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

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.

Time evolution of methotrexate-induced kidney injury: A comparative study between different biomarkers of renal damage in rats.

Methotrexate (MTX) is commonly used in the treatment of malignant diseases and autoimmune and chronic inflammatory disorders. Along with its effective therapeutic power, MTX has adverse effects on the kidneys. Discovery of new biomarkers is required to improve the early detection of renal damage and optimize the effectiveness of treatments. The aim of this study was to evaluate the time course of MTX-induced nephrotoxicity and to compare the urinary excretion of the organic anion transporter 5 (uOat5) with alterations in other markers of renal function, and to elucidate the possible molecular mechanisms involved in uOat5. Animals were exposed to a unique dose of MTX (80 mg/kg body weight, intraperitoneal). Experiments were carried out at days 2, 4, 8 or 14 after MTX administration. Markers of renal damage, such as creatinine and urea plasma levels, urinary activity of alkaline phosphatase, microalbuminuria, urinary excretion of neutrophil gelatinase-associated lipocalin (uNGAL) and histopathology, were evaluated. Renal organic anion transporter 5 (Oat5) expression and its presence in different urine fraction were assessed by western blotting. uOat5 was significantly increased 2 days after MTX treatment, before than any alteration in other parameters of kidney injury or renal morphology occurred. uNGAL showed an inverted pattern of urinary excretion compared to uOat5. Exosomal pathway is involved in the urinary excretion of Oat5 and depends on the degree of damage induced by MTX. These experimental data allow proposing uOat5 as a potential non-invasive biomarker for early detection of MTX-induced nephrotoxicity.

Expression and function of renal and hepatic organic anion transporters in extrahepatic cholestasis.

Obstructive jaundice occurs in patients suffering from cholelithiasis and from neoplasms affecting the pancreas and the common bile duct. The absorption, distribution and elimination of drugs are impaired during this pathology. Prolonged cholestasis may alter both liver and kidney function. Lactam antibiotics, diuretics, non-steroidal anti-inflammatory drugs, several antiviral drugs as well as endogenous compounds are classified as organic anions. The hepatic and renal organic anion transport pathways play a key role in the pharmacokinetics of these compounds. It has been demonstrated that acute extrahepatic cholestasis is associated with increased renal elimination of organic anions. The present work describes the molecular mechanisms involved in the regulation of the expression and function of the renal and hepatic organic anion transporters in extrahepatic cholestasis, such as multidrug resistance-associated protein 2, organic anion transporting polypeptide 1, organic anion transporter 3, bilitranslocase, bromosulfophthalein/bilirubin binding protein, organic anion transporter 1 and sodium dependent bile salt transporter. The modulation in the expression of renal organic anion transporters constitutes a compensatory mechanism to overcome the hepatic dysfunction in the elimination of organic anions.