: The pharmacokinetic parameters for 0 - infinite time and the absorption rate were calculated based on the plasma level-time profiles in the intravenous (1 mg/kg), buccal (10 mg/kg) and intragastric (10 mg/kg) dosings using rats. The drug concentrations in buccal mucosa and the remaining drug amounts in the oral cavity were examined over time after the buccal administration. From those drug distributions and drug absorption rates, the kinetic aspects were discussed. RESULTS: The absolute bioavailabilities of RD were 14.2% and 4.3% in buccal and intragastric (0.043) administrations, respectively. The oral cavity concentration was quickly eliminated within 0.5 h, and then decreased slowly. In both the administration site and distant region, the mucosal RD concentrations were observed at several dozen to approximately 100 µg/g during 0.5-4 h, indicating the rapid diffusion in the oral cavity. For both the mucosal parts, the buccal mucosal level reached a maximal level at 1 h, and then was slowly eliminated. The absorption rates were not related linearly to the buccal mucosal level, suggesting that the other mucosal parts such as sublingual mucosa and tongue ventral surface should be involved considerably in the absorption. CONCLUSION: The changes in RD concentration in oral cavity and oral mucosa showed the drug behavior in vivo. The present study revealed that RD is not accumulated in the buccal mucosa and transfers relatively fast from the oral mucosa to systemic circulation. It was suggested that the buccal dosing of RD should be acceptable even in the repeated manner as an alternative to the intravenous or oral administration of RD.

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.

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.

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 and pharmacodynamics of ritodrine hydrochloride administered orally and intramuscularly to female healthy volunteers.

Ritodrine hydrochloride ((R,S)-4-hydroxy-alpha-[1-[2-((4-hydroxyphenyl)ethyl]amino)ethyl]benzenemethanol, CAS 26652-09-5) is a direct-acting sympathomimetic agent with a predominant beta-adrenergic activity and a selective action on beta2-receptors. A clinical trial was carried out to investigate the pharmacokinetics, pharmacodynamics and safety of ritodrine hydrochloride administered at the doses of 10, 20 and 30 mg p.o. and 10 mg by i. m. route. A four-way randomised crossover design was adopted on 12 healthy female volunteers with a wash-out of at least 14 days. Concentrations of ritodrine and of the pool of ritodrine in plasma and concentrations of the pool of ritodrine in urine of volunteers were bioassayed with tandem mass spectrometry. The following pharmacokinetic parameters were calculated, using the non-compartmental model: Cmax, AUC0-t, AUC0-INF, t1/2, Vd/f, and Aet after each administration. The distribution volume of ritodrine proved to be about 3 times higher than that of the pool of ritodrine after i. m. injection, confirming the good permeability of ritodrine that massively enters tissue compartments. Statistical analyses of pharmacokinetic parameters ascertained that the p. o. absorption of ritodrine hydrochloride was linearly related with the doses administered in the 10-30 mg range. The pharmacodynamic parameters evaluated complied with the mechanism of action of this drug.

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 in twin pregnancy patients.

OBJECTIVES: To establish a rational ritodrine therapy in relation to serum ritodrine concentration, we examined 14 twin pregnancy patients and determined their pharmacokinetic data. METHODS: We measured serum concentrations of ritodrine in twin pregnancy patients using high-performance liquid chromatography (HPLC). RESULTS: The twin pregnancy patients all exhibited linear ritodrine pharmacokinetic profiles. There was a statistically significant but slight negative correlation between gestation period and ritodrine clearance (y=-0.038x+2.75, r=0.349, p<0.001) among all patients. However, when analyzed on an individual basis, there was a high correlation found in three of the 14 patients. CONCLUSION: 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.

