| While the use of GTN in pregnancy continues to increase, according to the literature, no studies have reported the fetal and maternal steady-state pharmacokinetics of GTN during maternal administration. Here we determine that the fetal to maternal (F:M) plasma GTN concentration [GTN] ratio in the fetal sheep was 20% during maternal GTN infusion at a previously reported tocolytic dose. GTN crosses the ovine placenta extremely rapidly as demonstrated by the steady-state fetal drug concentration after 5 minutes of maternal GTN infusion. In the isolated human cotyledon, during maternal perfusion with a tocolytic GTN concentration, the F:M [GTN] was approximately 20%. This F:M [GTN] ratio indicates that GTN crosses the human and ovine placentas with the same kinetic profile, and likely via the same mechanism. Next we obtained human preterm fetal blood samples from patients undergoing investigative fetal blood sampling for clinical assessment for other reasons. These patients received transdermal GTN at the proposed tocolytic dose (0.4 mg/hr) in advance of the procedure. While GTN was quantified in the maternal vein, GTN was detected in the fetus, but the levels were not quantifiable. Therefore, the human F:M [GTN] ratio was < 25%, which is essentially the same as the ratios reported in our previous studies. The lack of changes in fetal and maternal heart rates and mean arterial pressures demonstrate that at this dose of GTN, no cardiovascular effects occur.; From the literature, GTN biotransformation is augmented at low oxygen levels. This may present a concern because the fetus operates at much lower pO2 compared to the adult. The incubation of GTN in human adult and fetal blood at various oxygen levels demonstrated that GTN biotransformation in fetal blood was augmented at very low oxygen, but with physiological oxygen, the fetal and maternal blood biotransformed GTN at the same rate.; Here we demonstrate that maternal tocolytic doses of GTN result in a F:M [GTN] ratio of 20-25%, the fetus biotransforms all of the GTN to which it is exposed, and no fetal vascular effects occur. |
