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Furosemide Pharmacokinetics in Adult Rats become Abnormal with an Adverse Intrauterine Environment and Modulated by a Post‐Weaning High‐Fat Diet
Author(s) -
DuBois Barent N.,
Pearson Jacob,
Mahmood Tahir,
Thornburg Kent,
Cherala Ganesh
Publication year - 2016
Publication title -
basic and clinical pharmacology and toxicology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.805
H-Index - 90
eISSN - 1742-7843
pISSN - 1742-7835
DOI - 10.1111/bcpt.12523
Subject(s) - pharmacokinetics , offspring , furosemide , endocrinology , medicine , weaning , intrauterine growth restriction , volume of distribution , pharmacodynamics , biology , physiology , fetus , pregnancy , genetics
Adult individuals born with intrauterine growth restriction ( IUGR ) have physiological maladaptations that significantly increase risk of chronic disease. We suggested that such abnormalities in organ function would alter pharmacokinetics throughout life, exacerbated by environmental mismatch. Pregnant and lactating rats were fed either a purified control diet (18% protein) or low‐protein diet (9% protein) to produce IUGR offspring. Offspring were weaned onto either laboratory chow (11% fat) or high‐fat diet (45% fat). Adult offspring (5 months old) were dosed with furosemide (10 mg/kg i.p.) and serum and urine collected. The overall exposure profile in IUGR males was significantly reduced due to a ~35% increase in both clearance and volume of distribution. Females appeared resistant to the IUGR phenotype. The effects of the high‐fat diet trended in the opposite direction to that of IUGR , with increased drug exposure due to decreases in both clearance (31% males, 46% females) and volume of distribution (24% males, 44% females), with a 10% longer half‐life in both genders. The alterations in furosemide pharmacokinetics and pharmacodynamics were explained by changes in the expression of renal organic anion transporters 1 and 3, and sodium–potassium–chloride cotransporter‐2. In summary, this study suggests that IUGR and diet interact to produce subpopulations with similar body‐weights but dissimilar pharmacokinetic profiles; this underlines the limitation of one‐size‐fits‐all dosing which does not account for physiological differences in body composition resulting from IUGR and diet.