Implicación de los betamiméticos en el aumento de la supervivencia tras procedimientos quirúrgicos en el feto del cordero común / Involvement ofbetamimetics as increase of survival during fetal surgery in sheep

La cirugía fetal es actualmente una realidad terapéutica en algunos centros a nivel mundial. La investigación en este campo obliga a utilizar modelos animales experimentales. El problema principal de estos modelos es el control del trabajo de parto prematuro. Objetivos: Encontrar un régimen tocolítico que minimice las pérdidas fetales tras procedimientos quirúrgicos en el feto de oveja común. Material y métodos: Partiendo de dos grupos de ovejas gestantes elegidas mediante método aleatorio simple, a los 70 días de gestación son intervenidas, realizándose un mielomeningocele quirúrgico en el feto. Durante el postoperatorio se monitorizó los valores bioquímicos de urea y creatinina en líquido amniótico, mediante la realización de una amniocentesis semanal guiada con control ecográfico. El grupo A (n =6) fue tratado preoperatoriamente con indometacina y postoperatoriamente con sulfato de magnésico, que se mantenía durante 24 horas. En el grupo B (n = 8) se utilizó diclofenaco preoperatorio asociado a ritodrina postoperatoria, mantenida hasta la finalización de la gestación. Resultados. En el grupo A encontramos una supervivencia del 50% (n= 3), siendo en el grupo B del 87% (n = 7). El peso comparado de los fetos en ambos grupos fue menor en los tratados con ritodrina, así como también fue menor la ganancia ponderal de las madres de dicho grupo. Encontramos un incremento en la frecuencia cardíaca materna y fetal en el grupo B. Los valores de urea y creatinina en líquido amniótico fueron mayores en el grupo B, aunque no de forma significativa. Conclusión: El uso de ritodrina como agente tocolítico reduce las pérdidas fetales de forma significativa en el modelo de cirugía fetal basado en la oveja común. La ritodrina aumenta el gasto cardíaco materno y fetal ocasionando pérdidas de peso (AU)

Alterations in ovine myometrial beta-adrenergic cascade do not mediate tachyphylaxis to ritodrine.

The purpose of this study was to determine in vivo the dose response relationship between beta-adrenergic receptor (BAR) agonist concentration and various elements of the BAR cascade: receptor density, hormone-stimulable adenylyl cyclase activity, and contraction inhibition. A previously described, chronically-catheterized ovine model was used. Ritodrine was infused continuously over 24 h in 22 mixed-breed sheep. Each animal received a single, constant infusion rate. Myometrial biopsies were obtained before and after the drug infusions. BAR density was determined using tritiated dihydroalprenolol. Adenylyl cyclase activity was determined using the Gilman competitive protein-binding assay. Intermittent oxytocin boluses were given into the maternal aorta and contractile response was determined. Infusion rates of 0.06-4.0 micrograms/kg/min yielded steady-state ritodrine serum concentrations of 5-168 ng/ml. No significant correlation was found between the ritodrine concentration and the magnitude of decrease in BAR density. Significant correlations existed, however, between the ritodrine concentration and both the magnitude of decrease in adenylyl cyclase activity and the loss of contraction inhibition. There was no correlation noted between the BAR cascade alterations and the loss of contraction inhibition. Despite significant reductions in receptor density (down regulation) and dose-related reductions in hormone-stimulable adenylyl cyclase activity (uncoupling), ritodrine at low concentrations was still able to inhibit oxytocin-induced contractions, i.e., tachyphylaxis did not occur. Tachyphylaxis appeared to correlate only with the serum ritodrine concentration. Hence, alterations in the BAR cascade do not necessarily equate with a loss of end-organ response (tachyphylaxis). Previous concepts based on in vitro studies about the interaction of the BAR agonist with its receptor, the subsequent generation of intracellular messengers, and the resultant end-organ response may not apply in the intact animal.

[Effect of ritodrine hydrochloride on fetal perfusion pressure in dually perfused human placenta].

Ritodrine hydrochloride is widely used in clinical obstetrics for the prevention of premature labor, but the knowledge of its effect on fetal circulation is limited. The purpose of this study was to elucidate changes in vascular resistance in the fetal placental circulation by using the dually perfused human placenta in vitro. The viability of the perfused placenta was maintained during the experiments because the production rate of hCG was constant. The transfer of ritodrine hydrochloride was observed and its concentration on the fetal side was about one third of maternal side at 120 min subsequent to the injection. The fetal perfusion pressure during the control period was 38.6 +/- 7.0 mmHg (mean +/- S.D., n=3). After the addition of ritodrine hydrochloride to the maternal circulation, the fetal perfusion pressure was decreased dose-dependently. The pressure was 95.4 +/- 1.8% at 80 ng/ml of ritodrine hydrochloride which was within the clinical concentration limits. It is concluded that ritodrine hydrochloride acts as a vasodilator on the fetal vasculature in the human placenta.

