Pharmacokinetics of betamethasone after maternal or fetal intramuscular administration

OBJECTIVE: The purpose of this study was to determine the pharmacokinetics of betamethasone in maternal and fetal circulations after maternal or fetal intramuscular administration. STUDY DESIGN: Ewes that bore single fetuses underwent surgery at approximately 96 days of pregnancy for the implantation of fetal and maternal vascular catheters. At approximately 103 days, five ewes were injected intramuscularly with betamethasone (0.5 mg/kg body weight) or five fetuses received ultrasound-guided intramuscular injections of betamethasone (0.5 mg/kg estimated fetal weight). Maternal and fetal blood samples were collected serially for the measurement of plasma betamethasone concentrations. RESULTS: Fetal injection caused higher peak fetal betamethasone concentrations (341.2+/-23.7 nmol/L) than maternal injection (37.6+/-3.7 nmol/L; P<.001) and greater cumulative betamethasone exposure. The half-life of betamethasone in the fetal circulation was shorter after fetal injection (1.1+/-0.3 hours) than after maternal injection (8.5+/-2.0 hours; P=.006). CONCLUSION: The duration of fetal and maternal exposure to betamethasone can be minimized by direct fetal intramuscular administration that, in sheep, affords lung maturation without adverse effects on fetal growth.     

Pharmacodynamics of ritodrine in pregnant women during preterm labor

We evaluated the relationship of ritodrine concentration to several maternal variables and to fetal heart rate in 17 women who received the drug for inhibition of preterm labor. Ritodrine was measured by high-performance liquid chromatography with electrochemical detection. Ritodrine increased maternal and fetal heart rate and decreased serum potassium in a dose-related manner, but wide variability was noted between patients and within individual patients. Tachyphylaxis of the maternal heart rate response to continuing treatment with ritodrine was seen in at least seven women. Maternal blood pressure, serum glucose concentration, and frequency of uterine contractions were changed by ritodrine treatment, but the changes in these variables were not closely correlated to the concentration of ritodrine (r less than or equal to 0.30 in all cases). The maximal infusion rate and the concentration of ritodrine in maternal serum after 4 hours of treatment were significantly (p less than 0.001) correlated with the frequency of uterine contractions prior to treatment. Successful inhibition of labor was achieved with serum concentrations of 15 to 31 ng/ml in 10 of 17 women; in six of the other seven women, labor could not be inhibited in spite of serum concentrations of 90 to 146 ng/ml. Side effects, such as hypotension, vomiting, chest discomfort, and shortness of breath, were most commonly observed when the infusion rate and concentration of ritodrine were increasing.     

Cardiac and uterine hemodynamic responses to ritodrine hydrochloride administration in pregnant sheep.

The changes in the maternal circulation following administration of ritodrine hydrochloride were investigated in chronically prepared pregnant sheep. Low infusion rates of ritodrine (see text) elevated the maternal heart rate and cardiac output and decreased peripheral vascular resistance. Stroke work fell while minute work increased. The distribution of uterine blood flow did not change, as measured with microspheres. Simultaneously measured fetal cardiac output and umbilical blood flow were not altered. When ritodrine infusion rates (see text) were increased there was a slight but significant decrease in uterine perfusion pressure, and an increase in uterine vascular resistance with uterine blood flow decreasing. These changes were observed when the ewes were not in labor, and similar changes were again recovered with ewes in labor despite the simultaneous inhibition of uterine contractions. Selective beta blockade with practolol during ritodrine administration decreased the maternal tachycardia without affecting cardiac output, peripheral vascular resistance, or uterine vascular resistance.     

Changes in thyroid status in pregnant women treated with ritodrine

In a clinical study of 17 pregnant women treated with ritodrine, a beta 2-sympathomimetic agent used for tocolysis, thyroid hormone status was assessed longitudinally. This was done in order to verify the hypothesis that an increase in T3 levels could result from adrenergic stimulation, since propranolol, a beta blocking agent, has proved to decrease T3 levels in man. Indeed, a statistically significant increase in T3 serum concentration and in T3/T4 ratio was found on the second day after the start of treatment with ritodrine (p less than 0.02 and less than 0.01 respectively). After discontinuation of treatment a decrease in T3 serum levels, compared to both treatment and pretreatment levels, was observed. The free T4 concentration showed a significant drop after the first week of treatment (p less than 0.01), but no changes were found in T4 and TSH levels. It was concluded that the beta 2-mimetic-mediated changes in thyroid status provide one more reason for restriction of the use of beta-mimetic drugs in hyperthyroidic patients and might offer an additional explanation for the undesirable chronotropic cardiac side-effects of the therapy.     

