Abstract

In this study, two factors that could affect fetal drug exposure were examined: 1) the extent of elimination of drug delivered to the fetal liver from the placenta via the umbilical vein; and 2) the degree to which there is preferential distribution of drug in umbilical venous blood to the fetal upper body, as is the case with oxygen and other endogenous substances. Studies were conducted with the histamine H1 antagonist, diphenhydramine (DPHM), in chronically instrumented nonpregnant and pregnant sheep (115-138 days gestation). Hepatic presystemic DPHM elimination was assessed using simultaneous and separate administration of DPHM and stable isotope labeled DPHM ([2H10]DPHM) via the umbilical vein (test route) and abdominal inferior vena cava (control route) in fetal lambs by either bolus injection (N = 6) or 90-min infusion (N = 5), and in nonpregnant sheep (N = 5), by simultaneous and separate bolus injections of the two forms of the drug via the mesenteric vein (test route) and abdominal inferior vena cava (control route). With the bolus injection protocol, hepatic presystemic elimination was estimated by the ratio of the area under the arterial drug concentration vs. time curve for the test and control routes of drug administration, whereas with the fetal infusion study it was calculated as the difference in fetal DPHM clearance values for the test and control routes of administration. To test for isotope effects in the disposition of [2H10]DPHM in the ewe or fetus, both DPHM and [2H10]DPHM were simultaneously injected via the inferior vena cava; however, no isotope effects were noted. In the ewe, there was extensive (93.2 +/- 1.4%) presystemic elimination of DPHM (F 0.068 +/- 0.014). However, in the fetus, this did not occur with bolus drug injection (F = 1.10 +/- 0.07), nor were there differences in the fetal DPHM clearance values estimated from the tarsal and umbilical venous infusions. During the latter experiments, DPHM levels were higher in the femoral artery than in carotid artery, with both umbilical venous and inferior vena caval drug infusion, and this was opposite of the differences in the concentrations of glucose, lactate, and oxygen between these two vessels. Thus, there is extensive hepatic presystemic elimination of DPHM in adult sheep, but no evidence for this phenomenon in the fetus. Furthermore, the preferential distribution of umbilical venous blood to the upper body of the fetal lamb does not result in higher drug levels in ascending aortic blood.