Furosemide Pharmacokinetics in Adult Rats become Abnormal with an Adverse Intrauterine Environment and Modulated by a Post-Weaning High-Fat Diet

Barent N. Dubois, Jacob Pearson, Tahir Mahmood, Kent Thornburg, Ganesh Cherala

    Research output: Contribution to journalArticle

    Abstract

    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.

    Original languageEnglish (US)
    Pages (from-to)432-439
    Number of pages8
    JournalBasic and Clinical Pharmacology and Toxicology
    Volume118
    Issue number6
    DOIs
    StatePublished - Jun 1 2016

    Fingerprint

    Pharmacokinetics
    Furosemide
    High Fat Diet
    Nutrition
    Weaning
    Rats
    Fats
    Growth
    Diet
    Sodium-Potassium-Chloride Symporters
    Pharmacodynamics
    Organic Anion Transporters
    Protein-Restricted Diet
    Proteins
    Body Composition
    Half-Life
    Chronic Disease
    Body Weight
    Urine
    Phenotype

    ASJC Scopus subject areas

    • Pharmacology
    • Toxicology

    Cite this

    Furosemide Pharmacokinetics in Adult Rats become Abnormal with an Adverse Intrauterine Environment and Modulated by a Post-Weaning High-Fat Diet. / Dubois, Barent N.; Pearson, Jacob; Mahmood, Tahir; Thornburg, Kent; Cherala, Ganesh.

    In: Basic and Clinical Pharmacology and Toxicology, Vol. 118, No. 6, 01.06.2016, p. 432-439.

    Research output: Contribution to journalArticle

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