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.     

Pharmacokinetics of the contraceptive steroids levonorgestrel and gestodene after single and multiple oral administration to women

Little is known about the pharmacokinetics of the two progestins levonorgestrel and gestodene during long-term administration compared with single-dose pharmacokinetics. The predictive value of single-dose administration for the pharmacokinetic behavior of a progestin during long-term treatment was investigated for two triphasic oral contraceptives. One contained levonorgestrel and the other gestodene, each in combination with ethinyl estradiol. In eight Japanese women who received the levonorgestrel-containing formulation over a treatment cycle, steady-state trough levels of levonorgestrel were higher than those obtained by computer simulation based on single-dose administration. An analogous observation was made in a group of 10 white women who received the gestodene-containing formulation. A close correlation between gestodene and sex hormone-binding globulin concentrations was demonstrated for eight subjects; the other two patients already had initially high sex hormone-binding globulin levels. Ethinyl estradiol-induced production of sex hormone-binding globulin seems to be a major factor that contributes to the accumulation of the two progestins in the plasma. Computer simulation, based on single-dose pharmacokinetics, allows an estimation of this contribution.     

Pharmacokinetics of anti-D IgG in pregnant RhD-negative women

Objective To assess the pharmacokinetics of anti-D IgG in pregnant Rhesus D-negative women after intramuscular and intravenous administration of 300 μg of Rhophylac.
Design An open, randomised, multicentre study.
Setting Seven gynaecological practices in Germany.
Sample Fourteen RhD-negative pregnant women at risk of becoming Rhesus D immunised received study drug at 28th week of pregnancy either by intramuscular or intravenous route.
Main outcome measures Anti-D IgG concentrations of serum samples obtained up to 11 weeks following antenatal Rhesus D prophylaxis were quantified by flow cytometry.
Results Mean anti-D IgG concentrations after intravenous and intramuscular administration differed up to seven days post-injection, from two weeks onwards they were comparable to each other. Irrespective of the administration route, anti-D IgG in serum was detectable in all women up to at least nine weeks post-administration.
Conclusions The serum concentrations of anti-D IgG measured after administration of Rhophylac were very similar to those obtained with 300 μg of a different anti-D immunoglobulin product.     

Pharmacokinetics of salbutamol in the pregnant woman after subcutaneous administration with a portable pump.

OBJECTIVE: We sought to determine whether subcutaneous administration of salbutamol resulted in plasma levels comparable to those achieved after intravenous or oral administration. METHODS: Twenty-nine women with preterm labor received subcutaneous infusion of salbutamol through a portable pump. We used three different rates of continuous infusion: a low rate of 3.33 micrograms/minute (20 subjects), an intermediate rate of 6.66 micrograms/minute (four subjects), and a high rate of 9.99 micrograms/minute (five subjects). Plasma salbutamol concentrations were assayed by high-performance liquid chromatography after 48 hours of continuous infusion in the subcutaneous tissue and after bolus injections (184 micrograms in the low-rate group and 368 micrograms in the intermediate- and high-rate groups). RESULTS: Plasma salbutamol concentrations after 48 hours of subcutaneous infusion increased almost linearly with the rate of infusion: 6.29 +/- 1.58, 15.5 +/- 1.0, and 21.7 +/- 4.26 ng/mL in the low-, intermediate-, and high-rate groups, respectively (P less than .001 between the three groups). After bolus injection, maximum plasma concentrations were significantly different between the three groups (P less than .001) and from their respective baseline values (P less than .001): 8.33 +/- 1.9, 18.85 +/- 2.0, and 25.86 +/- 4.8 ng/mL in the low-, intermediate-, and high-rate groups, respectively. CONCLUSION: Subcutaneous tocolysis can provide plasma salbutamol levels similar to the levels obtained orally or intravenously.     

