A Pilot Study of the Maternal-Fetal Pharmacokinetics of Furosemide in Plasma, Urine, and Amniotic Fluid of Hypertensive Parturient Women Under Cesarean Section

J Clin Pharmacol. 2020 Dec;60(12):1655-1661. doi: 10.1002/jcph.1681. Epub 2020 Jun 20.

Abstract

The third trimester of pregnancy is related to physiological changes that can modify the process of absorption, distribution, metabolism, and excretion and, consequently, the efficacy and toxicity of drugs. However, little is known about furosemide pharmacokinetics and placental transfer in pregnancy. This study evaluated the maternal-fetal pharmacokinetics and distribution to amniotic fluid of furosemide in hypertensive parturient women under cesarean section. Twelve hypertensive parturient women under methyldopa (250 mg/8 h) and/or pindolol (10 mg/12 h) treatment received a 40-mg single oral dose of furosemide 1 to 10 hours before delivery by cesarean section. Blood and urine samples were collected for 12 hours after furosemide administration. At delivery, samples were obtained from maternal and umbilical cord blood (n = 8) to assess the transplacental transfer. Amniotic fluid (n = 4) was collected at the time of delivery. The following furosemide pharmacokinetic parameters were obtained as median (interquartile range): Cmax , 403 ng/mL (229 to 715 ng/mL); Tmax , 2.00 hours (1.50 to 4.83 hours); elimination half-life (t1/2 ), 2.50 hours (1.77 to 2.97 hours); AUC0-12 h , 1366 ng⋅h/mL (927 to 2531 ng⋅h/mL); AUC0-∞ , 1580 ng⋅h/mL (1270 to 2881 ng⋅h/mL); CL/F 25.3 L/h (13.8 to 31.4 L/h); CLR, 2.50 L/h (1.77 to 2.97 L/h); CLNR, 22.7 L/h (12.1 to 25.6 L/h); and Vd /F 82.8 L (34.4 to 173 L). The transplacental transfer of furosemide was 0.43 (0.10 to 0.73), and the amniotic fluid concentration was 11.0 ng/mL (5.51 to 14.6 ng/mL). From a clinical point of view, these results suggest that substrates of uridine diphosphate-glucuronosyltransferase isoenzymes such as furosemide may have increased clearance during pregnancy and could require dose adjustment in this population.

Keywords: amniotic fluid; furosemide; organic anion transporter; pharmacokinetics; pregnancy; transplacental transfer; ugt.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Administration, Oral
  • Adult
  • Amniotic Fluid / metabolism*
  • Cesarean Section
  • Diuretics / administration & dosage
  • Diuretics / blood
  • Diuretics / pharmacokinetics*
  • Diuretics / urine
  • Drug Dosage Calculations
  • Drug Elimination Routes
  • Female
  • Fetal Blood / metabolism
  • Furosemide / administration & dosage
  • Furosemide / blood
  • Furosemide / pharmacokinetics*
  • Furosemide / urine
  • Glucuronosyltransferase / metabolism
  • Humans
  • Hypertension / blood
  • Hypertension / drug therapy*
  • Hypertension / urine
  • Hypertension, Pregnancy-Induced*
  • Maternal-Fetal Exchange / physiology*
  • Parturition / blood
  • Parturition / urine
  • Pilot Projects
  • Pregnancy

Substances

  • Diuretics
  • Furosemide
  • Glucuronosyltransferase