Decreased Cyclosporin A Concentrations in the Absorption Phase Using Microemulsion Preconcentrate Formulation in Rats with Cisplatin-Induced Acute Renal Failure

Igarashi, Takayuki; Yano, Ikuko; Saya, Hideyuki; Inui, Ken Ichi

doi:10.1248/bpb.26.1591

Cited by 6 publications

(11 citation statements)

References 21 publications

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“…20,21) Actually, in the present study, the blood concentrations of cyclosporine and tacrolimus after 240 min were 1,458±183 ng/mL and 3.8±0.9 ng/mL (mean±SE, n＝4-5) with a fluorescence polarization immunoassay method and a microparticle enzyme immunoassay method, respectively. From our results, cyclosporine significantly decreased the CL, and increased the F of everolimus after intraintestinal administration, while tacrolimus showed a less potent effect than cyclosporine.…”

Section: Discussionsupporting

confidence: 42%

“…On one hand, the bioavailability of tacrolimus and cyclosporine, typical substrates of CYP3A subfamily, in humans are poor and varies from 4% to 89% (mean approximately 25%) and from º5% to 89% (average approximately 30%, classical formulation), respectively, 18,19) and the reported bioavailability in rats are similar to the mean values in humans. 20,21) Everolimus has been on the market only as an oral formulation, and there is no information about its bioavailability in humans. Therefore, we investigated the effect of intestinal and hepatic first-pass extraction on the pharmacokinetics of everolimus in rats to understand the bioavailability in humans, although the species difference should be taken into consideration.…”

Section: Discussionmentioning

confidence: 99%

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Effect of Intestinal and Hepatic First-pass Extraction on the Pharmacokinetics of Everolimus in Rats

Yokomasu

Yano

Sato

et al. 2008

Drug Metabolism and Pharmacokinetics

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The aim of this study was to quantitatively evaluate the effects of intestinal and hepatic extraction on the pharmacokinetics of everolimus in rats. Everolimus was administered intravenously, intraportally or intraintestinally in order to separately evaluate the intestinal and hepatic first-pass extraction. Cyclosporine or tacrolimus was administered into rat intestines, and after 10 min everolimus pharmacokinetics were evaluated. The blood concentrations of everolimus were measured by the high-performance liquid chromatography with tandem mass spectrometry. Total body clearance of everolimus was constant in the dosage from 0.2 to 1.0 mg/kg. The bioavailability after intraportal and intraintestinal administration were 48.0% and 21.2%, respectively. Concomitantly administered cyclosporine (5 mg/kg) , but not tacrolimus (1 mg/kg), significantly decreased the total body clearance of everolimus compared with the control, and also increased the bioavailabilty of everolimus after intraintestinal administration 1.75-fold. Cyclosporine significantly increased the area under the blood concentration-time curve of everolimus after the intraintestinal constant infusion 3-fold, and increased that after the intraportal constant infusion only 1.35-fold. In conclusion, the intestine as well as liver contributes to the first-pass extraction for everolimus in rats. Intestinally administered cyclosporine inhibited the intestinal extraction of everolimus more than its hepatic extraction.

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Section: Discussionsupporting

confidence: 42%

Section: Discussionmentioning

confidence: 99%

Effect of Intestinal and Hepatic First-pass Extraction on the Pharmacokinetics of Everolimus in Rats

Yokomasu

Yano

Sato

et al. 2008

Drug Metabolism and Pharmacokinetics

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“…Since TAC is well absorbed from the upper section of the small intestine [42], we performed the in situ absorption study using the upper section of the small intestine. The bile dose administered into the intestine (1.28 mL/kg) was based on the previously reported value of bile flow in rats (3.2 mL/h/kg) [43] and the blood sampling time of 2 h. Upon intraloop administration of TAC with undiluted bile, double-diluted bile, or saline, the AUC 0-2 of TAC showed a positive correlation with the amount of bile (Figure 4 and Table 2). Sauer et al, reported that after BDL, the intestinal absorption rate of a bile acid taurocholate reduced and that the intestinal absorption of bile acids appears to be regulated by their systemic concentration [44].…”

