title: Clearance and disposition of indometacin in chronically instrumented fetal lambs following a 3-day continuous intravenous infusion.
abstract: Indometacin is used in pregnancy for the treatment of premature labour, but there are limited data on the disposition of the drug in the fetus. In order to elucidate fetal indometacin pharmacokinetics at plasma levels and duration comparable with those occurring with use of the drug for tocolysis in humans, indometacin was administered at doses of 1.9 (low dose, LD; n = 5) or 7.5 (high dose, HD; n = 9) microg min(-1) to steady state over a 3-day period in chronically instrumented fetal lambs. Indometacin concentrations in biological fluid samples were analysed by a sensitive capillary gas chromatography-electron capture detection method. The mean steady-state fetal arterial plasma indometacin concentrations were 68.6+/-16.5 ng mL(-1) in the LD infusion and 230.3+/-28.8 ng mL(-1) in the HD infusion. Indometacin concentrations in amniotic fluid were approximately 10% of those in fetal plasma, and below assay detection limits in tracheal fluid. Total body clearance (TBC) in the LD and HD infusions were not different and the overall mean was 11.3+/-1.2 mL min(-1) kg(-1). In the 11 experiments where paired fetal arterial and umbilical venous samples were collected, the extraction of indometacin across the placenta averaged only 5.2+/-1.1%, indicating low placental permeability to the drug in sheep. However, fetal placental clearance (CLpl) of indometacin (10.0+/-2.5 mL min(-1) kg(-1), n = 10) averaged 115.1+/-41.2% of TBC in these animals and the calculated value for fetal non-placental clearance (0.6+/-2.8 mL min(-1) kg(-1)) was not significantly different from zero. Fetal renal clearance of intact indometacin (3.8+/-1.1 microL min(-1) kg(-1); n = 12) was also very low. However, treatment of fetal urine with glucuronidase indicated the presence of glucuronide conjugates and these comprised 69.9+/-8.2% of the total drug concentration (i.e. intact+conjugated) in urine. Thus, the fetal lamb appears to be able to glucuronidate indometacin, but the contribution of this and other non-placental routes to overall fetal elimination of the drug appear minimal. CLpl of the drug is also low owing to the physicochemical properties of indometacin (high polarity) and the permeability characteristics of the sheep placenta.
authors.affiliation: Faculty of Pharmaceutical Sciences, The University of British Columbia, Vancouver, Canada.
authors.forename: Rajesh
authors.initials: R
authors.lastname: Krishna
authors.forename: K Wayne
authors.initials: KW
authors.lastname: Riggs
authors.forename: Eddie
authors.initials: E
authors.lastname: Kwan
authors.forename: Harvey
authors.initials: H
authors.lastname: Wong
authors.forename: Andras
authors.initials: A
authors.lastname: Szeitz
authors.forename: Martin P R
authors.initials: MP
authors.lastname: Walker
authors.forename: Dan W
authors.initials: DW
authors.lastname: Rurak
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D004305:Dose-Response Relationship, Drug; D005260:Female; D005333:Fetus / Q000378:metabolism*; D007213:Indomethacin / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000652:urine; D007262:Infusions, Intravenous; D008431:Maternal-Fetal Exchange; D008657:Metabolic Clearance Rate; D010920:Placenta / Q000378:metabolism*; D011247:Pregnancy; D012756:Sheep
chemical_list: D007213:Indomethacin