Effect of pregnancy on nitrofurantoin disposition in mice.
We investigated the effect of pregnancy on nitrofurantoin (NFT) disposition in wild-type and Bcrp1(-/-) mice. Pregnant and non-pregnant mice were administered NFT intravenously (5 mg/kg) or orally (10 mg/kg). Blood samples were collected at various times (5-60 min) after drug administration, plasma NFT concentrations determined by HPLC/UV, and pharmacokinetic parameters estimated. Dose-normalized area under the plasma concentration-time curve (AUC), terminal plasma half-life (T(1/2)), total plasma clearance (CL), and steady-state volume of distribution (V(ss)) of intravenous NFT in wild-type or Bcrp1(-/-) mice were not altered by pregnancy. After oral administration, pregnancy did not affect dose-normalized AUC of NFT in wild-type mice; however, dose-normalized AUC in Bcrp1(-/-) mice was decreased by approximately 70% by pregnancy. In conclusion, since Bcrp1 plays a minor role in the systemic clearance of NFT in female mice, pregnancy did not affect disposition of intravenous NFT despite the fact that Bcrp1 expression in the liver and kidney of mice is significantly induced by pregnancy. On the other hand, pregnancy may affect expression and activity of certain intestinal efflux transporters and/or metabolic enzymes in Bcrp1(-/-) mice, resulting in a drastic decrease in the systemic exposure of oral NFT in pregnant Bcrp1(-/-) mice.
Department of Pharmaceutics, School of Pharmacy, University of Washington, Seattle, Washington 98195-7610, USA.
Yi
Y
Zhang
Lin
L
Zhou
Jashvant D
JD
Unadkat
Qingcheng
Q
Mao
D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D000892:Anti-Infective Agents, Urinary / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics*; D019540:Area Under Curve; D002851:Chromatography, High Pressure Liquid; D004305:Dose-Response Relationship, Drug; D005260:Female; D006207:Half-Life; D007275:Injections, Intravenous; D008657:Metabolic Clearance Rate; D051379:Mice; D018345:Mice, Knockout; D009582:Nitrofurantoin / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics*; D011247:Pregnancy; D013056:Spectrophotometry, Ultraviolet; D014018:Tissue Distribution / Q000187:drug effects
D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters; C501412:Abcg2 protein, mouse; D000892:Anti-Infective Agents, Urinary; D009582:Nitrofurantoin