Currently recommended oral regimens for ritodrine tocolysis result in extremely low plasma levels.

OBJECTIVE: Our aim was to compare plasma drug levels in patients receiving ritodrine intravenously with those in patients receiving ritodrine orally at recommended dosages. STUDY DESIGN: Plasma samples from 20 pregnant patients treated with intravenous ritodrine (50 to 300 micrograms/min), 9 patients treated with oral ritodrine only (60 to 120 mg per 24 hours), and 9 patients treated first with intravenous and subsequently with oral ritodrine were analyzed for ritodrine concentration with the use of high-performance liquid chromatography. RESULTS: Average plasma ritodrine levels of patients receiving different intravenous dosages ranged from 27.8 +/- 3.5 to 113.3 +/- 38.8 ng/ml. Levels during oral therapy ranged between 9.8 +/- 3.2 and 13.8 +/- 4.4 ng/ml. In both modes of drug delivery, concentrations were significantly correlated with doses. In patients treated first with intravenous ritodrine and subsequently with the oral form, plasma concentrations during oral therapy averaged 27.7% +/- 18.8% of those obtained during intravenous infusion. CONCLUSION: Subtherapeutic plasma concentrations might be responsible for the failure to demonstrate clinical benefits of oral ritodrine in prevention of recurrent preterm labor. A twofold to threefold increase in the maximum recommended oral dosage of ritodrine should be considered, especially for patients who had previously required relatively high intravenous infusion rates (> 100 micrograms/min).

Fetal and neonatal excretion of free and conjugated ritodrine.

The ability of the human fetus and neonate to conjugate and excrete ritodrine, a beta 2-sympathomimetic drug, was investigated. Free and conjugated ritodrine concentrations in the plasma, amniotic fluid and urine were measured in 11 mother-infant pairs, to whom intravenous ritodrine had been administered before elective cesarean section at term. Ritodrine was determined by HPLC with electrochemical detection. At delivery, conjugated ritodrine values were significantly higher than those for the free form in maternal and fetal plasma. There were significant positive correlations between the concentrations in the maternal and umbilical vein plasma for both free and conjugated ritodrine. In the amniotic fluid, the total ritodrine concentrations were much higher than those in the fetal plasma, the conjugated form accounting for 90.2% of the total. Furthermore, the percentages of conjugated ritodrine in the amniotic fluid and neonatal urine were significantly higher than the percentage in the maternal urine on the day of birth. In the neonatal urine, the concentrations of free and conjugated ritodrine decreased rapidly after birth as did those in the maternal urine, on day 3 postpartum being less than 2% of the values on the day of parturition. These results indicate that the fetus at term is capable of forming conjugated metabolites of ritodrine and of excreting free and conjugated ritodrine in its urine.

Clearance and disposition of ritodrine in the fluid compartments of the fetal lamb during and after constant rate fetal intravenous infusion.

The disposition of the beta-2 adrenoreceptor agonist, ritodrine, has been examined in the fetal lamb during and after constant rate fetal intravenous infusion (8-24 h). Samples were collected from the fetal femoral artery, umbilical vein, maternal femoral artery, uterine vein, fetal trachea and the amniotic activity for ritodrine quantitation. The amniotic fluid was also analyzed for conjugated metabolites of ritodrine. Ritodrine appears to be cleared across the sheep placenta only to a limited extent (placental clearance 9.2 +/- 2 ml/min/kg; mean +/- S.E.M.). There is, however, significant fetal nonplacental clearance of ritodrine (fetal nonplacental clearance 52.8 +/- 8.0 ml/min/kg). At least part of this clearance appears to be due to fetal drug metabolism, as evidenced by the accumulation of glucuronide conjugates of ritodrine in the amniotic fluid. Ritodrine was also shown to accumulate in the amniotic and fetal tracheal fluids and persist after fetal arterial plasma ritodrine concentrations became undetectable. The accumulation of ritodrine in the tracheal fluid may be of pharmacologic significance, given the well documented, potent effects of beta-2 agonists on fetal lung function and development.

