Fetal hepatic drug elimination

The majority of studies of fetal hepatic elimination have concentrated on t he expression and activity of the metabolizing enzymes, but the unique phys iologic milieu of the fetal liver should also be considered. The basic stru cture of the liver is formed by the end of the first trimester. The fetal h epatic circulation differs substantially from that of the adult in that the re is an extra input vessel, the umbilical vein, and there is shunting of 3 0-70% of hepatic blood flow via the ductus venosus, The left and right lobe s of the fetal liver seem to function independently with respect to a varie ty of biochemical parameters, due at least in part to the lower oxygen supp ly to the right lobe. The zonation of drug-metabolizing enzymes along the h epatic acinus, which is prominent in the adult liver, is absent in the feta l liver. Unlike rodent species, the human fetal liver has a significant cap acity for drug metabolism. Of the oxidative enzymes, CYP3A7 accounts for up to 50% of total fetal hepatic cytochrome P450 content. Expression of this enzyme decreases dramatically after birth. CYP1A1 and CYP2D6 have also been detected in human fetal liver, but whether CYP2E1 is expressed remains con troversial. Several other cytochrome P450s have been identified and await c haracterization. Fetal hepatic drug conjugation may prolong fetal exposure to the metabolites produced, which, being more water soluble, do not readil y cross the placenta back to the mother and, if excreted in fetal urine, ca n be recycled in the fetus via amniotic fluid and fetal swallowing. Limited activity of glucuronidation enzymes has been demonstrated in human fetal l iver in contrast to the activity of sulfation enzymes, which is significant . Limited in vivo studies in fetal sheep have demonstrated significant feta l hepatic drug elimination, and this has been confirmed in studies of the i solated perfused fetal sheep liver. Our understanding of fetal hepatic elim ination processes has advanced steadily over the years. Future developments , however, should consider more fully the influence of the unique physiolog ical milieu of the fetal liver, in addition to the expression and activity of drug metabolizing enzymes. (C) 1999 Elsevier Science Inc. All rights res erved.