Placental Transfer of Omeprazole in Maternal and Fetal Sheep

Abstract

The placental transfer of omeprazole was studied over a 4-fold dose range in 7 nonanesthetized near-term pregnant sheep. There was a 5 to 1 maternal to fetal transplacental gradient of steady-state total omeprazole concentrations after both low dose (maternal plasma 556 ± 361 ng/ml, fetal plasma 101 ± 57 ng/ml) and high dose (maternal plasma 2,660 ± 1,130 ng/ml, fetal plasma 563 ± 182 ng/ml). Although this was in part due to differences in plasma protein binding between mother (unbound fraction 6.6 ± 5.5%) and fetus (unbound fraction 11.9 ± 2.4%), a 2 to 1 maternal to fetal gradient of steady-state unbound omeprazole concentration was still present (144 ± 73 ng/ml vs. 64 ± 32 ng/ml). Fetal omeprazole total plasma concentrations correlated strongly with maternal total drug concentrations (r = 0.84, p < 0.025) and with the inverse of maternal omeprazole total systemic clearance (r = 0.77, p < 0.05), indicating that maternal drug disposition was a major determinant of fetal omeprazole plasma concentrations. Urinary clearance of omeprazole was low in both mother (0.137 ± 0.046 ml/min) and fetus (0.067 ± 0.039 ml/min). This study demonstrates that the fetus is exposed to about one half of the unbound omeprazole concentration in maternal plasma and suggests that the extent of fetal exposure is largely dictated by maternal drug distribution and elimination characteristics. Introduction

Omeprazole for Refractory Gastroesophageal Reflux Disease during Pregnancy and Lactation

“…Because breast milk has a slightly lower pH than that of plasma, it might be anticipated that weak bases such as omeprazole would achieve higher concentration in breast milk. However, because omeprazole is highly protein-bound in plasma, it could be argued that only a small fraction is available for diffusion and that the actual concentration in breast milk is low (12). In support of the latter hypothesis, we demonstrated a peak concentration of omeprazole in expressed breast milk of 58 nM, 3 h after ingestion of a 20 mg tablet.…”

“…Animal studies suggest that placental transfer may expose the fetus to plasma omeprazole levels of approximately one half those detected in the mother (12). However, it is not known whether omeprazole is teratogenic.…”

The Safety of Fetal Exposure to Proton-Pump Inhibitors During Pregnancy

“…Omeprazole has been shown to cross the placenta of sheep and in humans [4,5]; reproductive toxicology studies have failed to show that PPIs are teratogenic [6]. Recently, Pasternak et al published the results of a large computerized database cohort suggesting fetal safety of PPIs [7]; however, their study did not include data on medical abortions, which may lead to bias toward the null hypothesis [8].…”

The safety of proton pump inhibitors in pregnancy

“…2 Omeprazole, one of the most widely used proton pump inhibitors, crosses the human placenta. 3 Studies of the use of omeprazole in human pregnancy have mainly been related to intensive care treatment, 4 and data from human follow-up studies have mainly been restricted to two recently published studies. 5,6 We therefore assessed the safety of proton pump inhibitors in a population-based cohort of Danish pregnant women.…”