title: Evaluation of early fetal exposure to vaginally-administered metronidazole in pregnant cynomolgus monkeys.
abstract: Given concern about potential embryo-fetal harm following seminal exposure to drugs with teratogenic potential, pharmaceutical companies use theoretical calculations to estimate seminal concentrations, maternal exposure, and distribution across the placenta to the embryo-fetal compartment for risk assessment. However, it is plausible that there are additional mechanisms whereby the conceptus is exposed. In order to determine if theoretical calculations are sufficiently conservative to predict embryo-fetal exposure from drugs in semen, pregnant cynomolgus monkeys were given a vaginal dose of metronidazole during the early fetal period and cesarean-sectioned. Maternal, fetal, and amniotic fluid samples were analyzed for metronidazole and 2-hydroxymetronidazole. Exposure to metronidazole and its metabolite were comparable in all matrices. These data demonstrated no preferential transfer mechanism to conceptus following intravaginal administration of a small molecule drug; and therefore, suggest that traditional modeling for embryo-fetal exposure to drugs in semen in support of risk assessment for pharmaceutical agents is sufficiently conservative.
authors.affiliation: Reproductive Toxicology, Drug Safety Evaluation, Research & Development, Bristol-Myers Squibb Company, New Brunswick, NJ 08903, United States. Electronic address: kary.thompson@bms.com.
authors.forename: Kary E
authors.initials: KE
authors.lastname: Thompson
authors.affiliation: Preclinical Services, Charles River Laboratories, Reno, NV 89511, United States.
authors.forename: Deanna L
authors.initials: DL
authors.lastname: Newcomb
authors.affiliation: Amgen Inc., Thousand Oaks, CA 91320, United States.
authors.forename: Graeme J
authors.initials: GJ
authors.lastname: Moffat
authors.affiliation: Amgen Inc., Thousand Oaks, CA 91320, United States.
authors.forename: Julie
authors.initials: J
authors.lastname: Zalikowski
authors.affiliation: Preclinical Services, Charles River Laboratories, Reno, NV 89511, United States.
authors.forename: Gary J
authors.initials: GJ
authors.lastname: Chellman
authors.affiliation: Reproductive Toxicology, Drug Safety Evaluation, Research & Development, Bristol-Myers Squibb Company, New Brunswick, NJ 08903, United States.
authors.forename: Mary Ellen
authors.initials: ME
authors.lastname: McNerney
mesh_terms: D000282:Administration, Intravaginal; D000653:Amniotic Fluid / Q000378:metabolism*; D000818:Animals; D000890:Anti-Infective Agents / Q000008:administration & dosage* / Q000097:blood / Q000633:toxicity; D001711:Biotransformation; D005260:Female; D005333:Fetus / Q000187:drug effects / Q000378:metabolism*; D008252:Macaca fascicularis; D018811:Maternal Exposure / Q000009:adverse effects; D008795:Metronidazole / Q000008:administration & dosage* / Q000031:analogs & derivatives / Q000097:blood / Q000378:metabolism / Q000633:toxicity; D010539:Permeability; D011247:Pregnancy; D018570:Risk Assessment; D014621:Vagina / Q000378:metabolism*
chemical_list: D000890:Anti-Infective Agents; D008795:Metronidazole; C020910:1-(2-hydroxyethyl)-2-hydroxymethyl-5-nitroimidazole
keywords: Fetus; Intravaginal administration; Metronidazole; Risk assessment; Semen; Small molecule drug