Altered Pharmacokinetics of Paclitaxel in Experimental Hepatic or Renal Failure

Jiko, Mari; Yano, Ikuko; Okuda, Masahiro; Inui, Kentaro

doi:10.1007/s11095-004-1190-6

Cited by 16 publications

(13 citation statements)

References 23 publications

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“…In the present study, CCl 4 treatment induced apparent liver dysfunction without renal damage, and glycerol treatment induced marked renal dysfunction with little liver injury. These results are mostly consistent with the previous studies [5,10]. Therefore, our results confirm that CCl4 and glycerol treatment induce selective hepatic and renal dysfunction.…”

Section: -Note-supporting

confidence: 93%

Effects of Acute Hepatic and Renal Failure on Pharmacokinetics of Flunixin Meglumine in Rats

Hwang

Yun

2011

Exp. Anim.

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Abstract:The aim of this study was to investigate the effects of hepatic and renal failure on the pharmacokinetics of flunixin in carbon tetrachloride (CCl 4 )-and glycerol-treated rats. After intravenous administration of flunixin (2 mg/kg), the plasma concentration of flunixin was measured by high-performance liquid chromatography. Both acute hepatic and renal failure resulted in significantly increased area under the curve (AUC), prolonged elimination half-life (t 1/2β ), and reduced total body clearance (Cl tot ) compared with respective controls (P<0.05). In conclusion, hepatic failure as well as renal failure modified the pharmacokinetics of flunixin.

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Section: -Note-supporting

confidence: 93%

Effects of Acute Hepatic and Renal Failure on Pharmacokinetics of Flunixin Meglumine in Rats

Hwang

Yun

2011

Exp. Anim.

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“…A formal preclinical toxicity study was not completed because it was only necessary to identify a safe dose in rats that could be used for subsequent studies to determine the bioavailability of paclitaxel following the oral administration of Taxol TM and other formulations. Relatively few studies have reported the pharmacokinetic parameters for paclitaxel following Taxol TM in rats [18,19]. About 100 studies identified using PubMed TM with the search terms: rats, pharmacokinetics and paclitaxel were examined; however, only two studies described the pharmacokinetics of Taxol TM following an intravenous bolus in rats [18,19].…”

Section: Discussionmentioning

confidence: 99%

Intravenous administration of paclitaxel in Sprague‐Dawley rats: what is a safe dose?

Shord

Camp

2006

Biopharm & Drug Disp

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Few studies describe the administration of Taxol to rats; however, rats are typically used to study the toxicity of new drugs or novel formulations. A dose finding study was conducted to determine a safe dose of Taxol following intravenous administration in rats. Male Sprague-Dawley rats received a bolus of paclitaxel 5-20 mg/kg i.v. Blood was drawn before administration and at the following times after administration: 0.5, 1, 2, 3, 4, 6, 8, 12, 16, 20 and 24 h. Plasma concentrations were determined using high performance liquid chromatography. Two rats received paclitaxel 20 mg/kg and died immediately. Nine rats received paclitaxel 10 mg/kg; seven of these rats died within 12 h and two rats were killed due to moribund conditions. Ten rats received paclitaxel 5 mg/kg with no morbidity. The following pharmacokinetics for paclitaxel in the plasma were estimated: C0, 8977 ng/ml; AUC(0 --> infinity), 7477 ng*h/ml; CL(s), 668 ml/h*kg; V(ss), 1559 ml/kg; V(z) 2557 ml/kg and t(1/2), 2.6 h. It is concluded that further pharmacokinetic studies that are rationally designed to include appropriate measures of preclinical toxicity associated with paclitaxel are needed to identify formally the safest dose in rats following intravenous administration; however, these data indicate that male Sprague-Dawley rats can safely receive Taxol in a 5 mg/kg i.v. bolus.

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“…In previous kinetic analyses of TST 6b-hydroxylation by rat liver microsomes, velocity data were fitted to a one-enzyme hyperbolic kinetic model (Jimenez et al, 1992;Murray and Butler, 1996;Jiko et al, 2005;Velenosi et al, 2012) or to a sigmoidal kinetics with low degree of autoactivation [Hill coefficients of 1.2-1.4 (Carr et al, 2006)]. This did b CL int is expressed as ml/min per mg protein for liver microsomes and ml/min per pmol P450 for recombinant enzymes.…”

Section: Discussionmentioning

confidence: 99%

Differential Effect of Liver Cirrhosis on the Pregnane X Receptor–Mediated Induction of CYP3A1 and 3A2 in the Rat

et al. 2014

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Conflicting results have been obtained by clinical studies investigating the effect of liver cirrhosis on enzyme induction. Because ethical concerns do not give consent for methodologically rigorous studies in humans, we addressed this question by examining the effect of the prototypical inducer dexamethasone (DEX) on the pregnane X receptor (PXR)-mediated induction of CYP3A1 and 3A2 in a validated animal model of liver cirrhosis obtained by exposure of rats to carbon tetrachloride. For this purpose, we assessed mRNA levels, protein expressions, and enzymatic activities of both CYP3A enzymes, as well as mRNA and protein expressions of PXR in rat populations rigorously stratified according to the severity of liver insufficiency. Constitutive mRNA and protein expressions of CYP3A1 and CYP3A2 and their basal enzyme activities were not affected by liver dysfunction. DEX treatment markedly increased steadystate mRNA level, protein content, and enzymatic activity of CYP3A1 in healthy and cirrhotic rats, irrespective of the degree of liver dysfunction. On the contrary, the inducing effect of DEX on gene and protein expressions and enzyme activity of CYP3A2 was preserved in moderate liver insufficiency, whereas it was greatly curtailed when liver insufficiency became severe. mRNA and protein expressions of PXR were neither reduced by liver dysfunction nor increased by DEX treatment. These results indicate that even the inducibility of cytochrome P450 isoforms under the transcriptional control of the same nuclear receptor may be differentially affected by cirrhosis and may partly explain why conflicting results were obtained by human studies.

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Altered Pharmacokinetics of Paclitaxel in Experimental Hepatic or Renal Failure

Abstract: These results suggested that not only hepatic failure but also renal failure could modify the pharmacokinetics of paclitaxel in vivo.

Cited by 16 publications

References 23 publications

Effects of Acute Hepatic and Renal Failure on Pharmacokinetics of Flunixin Meglumine in Rats

Effects of Acute Hepatic and Renal Failure on Pharmacokinetics of Flunixin Meglumine in Rats

Intravenous administration of paclitaxel in Sprague‐Dawley rats: what is a safe dose?

Differential Effect of Liver Cirrhosis on the Pregnane X Receptor–Mediated Induction of CYP3A1 and 3A2 in the Rat

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