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 nonplacental clearances in pregnant sheep using a two-compartment open model have revealed higher values of fetal placental clearance (CLfm) compared to the maternal placental clearance (CLmf) for most drugs. This includes the antihistamine diphenhydramine (DPHM), which also has the highest weight-corrected fetal nonplacental clearance (CLfo) among the drugs studied. This study was designed to determine the reasons for this CLfm - CLmf difference and to identify the sites of high CLfo for DPHM. DPHM and a stable isotope-labeled analog, [2H(10)]DPHM, were simultaneously 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(-1)/kg(-1), respectively. By measuring diphenylmethoxyacetic acid and [2H(10)]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 CLfo. 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 CLmf. When the CLmf estimate is corrected for this factor and for maternal-fetal DPHM plasma protein binding differences, its value approaches CLfm. Fetal hepatic first-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 with CLfm provides evidence for significant fetal hepatic uptake of these compounds.
Kumar
S
S
Division of Pharmaceutics and Biopharmaceutics, Faculty of Pharmaceutical Sciences, University of British Columbia, Vancouver, Canada.
Tonn
G R
GR
Kwan
E
E
Hall
C
C
Riggs
K W
KW
Axelson
J E
JE
Rurak
D W
DW
D000818:Animals; D001798:Blood Proteins / Q000378:metabolism; D004155:Diphenhydramine / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics*; D005260:Female; D008099:Liver / Q000196:embryology* / Q000378:metabolism*; D008431:Maternal-Fetal Exchange; D010920:Placenta / Q000378:metabolism*; D011247:Pregnancy; D011270:Pregnancy, Animal; D011485:Protein Binding; D012756:Sheep / Q000196:embryology*; D014471:Umbilical Veins
D001798:Blood Proteins; D004155:Diphenhydramine