Programming of Furosemide Pharmacokinetics by Intrauterine Growth Restriction and High Fat Diet in the Adult Rat Public Deposited

http://ir.library.oregonstate.edu/concern/graduate_thesis_or_dissertations/n009w463g

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  • Perinatal growth restriction programs higher risk for chronic disease during adulthood via morphological and physiological changes in organ systems. Perinatal growth restriction is highly correlated with a decreased nephron number, altered renal function and subsequent hypertension. I hypothesize that such renal maladaptations result in altered pharmacologic patterns for life. Pregnant and lactating rats were fed either a purified control diet (18% protein) or low protein diet (9% protein) to produce perinatal growth restriction, also known as intrauterine growth restriction (IUGR) in the offspring. The diuretic response of furosemide (2mg/kg single i.p dose) in adult IUGR rats was investigated. Diuresis, natriuresis and renal excretion of furosemide were significantly reduced relative to controls, indicative of decreased efficacy. In the follow-up study, offspring were weaned onto either lab chow (11% fat) or high fat diet (45% fat). Adult offspring were dosed with furosemide (10mg/kg i.p. dose), and serum and urine collected. The pharmacokinetic parameters were significantly altered by both IUGR and the high-fat diet; these effects appeared to be additive. The overall exposure profile in IUGR males was significantly reduced due to a ~35% increases 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 NKCC2. In summary, this study suggests that IUGR and diet interact to produce sub-populations 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.
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