Transplacental transfer of ritodrine and its effect on placental glucose and oxygen consumption in an in vitro human placental cotyledon perfusion.

Maternofetal transfer of ritodrine and its effect on placental glucose and oxygen consumption were studied using a recycling perfusion of maternal and fetal circulations of an isolated cotyledon of a term human placenta. 3H-labeled ritodrine was introduced into the maternal side of the perfusion system. Transfer was calculated from the linear rise of ritodrine concentrations on the fetal side and was found to be 7.31 +/- 1.02 ng/g placental wet weight/min (SEM) when 1.4 micrograms/ml of ritodrine was used (n = 3) and 14.7 +/- 1.06 ng/g placental wet weight/min when the concentration was 2.8 micrograms/ml (n = 5). The antipyrine transfer rate, 4.1 +/- 0.51 mg/kg/min (n = 8), was used to demonstrate perfusion adequacy and served as an internal standard. Upon computing the mass balance of ritodrine and antipyrine at the end of the experiment, it was found that 17% of ritodrine disappeared from the perfusion system compared to 0.7% of antipyrine (p less than 0.01). The introduction of ritodrine into the perfusion system did not affect placental glucose and oxygen consumption rates of 0.35 +/- 0.01 mumol/g/min (n = 7) and 0.19 +/- 0.013 mumol/g/min (n = 5), respectively.

Pharmacokinetics and pharmacodynamics of ritodrine after intramuscular administration to pregnant women.

To define the pharmacokinetics and pharmacodynamics of ritodrine after intramuscular injection, we administered 5 or 10 mg ritodrine into the gluteus or deltoid muscles of 12 pregnant volunteers. Six women received 5 mg and six received 10 mg into each muscle group on different days. We withdrew blood samples before and 12 times in the 6 hours after ritodrine injection. Blood pressure and heart rate were recorded at each time. Ritodrine was measured by high-performance liquid chromatography. Peak ritodrine concentrations (mean +/- SD) after a single 5 mg injection in the deltoid or gluteus were 38 +/- 13 and 26 +/- 8 ng/ml, respectively. After a 10 mg dose in the deltoid or gluteus, peak concentrations were 59 +/- 30 and 47 +/- 22 ng/ml, respectively. Although higher, the peak plasma concentrations after injections into the deltoid were not significantly greater than those after injection into the gluteus. None of the pharmacokinetic parameters differed according to dose or injection site. The pharmacodynamic effects of ritodrine were unaffected by injection site, but ritodrine caused a dose-related increase in heart rate and systolic blood pressure and a dose-related decrease in diastolic blood pressure. After a 10 mg injection, the maximal changes in heart rate, systolic, and diastolic blood pressure were 22%, 10%, and 19%, respectively. However, mean blood pressure was not altered by either the 5 or 10 mg dose. These findings indicate that there are few differences in pharmacokinetic parameters between deltoid and gluteal injection of ritodrine. The single intramuscular injection of 5 or 10 mg ritodrine results in labor-inhibiting concentrations with clinically insignificant cardiovascular effects.

Pharmacokinetics of ritodrine administered intravenously: recommendations for changes in the current regimen.

We define the pharmacokinetics of ritodrine in 13 pregnant women who received the drug intravenously. With constant infusion of 50 micrograms/minute, steady state ritodrine concentrations reached 28 +/- 11 ng/ml (SD) with a range of 15 to 45 ng/ml. This wide variation is a result of differences in plasma clearance, which ranged from 1.0 to 3.3 L/min, mean 1.94 +/- 0.71 L/min. The apparent volume of distribution was 6.95 +/- 3.54 L/kg, indicating that ritodrine is extensively bound to extravascular tissue. When an infusion of ritodrine is stopped, plasma concentrations fall rapidly initially with a distribution half-life of 5.9 +/- 6.0 minutes. After the initial rapid fall, plasma concentrations decrease more slowly with a mean disposition half-life of 156 +/- 51 minutes. On the basis of the pharmacokinetic parameters defined, we recommend that the current infusion regimen for ritodrine be changed. The infusion rate of ritodrine should start at 50 micrograms/minute rather than 100 micrograms/minute. The maximal infusion rate of 350 micrograms/minute should be increased and once labor is inhibited, the infusion rate should be reduced.