Peritoneal Dialysis Alters Tolbutamide Pharmacokinetics in Rats with Experimental Acute Renal Failure

Aiba, Tetsuya; Horiuchi, Mizuki; Makita, Takashi; Komori, Yukiko; Kawasaki, Hiromu; Kurosaki, Yuji

doi:10.2133/dmpk.21.291

Cited by 9 publications

(14 citation statements)

References 23 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…They were housed at 20-25°C and 40-50% humidity on a 12-h light/dark cycle, and were allowed free access to a standard laboratory diet (MF, Oriental Yeast Co., Ltd., Tokyo, Japan) and water prior to the experiments. For the experiments with glycerolinduced ARF rats, rats were injected with 50% glycerol saline solution (10 ml/kg) in the left and right leg muscles after 24-h water deprivation (32). They were normally fed thereafter.…”

Section: Animalsmentioning

confidence: 99%

Decreased Lithium Disposition to Cerebrospinal Fluid in Rats with Glycerol-induced Acute Renal Failure

et al. 2008

Self Cite

View full text Add to dashboard Cite

show abstract

Section: Animalsmentioning

confidence: 99%

Decreased Lithium Disposition to Cerebrospinal Fluid in Rats with Glycerol-induced Acute Renal Failure

et al. 2008

Self Cite

View full text Add to dashboard Cite

show abstract

“…Protein binding:T hereweref ewinstancesof increased free fraction of the drug( tolbutamide;CAS 64-77-7 [24], lidocaine;CAS 137-58-6 [36])and one instance of unaltered free fraction (oltipraz)o rdecreased free fraction (diltiazem [46])i nARF rats.…”

Section: 2distribution Related Changesmentioning

confidence: 99%

Altered disposition of drugs in acute renal failure rat models: drug development strategies and perspectives

Srinivas¹

2011

Arzneimittelforschung

View full text Add to dashboard Cite

In the evolving paradigm of drug development it is a reasonable strategy to avoid and/or anticipate potential risks in drug development for select drugs by performing in vitro and/or preclinical studies in appropriate animal models. The availability of acute renal failure (ARF) rat models provides an opportunity to explore the pharmacokinetic disposition of drugs and associated metabolites in conditions that mimic the pathophysiology of the disease in humans. Such studies may help in drug(s) selection for development, differentiating certain drug classes, and/or arriving at a dose strategy decision in the clinic. Scores of compounds, belonging to various therapeutic areas, have undergone pharmacokinetic investigations in ARF models induced by uranyl nitrate (CAS 10102-06-4), glycerol (CAS 56-81-5), cisplatin (CAS 15663-27-1) or gentamicin (CAS 1403-66-3) in rats. The published pharmacokinetic disposition data has unequivocally suggested that ARF conditions leads to decreased renal elimination of the drug and associated metabolites; however, the influence on the overall body clearance is dependent on the propensity of the contribution of renal versus non-renal mechanisms of elimination. In the case studies assembled for this review, 52.5% of the drugs showed an increased drug exposure, 35% of the drugs showed a decreased drug exposure and 12.5% of the drugs showed no altered exposure, in ARF rat models relative to control rats. Interestingly, ARF can have an overall impact on drug absorption, distribution, metabolism, local transport and biliary excretion. Hence, the overall pharmacokinetic disposition may have to be interpreted with caution during ARF since there is the potential for competiting pathways to co-exist. For instance, due to reduced renal elimination as a result of kidney insult caused by ARF, compensatory biliary excretion mechanism may occur. Alternatively, intestinal and/or hepatic enzymatic expression level may go up to facilitate enhanced metabolism. However, there may be instances where uraemic toxins floating in the circulation may block the metabolism and/ or may also retard the absorption process. This review covers: 1) an illustration of a number of case studies providing tabulated information on the key altered pharmacokinetic parameters observed in ARF and the hypothesized mechanistic explanation; 2) a comprehensive description of altered absorption, distribution, metabolism, excretion and efflux transport related changes observed during ARF; 3) a general framework for drug development strategies and 4) a succinct discussion on the overall perspectives of the applicability of ARF rat models.

show abstract

“…After glycerol treatment, they were fed normally for another 24 h to develop and establish ARF [9]. The establishment of renal failure was confirmed by an increased serum creatinine concentration [8]. All animal experiments were performed in accordance with the guidelines for animal experimentation of Okayama University.…”

Section: Animalsmentioning

confidence: 99%

“…Tolbutamide concentration profiles in the plasma and peritoneal dialysate were examined in normal and ARF rats as reported previously, with slight modifications [8]. In brief, after being deeply anesthetized with pentobarbital (80 mg/kg, i.p.…”

Section: Measurement Of the Tolbutamide Concentration In The Plasma Amentioning

confidence: 99%

“…Sulfonamides such as sulfamethoxazole (SMZ) and sulfadimethoxine (SDM) are well known regarding their ability to displace tolbutamide bound to serum protein from the binding site [6,7]. Experiments were also performed using rats with experimentally induced renal failure, since the unbound fraction of tolbutamide was significantly increased when the kidney function was impaired [8]. In addition, the study pharmacokinetically characterized the dialysis process of tolbutamide, and showed that the efficacy of peritoneal dialysis does not always proportionally elevate as the unbound fraction increases.…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Efficacy of peritoneal dialysis of tolbutamide in rats under conditions of the plasma unbound fraction being increased

Makita

Aiba

Izuwa

et al. 2009

Biopharm & Drug Disp

Self Cite

View full text Add to dashboard Cite

Peritoneal dialysis of a highly protein-bound compound, tolbutamide, was examined in rats to clarify whether the efficacy of the peritoneal dialysis of such compounds increases proportionally as their unbound fractions increase. As expected, it was shown that the tolbutamide concentration of the peritoneal dialysate rose as the unbound fraction of tolbutamide increased. However, the efficacy of peritoneal dialysis of tolbutamide was proportionally elevated only when the unbound fraction was slightly increased by sulfamethoxazole treatment. When the unbound fraction of tolbutamide was increased 7.8 times by sulfadimethoxine treatment, the dialysis efficacy was increased to only 58% of that expected. This discrepancy between the observed and expected values regarding dialysis efficacy was more marked when experiments were performed in rats with experimentally induced acute renal failure. Pharmacokinetic analysis indicated that the intrinsic dialysis clearance of tolbutamide decreased when its unbound fraction was greatly increased. These findings suggest that peritoneal dialysis may be mediated not only by passive diffusion, but also by concentration-dependent processes. The efficacy of the peritoneal dialysis of therapeutic compounds may be overestimated if the estimation is based only on their unbound fraction measured under control conditions.

show abstract

Peritoneal Dialysis Alters Tolbutamide Pharmacokinetics in Rats with Experimental Acute Renal Failure

Cited by 9 publications

References 23 publications

Decreased Lithium Disposition to Cerebrospinal Fluid in Rats with Glycerol-induced Acute Renal Failure

Decreased Lithium Disposition to Cerebrospinal Fluid in Rats with Glycerol-induced Acute Renal Failure

Altered disposition of drugs in acute renal failure rat models: drug development strategies and perspectives

Efficacy of peritoneal dialysis of tolbutamide in rats under conditions of the plasma unbound fraction being increased

Contact Info

Product

Resources

About