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M Nadai

Publications and source records attributed to M Nadai.

61 records · Page 4Linked to original sources
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Pharmacokinetics and renal handling of enprofylline in pregnant rats.

The pharmacokinetics and renal handling of enprofylline during pregnancy were investigated in Sprague-Dawley rats. Significant differences in the pharmacokinetic parameters of enprofylline were observed between nonpregnant rats and pregnant rats on the 20th day of gestation: volume of distribution was higher, and systemic clearance was lower in pregnant rats. Parameters obtained from rats at 7 days postpartum were the same as those obtained from nonpregnant rats. There were no significant differences in the fraction of urinary excretion of enprofylline between nonpregnant and pregnant rats. The protein binding of enprofylline in the plasma of pregnant rats was significantly lower than in nonpregnant rats, as a decrease in the albumin concentration consequentially reduced the binding capacity of enprofylline. The volume of distribution for unbound enprofylline in pregnant rats was not significantly different from nonpregnant rats, although a significant decrease was observed in pregnant rats in the systemic clearance for unbound enprofylline. In addition, the clearance ratio was lower in pregnant rats (2.8) when compared with nonpregnant rats (6.4). Pregnancy caused a decrease in the apparent maximum capacity of transport (Vmax) from 29.9 to 20.8 micrograms/min and in the Michaelis-Menten constant (KM) from 2.59 to 2.26 micrograms/ml, indicating that the tubular secretion ability of enprofylline becomes reduced during pregnancy. These results suggest that changes that occur in the plasma protein binding behavior and in renal handling as a result of pregnancy are primary factors influencing the disposition of enprofylline during pregnancy.

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Effect of diabetes on disposition and renal handling of cefazolin in rats.

The effects of early-stage diabetes on disposition and renal handling of cefazolin (CEZ) were investigated in streptozotocin-induced diabetic rats. Significant increase in renal clearance was found in the diabetic rats (88%) and a strong correlation was obtained between renal and systemic clearance; however, there was no change in the volume of distribution. The results suggest that systemic clearance was increased as the result of enhancement of urinary excretion rate. Unbound fraction of CEZ in plasma was also increased by 60% in the diabetic rats and the increase may be due to the increase in glycosylated protein and plasma-free fatty acids. The filtration clearance for free drug in diabetic rats, which was estimated as glomerular filtration rate, was increased by about 1.9-fold compared to the normal rats, but the secretion clearance did not change in the two groups. Since kidney hypertrophy was observed in the diabetic rats, filtration and secretion clearance for free drug were normalized by means of kidney weight. After normalization for kidney weight, the two parameters were significantly reduced, indicating that the true kidney functions were impaired under the diabetic state. The parameters for CEZ secretion, maximum velocity and Michaelis-Menten constant, were also reduced in diabetic rats, suggesting that proximal tubule cell functions for secretion were altered in the diabetic rats. These results suggest that systemic and renal clearance was apparently increased in early-stage diabetes, whereas true kidney functions were impaired.

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Alterations in the pharmacokinetics and protein binding of enprofylline in Eisai hyperbilirubinemic rats.

Mutant rats possessing conjugated hyperbilirubinemia have recently been established from Sprague-Dawley rats (SDRs) and are called Eisai hyperbilirubinemic rats (EHBRs). The effects of hyperbilirubinemia on the disposition, renal handling, and protein binding behavior of enprofylline, which is mainly excreted into the urine by an active tubular secretion mechanism, were investigated in 9- and 19-week-old EHBRs and compared with their age-matched normal SDRs. Enprofylline was administered intravenously at a dose of 2.5 mg/kg, which exhibits linear kinetics. Pharmacokinetic parameters for both total and unbound enprofylline were estimated by model-independent methods. Both systemic clearance and volume of distribution at steady state of enprofylline significantly increased in 19-week-old EHBRs. However, there were no differences in the glomerular filtration rate estimated as inulin clearance and fraction of urinary excretion as unchanged drug between EHBRs and normal SDRs. Significant decreases in both the binding capacity and number of binding sites were observed in 19-week-old EHBRs, but no such changes were observed between 9-week-old EHBRs and SDRs. Hyperbilirubinemia in EHBRs had no effect on the pharmacokinetics and renal handling of unbound enprofylline. These results indicate that the pharmacokinetics of enprofylline, but not renal handling, glomerular filtration, or tubular secretion are modified in EHBRs by changes in protein binding behavior.

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The disposition and renal handling of enprofylline in endotoxemic rats by bacterial lipopolysaccharide (LPS).

The effects of lipopolysaccharide (LPS), isolated from Klebsiella pneumoniae (O3:K1-), on the pharmacokinetic behavior and renal handling of enprofylline, which is mainly excreted into the urine by an active tubular secretion mechanism, were investigated in rats. LPS (50 and 250 micrograms/kg) was infused for 20 to 30 min 2 hr before an intravenous administration of enprofylline (2.5 mg/kg). LPS induced a decrease in the systemic clearance and an increase in the volume of distribution at the steady state of enprofylline without any histological changes in the kidneys. No changes in the protein-binding parameters of enprofylline were observed between the control and LPS-pretreated groups, although LPS slightly decreased the albumin concentration in plasma. LPS caused decreases in the apparent maximum capacity of transport (Vmax) from 71.24 to 15.02 micrograms/min, in the Michaelis-Menten constant (KM) from 3.04 to 1.42 micrograms/ml, and in the glomerular filtration rate as estimated for inulin clearance from 3.10 to 1.87 ml/min. These results indicate that LPS decreases both the affinity and capacity of the tubular transport system, and in turn decreases the tubular secretory intrinsic clearance of enprofylline as shown by Vmax/KM. The mechanism for inducing changes in the pharmacokinetic behavior and renal handling of enprofylline by LPS may be related to the effects of LPS on tubular secretion of enprofylline and its distribution in the organs and peripheral tissues.

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Renal excretion of famotidine and role of adenosine in renal failure induced by bacterial lipopolysaccharide in rats.

Our previous studies have reported that bacterial lipopolysaccharide (LPS) dramatically changes the ability of the active tubular anion secretory system in rats. The present study has investigated the effects of LPS on the pharmacokinetics and renal handling of famotidine, an organic cation drug excreted primarily by an active tubular secretion mechanism in rats. The role of adenosine in the LPS-induced renal failure was also investigated using theophylline, an adenosine antagonist. Pretreatment with LPS (250 micrograms/kg) significantly decreased the steady-state volume of distribution, systemic clearance, and renal clearance (CLr) of famotidine, but not nonrenal clearance. No significant differences in total urinary recovery of unchanged famotidine were observed between treatments. Pretreatment with LPS significantly decreased the glomerular filtration rate (GFR), estimated as inulin clearance. LPS increased the clearance ratio of famotidine (CLr/GFR), but not the net tubular secretion, indicating that LPS has little or no effect on the active tubular cation secretory system. Theophylline (10 mg/kg) improved LPS-induced decrease in GFR without causing any changes in the pharmacokinetic parameters of famotidine. These findings provide further evidence that LPS produces different effects on the distribution and the active tubular secretory systems of anion and cation drugs, and that adenosine may play an important role in the induction of renal failure by LPS.

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