Pharmacokinetics of oral cefatrizine in pregnant and non-pregnant women with reference to fetal distribution

OBJECTIVE: To investigate the effect of gestation on the pharmacokinetics of orally administered beta-lactams, choosing cefatrizine as the model antibiotic. SETTING: A tertiary teaching hospital. DESIGN: Prospective study. METHODS: In 20 women with affected fetuses, 17 by beta-thalassemia major and 3 with congenital malformations, termination of gestation between 19 and 24 weeks was induced by intra-amniotic administration of prostaglandin F(2)(alpha). Pharmacokinetics of cefatrizine in maternal and fetal blood were studied after the administration of three 1 g doses of oral cefatrizine, every 12 h. Twenty female non-pregnant volunteers consisted the control group. RESULTS: Gestation was found to decrease substantially both cefatrizine oral bioavailability and maximum serum plasma concentration (42.8 and 44.5%, respectively) but increased elimination half-life. This effect can be attributed to a substantial increase of the apparent volume of distribution of cefatrizine in relation to a moderate increase of clearance that occurs during pregnancy. Fetal serum cefatrizine levels were lower for the first few hours after administration and then exceeded the corresponding maternal ones. CONCLUSIONS: Our results indicate that gestation decreases the oral bioavailability of cefatrizine. A delay in the maternal drug elimination compared to non-pregnant controls was more pronounced in the fetus.     

ST segment depression in paired electrocardiograms and serum electrolytes in pregnant women receiving intravenous ritodrine

Forty-three women admitted for preterm labor had electrocardiograms and serum potassium and glucose levels determined before and two and four hours after the initiation of intravenous ritodrine tocolysis. The ST segment depression found at two and four hours was significant but not dependent upon a fall in potassium or increase in the heart rate or glucose level. Such symptoms as chest pain and dyspnea were also not dependent upon potassium, glucose or heart rate changes. These findings support the concept of an intrinsic drug effect.     

Metabolism and disposition of ritodrine in a pregnant baboon

Relatively little is known about the detailed metabolism of ritodrine. The aim of this study was to examine ritodrine metabolism and pharmacokinetics in the maternal and fetal baboon. A fetal-maternal model was made with use of Papio anubis at 144 days of gestation. Tritiated ritodrine was injected as an intravenous bolus into the mother. Maternal and fetal blood samples, amniotic fluid, and maternal urine were collected at time intervals. Samples were analyzed by a combination of high-pressure liquid chromatography and radiochromatography. Conjugated metabolites were recovered and characterized by cleavage studies with use of beta-glucuronidase and sulfatase. The distribution half-life of ritodrine in the mother was 6 minutes and the elimination half-life was 61 minutes. Metabolites were found in both fetal serum and amniotic fluid. The concentrations of ritodrine and its metabolites in fetal serum were at or above the concentrations in maternal serum at 2 hours after maternal intravenous injection. The principal metabolite identified was the sulfate conjugate. The fetus appears to accumulate metabolites. These data indicate that ritodrine crosses the placenta and, in the baboon, achieves levels in the fetus equal to or higher than those in the mother.     

Absorption of dihydrotestosterone (DHT) after its intramuscular administration

In order to produce a sustained release system for natural androgens, two groups of six hypogonadal males received intramuscular (IM) 40 mg crystalline dihydrotestosterone (DHT), either with particle size of less than 50 microns (DHT-M) or between 100 and 150 microns (DHT-C). Serum DHT was analyzed through 51 days of follow-up. In the DHT-M group, serum DHT was above pretreatment values for 17 days, whereas in the DHT-C group, this period was extended over 50 days. The area under the serum concentration-time curve and the half-life of absorption calculated for the DHT-C group were greater than those obtained for the DHT-M group (55.1 ng/day/ml and 21 days vs. 14.5 ng/day/ml and 6 days; P less than 0.01). The authors conclude that DHT injection appears to be an effective and convenient technique for restoring serum physiologic DHT levels. This approach is suitable for long-term substitution therapy.