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 highfat 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 sodiumpotassium-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.An adverse intrauterine environment -one where nutrient flow to the developing foetus is suppressed -produces suboptimal growth and development of foetal organ systems, now called 'intrauterine growth restriction' (IUGR) [1]. Robust evidence in human and animal models demonstrates a link between IUGR and increased risk of cardiovascular disease and the metabolic syndrome [2]; thus, this predisposition for chronic disease increases the likelihood that IUGR individuals will need to be treated with pharmaceutical agents over their life-time. However, it is not clear whether one-size-fits-all dosing will be sufficient to optimize pharmacotherapy in this population.The IUGR phenotype in human beings and animals is consistently associated with decreased (30%) numbers of nephrons and cardiomyocytes, leading to elevated risks of renal and cardiac dysfunction. These deficits also contribute to an increased risk of hypertension and many forms of cardiovascular disease [3][4][5][6]. In our model of IUGR, pregnant rats were fed a low-protein diet during gestation and lactation resulting in offspring with low birthweight and stunted postnatal growth [7][8][9][10]. The IUGR offspring had a reduced urinary excretion of the loop diuretic, furosemide, compared to rats that had a normal birthweight [11]. These experiments led to the studies reported here.The primary objective of the current study was to examine whether pharmacokinetic factors are a...

Of Mice and Men: The Effect of Maternal Protein Restriction on Offspring’s Kidney Health. Are Studies on Rodents Applicable to Chronic Kidney Disease Patients? A Narrative Review

“…In a subsequent study, these authors applied the same dietary protocol to 24 pregnancies, with 21 control CKD pregnancies with no dietary restrictions Severe protein restriction in pregnancy can also influence drug response in the offspring. DuBois reported an impaired response to furosemide in programmed Sprague Dawley female rats due to increased renal organic anion transporter 1, irrespective of body weight, an important notion in drug dosing for physicians [86]. In addition, epithelial sodium channel (ENaC) activity, as well as sodium-potassium-chloride cotransporter (NKCC2) activity in the cortical collecting ducts seem to be caused by severe maternal protein restriction, which potentially affects renal sodium handling.…”

Unraveling the molecular pathobiology of vocal fold systemic dehydration using an in vivo rabbit model

“…Experimentally, systemic dehydration is commonly induced by water withholding, with or without food access, or use of diuretics, or a combination of both [28][29][30][31][32][33]. Furosemide is a diuretic with a relatively fast onset of action that has been used to induce dehydration in numerous studies with animal and human subjects [25,30,[34][35][36][37][38]. Regarding hydration and vocal folds, studies completed ex vivo and using animal and human subjects have shown that surface (i.e., fluid coating the vocal fold surface) and systemic hydration status have impacts on vocal fold biomechanics and physiology [12,21,30,32,39].…”