title: Limited fetal metabolism of rosiglitazone: Elimination via the maternal compartment in the pregnant ewe.
abstract: Despite the fact that fetal drug exposure is common, the disposition of drugs in the fetus is poorly understood. This study aimed to investigate fetal placental and non-placental disposition of rosiglitazone in the pregnant ewe. Steady state was reached after day 5 of fetal infusion, and were ∼1.8 fold higher than maternal concentrations (P<0.001). The AUC for fetal rosiglitazone concentration throughout the infusion was inversely correlated with placental and fetal weight. Metabolic activity of the fetal liver microsomes were ∼25 fold lower than maternal microsomes (P<0.001). The findings suggest that trans-placental transfer is the major route through which rosiglitazone is cleared from the fetal compartment, while non-placental hepatic elimination makes only a minor contribution. This supports a limited capacity of the fetus for eliminating this class of drugs, and highlights the potential for drug toxicity when administering pharmacotherapy to the mother/fetus in human pregnancy.
authors.affiliation: School of Pharmacy and Medical Sciences, Sansom Institute, University of South Australia, Australia. Electronic address: maryam.bazargan@mymail.unisa.edu.au.
authors.forename: Maryam
authors.initials: M
authors.lastname: Bazargan
authors.affiliation: School of Pharmacy and Medical Sciences, Sansom Institute, University of South Australia, Australia.
authors.forename: David Jr
authors.initials: DJ
authors.lastname: Foster
authors.affiliation: Early Origins of Adult Health Research Group, School of Pharmacy and Medical Sciences, Sansom Institute for Health Research, University of South Australia, Australia; FOOD plus Research Centre, School of Agriculture, Food and Wine, The University of Adelaide, Australia.
authors.forename: Beverly S
authors.initials: BS
authors.lastname: Muhlhausler
authors.affiliation: Early Origins of Adult Health Research Group, School of Pharmacy and Medical Sciences, Sansom Institute for Health Research, University of South Australia, Australia.
authors.forename: Janna L
authors.initials: JL
authors.lastname: Morrison
authors.affiliation: Early Origins of Adult Health Research Group, School of Pharmacy and Medical Sciences, Sansom Institute for Health Research, University of South Australia, Australia.
authors.forename: ICaroline
authors.initials: I
authors.lastname: McMillen
authors.affiliation: School of Pharmacy, Menzies Health Institute Queensland, Griffith University, Australia.
authors.forename: Andrew K
authors.initials: AK
authors.lastname: Davey
mesh_terms: D000653:Amniotic Fluid / Q000378:metabolism; D000818:Animals; D005260:Female; D005333:Fetus / Q000378:metabolism*; D007004:Hypoglycemic Agents / Q000097:blood / Q000493:pharmacokinetics*; D008431:Maternal-Fetal Exchange; D008862:Microsomes, Liver / Q000378:metabolism; D010920:Placenta / Q000378:metabolism; D011247:Pregnancy; D000077154:Rosiglitazone; D012756:Sheep; D045162:Thiazolidinediones / Q000097:blood / Q000493:pharmacokinetics*
chemical_list: D007004:Hypoglycemic Agents; D045162:Thiazolidinediones; D000077154:Rosiglitazone
keywords: Drug disposition; Non-placental; Pregnant ewe; Trans-placental