Section: Discussionmentioning

confidence: 99%

Effects of bile duct stricture on the pharmacokinetics of the immunosuppressant tacrolimus in rats

Kobuchi¹,

Fukushima²,

Maeda³

et al. 2013

Interact Med Chem

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Background: To investigate the effects of bile duct stricture on the pharmacokinetics of the immunosuppressant tacrolimus, the pharmacokinetics of tacrolimus in rats with bile duct ligation were evaluated and the effects of the amount of intestinal bile on intestinal tacrolimus absorption were determined. Methods:In vivo pharmacokinetic studies and in vitro metabolic studies in rats with bile duct ligation were performed. In addition, an in situ absorption study was performed. Results: After an intravenous bolus injection of tacrolimus, the area under the blood concentration-time curve in rats with bile duct ligation was approximately 1.9-fold greater than that in control rats. The total clearance and steady-state volume of distribution decreased in the rats with bile duct ligation by 44.1% and 40.4%, respectively. Moreover, the production ratios of demethyl-tacrolimus and hydroxy-tacrolimus in the hepatic microsomes of rats with bile duct ligation were 59-62% and 21-43%, respectively, lower than the corresponding ratios in control rats. The area under the blood concentration-time curve after intraloop administration of tacrolimus with double-diluted bile or with saline was significantly lesser than that with undiluted bile. Significant positive linear correlations were observed between the amount of intestinal bile and the area under the blood concentration-time curve of tacrolimus (r=0.999, p<0.05). Conclusions:The decrease in the hepatic intrinsic clearance of tacrolimus in rats with bile duct ligation suggests that the bile duct stricture might contribute to the clinically observed inter-and intra-patient pharmacokinetic variability. The amount of bile in the intestine is an important factor that should be considered during tacrolimus treatment. When the route of administration of tacrolimus is changed from injection to an oral one or during long-term oral administration of tacrolimus in patients with bile duct stricture, the decrease in absorption should be taken into account, and the dose should be adjusted accordingly. Taken together, the data indicate that personalized therapy is required for patients with bile duct stricture, and it is necessary to carefully evaluate therapeutic drug monitoring data for tacrolimus.

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“…Although reports relating toaltered absorption haven ot been extensivelydocumented in ARF ratmodels,there areafewinstancest od atethats uggest altered absorption:c yclosporine,Y JA-20379-8,diltiazem (CAS 42399-41-7),propranolol,metoprolol (CAS 83-43-2),oltipraz (CAS 64224-21-1),DA-7867,azosemide (CAS 27589-33-9) etc [ 21,25,30,40,41,46,53,55,56].Inthe caseo fcyclosporine in cisplatin,gentamicin,a nd glycerol induced ARF models (Table 2),therewasasignificantr eduction in the rateo fo ralabsorption and itw asalso attributed tothe diminished bile secretion whicho therwisem ayhavecontributed toani mproved solubility of cyclosporine in the intestinalfluids.Thisphenonmenon Glycerol (56-81-5) induced ARF The AUC values of tolbutamide were nearly 40 % lower in ARF rats relative to control rats. This was accompanied by moderate increase in the body clearance of tolbutamide in ARF rats.…”

Section: Absorption Related Changesmentioning

confidence: 99%

“…2003 [53] Cisplatin induced ARF The pharmacokinetics of cyclosporine A was unaltered between ARF and control rats after intravenous dosing. However, after oral dosing in ARF rats the plasma concentrations of cyclosporine A were significantly lower (3-fold lowered peak concentration was observed) in comparison to control rats.…”

Section: M2 M3 and M4)mentioning

confidence: 99%

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

Srinivas¹

2011

Arzneimittelforschung

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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.

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Decreased Cyclosporin A Concentrations in the Absorption Phase Using Microemulsion Preconcentrate Formulation in Rats with Cisplatin-Induced Acute Renal Failure

Cited by 6 publications

References 21 publications

Effect of Intestinal and Hepatic First-pass Extraction on the Pharmacokinetics of Everolimus in Rats

Effect of Intestinal and Hepatic First-pass Extraction on the Pharmacokinetics of Everolimus in Rats

Effects of bile duct stricture on the pharmacokinetics of the immunosuppressant tacrolimus in rats

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

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