title: Furosemide Pharmacokinetics in Adult Rats become Abnormal with an Adverse Intrauterine Environment and Modulated by a Post-Weaning High-Fat Diet.
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.
authors.affiliation: Department of Pharmacy Practice, College of Pharmacy, Oregon State University/Oregon Health & Science University, Portland, OR, USA.
authors.forename: Barent N
authors.initials: BN
authors.lastname: DuBois
authors.affiliation: Department of Pharmacy Practice, College of Pharmacy, Oregon State University/Oregon Health & Science University, Portland, OR, USA.
authors.forename: Jacob
authors.initials: J
authors.lastname: Pearson
authors.affiliation: Department of Pharmacy Practice, College of Pharmacy, Oregon State University/Oregon Health & Science University, Portland, OR, USA.
authors.forename: Tahir
authors.initials: T
authors.lastname: Mahmood
authors.affiliation: Center for Developmental Health, Oregon Health & Science University, Portland, OR, USA.
authors.forename: Kent
authors.initials: K
authors.lastname: Thornburg
authors.affiliation: Center for Developmental Health, Oregon Health & Science University, Portland, OR, USA.|Department of Obstetrics & Gynecology, School of Medicine, Oregon Health & Science University, Portland, OR, USA.
authors.forename: Ganesh
authors.initials: G
authors.lastname: Cherala
mesh_terms: D000818:Animals; D001823:Body Composition; D001835:Body Weight; D059305:Diet, High-Fat / Q000009:adverse effects*; D018753:Diet, Protein-Restricted / Q000009:adverse effects*; D005260:Female; D005317:Fetal Growth Retardation / Q000209:etiology / Q000378:metabolism*; D005665:Furosemide / Q000493:pharmacokinetics*; D006801:Humans; D007668:Kidney / Q000378:metabolism; D008297:Male; D027362:Organic Anion Transport Protein 1 / Q000378:metabolism; D029362:Organic Anion Transporters, Sodium-Independent / Q000378:metabolism; D011247:Pregnancy; D011297:Prenatal Exposure Delayed Effects / Q000378:metabolism*; D051381:Rats; D012737:Sex Factors; D049994:Sodium Potassium Chloride Symporter Inhibitors / Q000493:pharmacokinetics*; D064466:Solute Carrier Family 12, Member 1 / Q000378:metabolism; D014886:Weaning
chemical_list: D027362:Organic Anion Transport Protein 1; D029362:Organic Anion Transporters, Sodium-Independent; C578716:Slc12a1 protein, rat; C421043:Slc22a6 protein, rat; D049994:Sodium Potassium Chloride Symporter Inhibitors; D064466:Solute Carrier Family 12, Member 1; C114338:organic anion transport protein 3; D005665:Furosemide