Short Communication Clonidine Pharmacokinetics in Pregnancy

The objective of this study was to determine the pharmacokinetic parameters of clonidine during pregnancy compared with previously published data in nonpregnant subjects. Serial blood and urine samples were collected in 17 women during mid to late pregnancy over one steady-state dosing interval to determine clonidine noncompartmental pharmacokinetic parameters (n 17) and creatinine clearance. In six of these pregnant subjects, maternal and umbilical cord (venous and arterial) plasma samples were collected at the time of delivery for measurement of clonidine concentrations. Clonidine apparent oral clearance was found to be 440 168 ml/min during pregnancy compared with 245 72 ml/min as previously reported in nonpregnant subjects (p < 0.0001) (Cunningham et al., 1994). There was a strong correlation (r 0.82, p < 0.001) between clonidine renal clearance, adjusted for variation in glomerular filtration rate, and urine pH. Umbilical cord to maternal plasma clonidine concentration ratios were 1.0 0.1 (arterial) and 1.0 0.1 (venous). In conclusion, clonidine is cleared more rapidly in pregnant women than in nonpregnant subjects. At the time of delivery, the fetus is exposed to similar plasma clonidine concentrations as the mother. Chronic hypertension during pregnancy is associated with complications, including fetal growth restriction, premature birth, preeclampsia, placental abruption, hypertensive crisis, and in some cases fetal demise. Very little information is available on the pharmacokinetic changes that occur for antihypertensive medications during pregnancy. Clonidine, a centrally acting, -2 adrenergic agonist, has been used for the treatment of hypertension during pregnancy (Kobinger, 1978; Hartikainen-Sorri et al., 1987). In the nonpregnant population, approximately 60% of clonidine is eliminated unchanged by the kidneys (Davies et al., 1977). There are significant changes in kidney function during pregnancy, with creatinine clearance reported to increase by 50 to 60% (Davison and Noble, 1981). The pharmacokinetics of clonidine have not been studied during pregnancy. The objective of this study was to characterize the pharmacokinetics of clonidine during pregnancy. Materials and Methods After receiving written informed consent from patients, we examined steady-state pharmacokinetics of orally administered clonidine in the plasma of 17 pregnant women receiving clonidine during mid pregnancy (22–26 weeks gestation) or late pregnancy (34–38 weeks gestation). Six of these women participated in maternal and umbilical cord (arterial and venous) plasma sample collections at the time of delivery for measurement of clonidine concentrations. Gestational age was based on the last menstrual period or early ultrasound dating. Subject Selection. This study was approved by the University of Washington Investigational Review Board. Subjects were eligible to participate if they were pregnant, 18 years of age, had a hematocrit 28%, and were receiving oral clonidine for maternal hypertension. Dosing Regimen. Oral clonidine therapy was not altered for study purposes. Dosages ranged from 0.15 to 0.30 mg per day, given in divided doses. The duration of the pharmacokinetic study was dependent on the subject’s dosage interval, which ranged from 6 to 12 h. For 3 days before the study, oral clonidine tablets, from the same manufacturing lot, were provided. Subjects recorded the time of each dose on a study calendar. Subjects took their morning clonidine dose within 30 min of 8:00 AM. Subsequent doses were taken within 30 min of scheduled administration times. On the morning of the pharmacokinetic study, subjects were asked to fast, with the exception of clear liquids, for 5 h before clonidine administration until 1 h after dosing. Sample Collection. Serial plasma samples were collected at the following times: 0, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, and 12 h postdosing, or truncated to correspond to the subject’s dosing interval. Urine was collected over one dosing interval to determine clonidine renal clearance and creatinine clearance. Plasma samples, maternal and umbilical cord (arterial and venous), were collected at the time of delivery for quantifying clonidine concentrations. All samples were stored at 80°C until sample analysis. Clonidine Concentrations. Plasma clonidine concentrations were quantified using a validated liquid chromatography/mass spectrometry (LC/MS) assay. In brief, 250 l of plasma samples was mixed with 500 pg of internal standard (clonidine-d4) in 500 l of sodium carbonate (0.1 M) (pH 9.3) and 3 ml of heptane/isoamyl alcohol (98.5:1.5). Standards were prepared by spiking blank plasma with 0, 12.5, 25, 50, 100, 200, 250, 375, 500, and 750 pg of clonidine. Samples were shaken on a horizontal shaker for 15 min at room temperature. After centrifugation (1500g for 10 min), the samples were frozen on dry ice and the organic layer decanted to a clean culture tube. Two This work was supported in part by the National Institutes of Health National Institute of Child Health and Human Development [Grant 5U10-HD047892] (Unit Network Obstetric-Fetal Pharmacology Research); the National Institutes of Health National Center for Research Resources [Grants T32-RR023256, M01-RR00037, RR023256]; and the University of Washington Multidisciplinary Predoctoral Research