Vol. 282, Issue 2, 617-632, 1997

Estimation of Transplacental and Nonplacental Diphenhydramine Clearances in the Fetal Lamb: The Impact of Fetal First-Pass Hepatic Drug Uptake¹

Sanjeev Kumar² , George R. Tonn³ , Eddie Kwan, Caroline Hall, K. Wayne Riggs, James E. Axelson and Dan W. Rurak⁴

Division of Pharmaceutics and Biopharmaceutics, Faculty of Pharmaceutical Sciences (S.K., G.R.T., K.W.R., J.E.A.), and Department of Obstetrics and Gynecology, Faculty of Medicine (E.K., C.H., D.W.R.), University of British Columbia, Vancouver, B.C., Canada

Previous estimates of maternal and fetal placental and nonplacental clearances in pregnant sheep using a two-compartment open model have revealed higher values of fetal placental clearance (CL_fm) compared to the maternal placental clearance (CL_mf) for most drugs. This includes the antihistamine diphenhydramine (DPHM), which also has the highest weight-corrected fetal nonplacental clearance (CL_fo) among the drugs studied. This study was designed to determine the reasons for this CL_fm  CL_mf difference and to identify the sites of high CL_fo for DPHM. DPHM and a stable isotope-labeled analog, [²H₁₀]DPHM, were simultaneously infused to steady state to the mother and fetus, respectively, in five pregnant sheep. CL_mf, CL_fm, CL_mo and CL_fo averaged 50.3 ± 13.2, 214.4 ± 30.8, 36.6 ± 1.9 and 109.8 ± 22.3 ml/min¹/kg¹, respectively. By measuring diphenylmethoxyacetic acid and [²H₁₀]diphenylmethoxyacetic acid levels in samples obtained from our previous study of fetal hepatic first-pass DPHM uptake, the hepatic first-pass extraction ratio of the drug from umbilical venous blood was estimated to be 0.44 ± 0.05. This can account for virtually all of CL_fo. Fetal hepatic first-pass uptake of maternally derived DPHM in the paired infusion study reduces the fetal/maternal plasma DPHM concentration ratio and results in significant underestimation of CL_mf. When the CL_mf estimate is corrected for this factor and for maternal-fetal DPHM plasma protein binding differences, its value approaches CL_fm. Fetal hepatic first-pass uptake may also be a factor in the underestimation of CL_mf for most of the other drugs. Conversely, a lower value of CL_mf compared with CL_fm provides evidence for significant fetal hepatic uptake of these compounds.