Age-associated differences in transporter gene expression in kidneys of male rats.

Kidney transporters are involved in the secretion and reabsorption of endogenous and exogenous molecules. Numerous factors may influence their expression and affect drug disposition, efficacy and toxicity. The present study aimed to examine the development­ and age­associated variations in primary renal transporters in rats, including 6 uptake transporters: Organic anion transporter (OAT) 1 and 3, organic cation transporter (OCT) 1, 2 and 3 and organic anion­transporting polypeptide (OATP) 4C1, and 6 efflux transporters: Multidrug resistance protein 1 (MDR1), breast cancer resistance protein (BCRP), multidrug resistance­associated protein (MRP) 2 and 4, and multidrug and toxin extrusion protein (MATE) 1 and 2­K. Kidneys from male Sprague Dawley rats during development (­2, 1, 7, 14 and 21 days), maturation (28, 35 and 60 days) and aging (180, 540 and 850 days) were collected and total RNA was extracted, purified and subjected to reverse transcription­quantitative polymerase chain reaction analysis. Total proteins were extracted for western blot analysis. OAT1 and 3, OCT1, BCRP, MRP2 and 4 and MATE2­K expression levels were low in fetal kidneys, increased gradually following birth and markedly increased on maturation and adulthood. High levels were maintained until 850 days. OCT2, OATP4C1, Mdr1b and MATE1 expression levels were low in fetal kidneys, increased gradually following birth, and increased markedly on weaning, maturation and adulthood; however, levels were decreased on aging. OCT3 mRNA expression levels were low in fetal and newborn kidneys, and had two peaks at 35 and 850 days. The selected OAT1 and 3 and MDR1 protein expression levels revealed a similar expression pattern. Thus, kidney transporter expression is affected by ontogeny and aging, which may impact drug and toxicant disposition in children and the elderly.

Fate of orally administered 15N-labeled polyamines in rats bearing solid tumors.

We studied absorption, distribution, metabolism, and excretion of polyamines (putrescine, spermidine, and spermine) in the gastrointestinal tract using (15)N-labeled polyamines as tracers and ionspray ionization mass spectrometry (IS-MS). The relatively simple protocol using rats bearing solid tumors provided useful information. Three (15)N-labeled polyamines that were simultaneously administered were absorbed equally from gastrointestinal tract, and distributed within tissues at various concentrations. The uptake of (15)N-spermidine seemed preferential to that of (15)N-spermine since the concentrations of (15)N-spermidine in the liver and tumors were higher, whereas those of (15)N-spermine were higher in the kidney, probably due to the excretion of excess extracellular spermine. Most of the absorbed (15)N-putrescine seemed to be lost, suggesting blood and tissue diamine oxidase degradation. Concentrations of (15)N-spermidine and (15)N-spermine in the tumor were low. We also describe the findings from two rats that were administered with (15)N-spermine. The tissue concentrations of (15)N-spermine were unusually high, and significant levels of (15)N-spermidine were derived from (15)N-spermine in these animals.