HEPATIC FIRST-PASS UPTAKE OF DIPHENHYDRAMINE - A COMPARATIVE-STUDY BETWEEN FETAL AND ADULT SHEEP

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 w hich there is preferential distribution of drug in umbilical venous bl ood to the fetal upper body, as is the case with oxygen and other endo genous substances, Studies were conducted with the histamine H-1 antag onist, diphenhydramine (DPHM), in chronically instrumented nonpregnant and pregnant sheep (115-138 days gestation). Hepatic presystemic DPHM elimination was assessed using simultaneous and separate administrati on of DPHM and stable isotope labeled DPHM ([H-2(10)]DPHM) via the umb ilical vein (test route) and abdominal inferior vena cava (control rou te) in fetal lambs by either bolus injection (N = 6) or SD-min infusio n (N = 5), and in nonpregnant sheep (N = 5), by simultaneous and separ ate bolus injections of the two forms of the drug via the mesenteric v ein (test route) and abdominal inferior vena cava (control route). Wit h the bolus injection protocol, hepatic presystemic elimination was es timated 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 diffe rence in fetal DPHM clearance values for the test and control routes o f administration. To test for isotope effects in the disposition of [H -2(10)]DPHM in the ewe or fetus, both DPHM and [H-2(10)]DPHM were simu ltaneously injected via the inferior vena cava; however, no isotope ef fects were noted. In the ewe, there was extensive (93.2 +/- 1.4%) pres ystemic 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), no r were there differences in the fetal DPHM clearance values estimated from the tarsal and umbilical venous infusions. During the latter expe riments, DPHM levels were higher in the femoral artery than in carotid artery, with both umbilical venous and inferior vena caval drug infus ion, and this was opposite of the differences in the concentrations of glucose, lactate, and oxygen between these two vessels, Thus, there i s extensive hepatic presystemic elimination of DPHM in adult sheep, bu t no evidence for this phenomenon in the fetus. Furthermore, the prefe rential distribution of umbilical venous blood to the upper body of th e fetal lamb does not result in higher drug levels in ascending aortic blood.