The effect of diethyl ether, pentobarbitone and urethane anaesthesia on diflunisal conjugation and disposition in rats

Watt, J. A.; Dickinson, R. G.

doi:10.3109/00498259009046848

Cited by 12 publications

(4 citation statements)

References 16 publications

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“…In most hepatobiliary pharmacokinetic studies, rats have to be anesthetized for bile sampling and very few attempts have been made to address the effect of anesthesia for hepatobiliary pharmacokinetic studies [3,7].…”

Section: Introductionmentioning

confidence: 99%

Biliary clearance of bromosulfophthalein in anesthetized and freely moving conscious rat

Park

Shim

et al. 2009

Biopharm & Drug Disp

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The aim of this study was to investigate the effect of anesthesia on the pharmacokinetics of bromosulfophthalein (BSP) with focus on biliary clearance. The plasma concentration profile and biliary clearance of intravenously administered BSP was compared in conscious freely moving bile duct catheterized rats and rats anesthetized with ketamine or Zoletil. The plasma concentration of BSP in conscious rats was similar to that of anesthetized rats, irrespective of the anesthetic used. There was no significant difference in the volume of distribution, total body clearance and mean residence time of BSP between the groups. The biliary clearance of BSP in rats anesthetized using ketamine or Zoletil was also similar to that of conscious rats. Only bile flow was increased under anesthetization compared with conscious rats. These results demonstrate that the pharmacokinetics of BSP, including biliary clearance, in ketamine or Zoletil anesthetized rats is virtually identical to that in conscious rats and it may be related to blood flow limited hepatic disposition of BSP. Furthermore, they suggest the conscious rat model does not offer methodological advantage and the anesthesia model is suitable for a realistic approximation of the hepatobiliary transport of BSP.

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Section: Introductionmentioning

confidence: 99%

Biliary clearance of bromosulfophthalein in anesthetized and freely moving conscious rat

Park

Shim

et al. 2009

Biopharm & Drug Disp

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“…It is important to point out the existence of two experimental conditions that may have influenced the pharmacokinetic outcome of this study. Firstly, the use of ether anaesthesia, although commonly adopted in rodent pharmacokinetic studies, has the potential to influence the kinetics of a drug undergoing a phase II conjugation involving glucuronidation and/or sulfation [9]. Secondly, the use of a fed condition for the intravenous administration may have an impact on the kinetics if the drug has a high hepatic extraction ratio [10][11][12].…”

Section: Resultsmentioning

confidence: 99%

Intravenous pharmacokinetics, oral bioavailability and dose proportionality of ragaglitazar, a novel PPAR‐dual activator in rats

Kota

Chaluvadi

Mullangi

et al. 2004

Biopharm & Drug Disp

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Pharmacokinetics of ragaglitazar (a novel phenoxazine derivative of aryl propanoic acid), a potent insulin sensitizing and lipid-lowering compound was studied in Wistar rats. A single dose of 1, 3 or 10 mg/kg of ragaglitazar was given orally to male rats (n=4 per dose level) to evaluate dose proportionality. In another study, a single intravenous bolus dose of ragaglitazar was given to rats (n=4) at 3 mg/kg dose following administration through the lateral tail vein in order to obtain the absolute oral bioavailability and clearance parameters. Blood samples were drawn at predetermined intervals and the concentration of ragaglitazar in plasma was determined by a validated HPLC method. Plasma concentration versus time data were generated following oral and intravenous dosing and pharmacokinetic analysis was performed using non-compartmental analysis. The results revealed that Cmax and AUC(0-infinity) increased more than proportionally to the administered oral doses. As dose increased in the ratio of 1:3:10, the mean Cmax and AUC(0-infinity) increased in the ratio of 1:3.2:13 and 1:3.2:16, respectively. After intravenous administration the systemic clearance and volume of distribution of ragaglitazar in rats were 139+/-30 ml/h/kg and 463+/-51 ml/kg, respectively (mean+/-SD). Plasma concentrations declined mono-exponentially following intravenous administration and elimination half-life (t1/2) was about 2.6 h and not significantly different (p > 0.05) from the value from oral administration. Mean residence time (MRT) values for ragaglitazar were found to be 4.15+/-0.52 h (3.5 to 4.6 h). Absolute oral bioavailability of ragaglitazar across the doses tested was in the range of 68%-93%. In conclusion, ragaglitazar exhibits promising pharmacokinetic properties in rats.

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“…21 However, in rats the half-life of diflunisal in vivo is in the order of 90 min. 22 Our studies are performed in a single pass isolated perfused rat liver preparation with outflowing perfusate collected over 1 min (in the order of 0.01 times the halflife). While in vivo and isolated liver methods are not directly comparable, we believe that while possible, it would be unlikely that significant amount of diflunisal conjugate metabolites would be detected in outflowing perfusate over our collection period.…”

Section: Discussionmentioning

confidence: 99%

Hepatic Disposition and Metabolite Kinetics of a Homologous Series of Diflunisal Esters

Hung

Mellick

Anissimov

et al. 1998

Journal of Pharmaceutical Sciences

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The hepatic disposition and metabolite kinetics of a homologous series of diflunisal O-acyl esters (acetyl, butanoyl, pentanoyl, and hexanoyl) were determined using a single-pass perfused in situ rat liver preparation. The experiments were conducted using 2% BSA Krebs-Henseleit buffer (pH 7.4), and perfusions were performed at 30 mL/min in each liver. O-Acyl esters of diflunisal and pregenerated diflunisal were injected separately into the portal vein. The venous outflow samples containing the esters and metabolite diflunisal were analyzed by high performance liquid chromatography (HPLC). The normalized outflow concentration-time profiles for each parent ester and the formed metabolite, diflunisal, were analyzed using statistical moments analysis and the two-compartment dispersion model. Data (presented as mean +/- standard error for triplicate experiments) was compared using ANOVA repeated measures, significance level P < 0.05. The hepatic availability (AUC'), the fraction of the injected dose recovered in the outflowing perfusate, for O-acetyldiflunisal (C2D = 0.21 +/- 0.03) was significantly lower than the other esters (0.34-0.38). However, RN/fu, the removal efficiency number RN divided by the unbound fraction in perfusate fu, which represents the removal efficiency of unbound ester by the liver, was significantly higher for the most lipophilic ester (O-hexanoyldiflunisal, C6D = 16.50 +/- 0.22) compared to the other members of the series (9.57 to 11.17). The most lipophilic ester, C6D, had the largest permeability surface area (PS) product (94.52 +/- 38.20 mL min-1 g-1 liver) and tissue distribution value VT (35. 62 +/- 11.33 mL g-1 liver) in this series. The MTT of these O-acyl esters of diflunisal were not significantly different from one another. However, the metabolite diflunisal MTTs tended to increase with the increase in the parent ester lipophilicity (11.41 +/- 2.19 s for C2D to 38.63 +/- 9.81 s for C6D). The two-compartment dispersion model equations adequately described the outflow profiles for the parent esters and the metabolite diflunisal formed from the O-acyl esters of diflunisal in the liver.

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The effect of diethyl ether, pentobarbitone and urethane anaesthesia on diflunisal conjugation and disposition in rats

Cited by 12 publications

References 16 publications

Biliary clearance of bromosulfophthalein in anesthetized and freely moving conscious rat

Biliary clearance of bromosulfophthalein in anesthetized and freely moving conscious rat

Intravenous pharmacokinetics, oral bioavailability and dose proportionality of ragaglitazar, a novel PPAR‐dual activator in rats

Hepatic Disposition and Metabolite Kinetics of a Homologous Series of Diflunisal Esters

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