Clonidine Pharmacokinetics in Pregnancy

Abstract

ABSTRACT: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 MethodsAfter 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 Ն28%, and were receiving oral clonidine for maternal hypertension. Dosing Regi...

CYP2D6 Mediates 4-Hydroxylation of Clonidine In Vitro: Implication for Pregnancy-Induced Changes in Clonidine Clearance

“…However, clinical observations indicate that higher doses or more frequent dosing of clonidine may be required during pregnancy (Buchanan et al, 2009). Consistent with those observations, we have recently found that apparent oral clearance of clonidine in pregnant women is 80% higher compared with that reported in the literature for men and nonpregnant women (Buchanan et al, 2009).…”

“…Consistent with those observations, we have recently found that apparent oral clearance of clonidine in pregnant women is 80% higher compared with that reported in the literature for men and nonpregnant women (Buchanan et al, 2009). The renal component of clonidine clearance remained unchanged as we described previously (Buchanan et al, 2009), suggesting that alteration in bioavailability and/or nonrenal clearance is responsible for the observed change in clonidine pharmacokinetics during pregnancy. Limited studies have suggested that oral drug absorption is not altered in pregnancy (Anderson, 2005), which leaves modulation of nonrenal clearance as a more likely explanation for the change in oral clonidine clearance in pregnancy.…”

“…However, clinical observations indicate that higher doses or more frequent dosing of clonidine may be required during pregnancy (Buchanan et al, 2009). Consistent with those observations, we have recently found that apparent oral clearance of clonidine in pregnant women is 80% higher compared with that reported in the literature for men and nonpregnant women (Buchanan et al, 2009). The renal component of clonidine clearance remained unchanged as we described previously (Buchanan et al, 2009), suggesting that alteration in bioavailability and/or nonrenal clearance is responsible for the observed change in clonidine pharmacokinetics during pregnancy.…”

“…To verify the in vivo importance of CYP2D6 in the nonrenal clearance of clonidine, we conducted a retrospective analysis of the relationship between CYP2D6 genotypes and the apparent nonrenal clearance of clonidine in our earlier cohort of pregnant mothers (Buchanan et al, 2009). Of the original 17 subjects, 14 of the buccal swabs provided good quality genotyping by real-time PCR.…”

“…Analysis of 4-hydroxyclonidine in the incubation samples was performed by liquid chromatography-mass spectrometry (Buchanan et al, 2009) Genotyping. Genomic DNA was isolated from buccal swabs collected in our earlier clinical study in pregnant women (Buchanan et al, 2009) using Gentra Systems Buccal Cell Kit. DNA integrity was evaluated by agarose gel electrophoresis and A260/A280 ratio (1.8 -2.0).…”