ESTIMATION OF TRANSPLACENTAL AND NONPLACENTAL DIPHENHYDRAMINE CLEARANCES IN THE FETAL LAMB - THE IMPACT OF FETAL FIRST-PASS HEPATIC DRUG UPTAKE

Previous estimates of maternal and fetal placental and non-placental c learances in pregnant sheep using a two-compartment open model have re vealed higher values of fetal placental clearance (CLfm) compared to t he maternal placental clearance (CLmf) for most drugs. This includes t he antihistamine diphenhydramine (DPHM), which also has the highest we ight-corrected fetal non-placental clearance (CLfo) among the drugs st udied. This study was designed to determine the reasons for this CLfm - CLmf difference and to identify the sites of high CLfo for DPHM, DPH M and a stable isotope-labeled analog, [H-2(10)]DPHM, were simultaneou sly infused to steady state to the mother and fetus, respectively, in five pregnant sheep. CLmf, CLfm, CLmo and CLfo averaged 50.3 +/- 13.2, 214.4 +/- 30.8, 36.6 +/- 1.9 and 109.8 +/- 22.3 ml/min-l/kg(-1), resp ectively. By measuring diphenylmethoxyacetic acid and [H-2(10)]dipheny lmethoxyacetic acid levels in samples obtained from our previous study of fetal hepatic first-pass DPHM uptake, the hepatic first-pass extra ction ratio of the drug from umbilical venous blood was estimated to b e 0.44 +/- 0.05. This can account for virtually all of CLfo. Fetal hep atic first-pass uptake of maternally derived DPHM in the paired infusi on study reduces the fetal/maternal plasma DPHM concentration ratio an d results in significant underestimation of CLmf. When the CLmf estima te is corrected for this factor and for maternal-fetal DPHM plasma pro tein binding differences, its value approaches CLmf. Fetal hepatic fir st-pass uptake may also be a factor in the underestimation of CLmf for most of the other drugs, Conversely, a lower value of CLmf compared w ith CLfm provides evidence for significant fetal hepatic uptake of the se compounds.