Cyclosporin A-induced cholestasis

Stone, Bradford G.; Udani, Mahendra; Sanghvi, Ajit; Warty, Vijay; Plocki, Keith; Bedetti, Carlos D.; Thiel, David H. Van

doi:10.1016/0016-5085(87)91025-0

Cited by 87 publications

(14 citation statements)

References 22 publications

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“…Modest rise in bilirubin is the most frequent abnormality seen during cyclosporin therapy in humans. Stone et al [19] showed that cyclosporin lowers bile flow by inhibiting bile salt transport. Cyclosporin is highly lipid soluble and accumulates in the lipid regions of membranes.…”

Section: Discussionmentioning

confidence: 99%

Enhancement of cyclosporin A induced hepato‐ and nephrotoxicity by glutathione depletion

Inselmann

Lawerenz

Nellessen

et al. 1994

Eur J Clin Investigation

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The role of glutathione in cyclosporin A (cyclosporin) hepato- and nephrotoxicity has not been clarified yet. The hypothesis that a glutathione deficit enhances the hepato- and nephrotoxicity of cyclosporin was tested in an animal model. Glutathione depletion was achieved by administration of diethyl maleate (DEM). Adult Sprague Dawley rats were divided into four groups (A-D; n > or = 8) and treated for 8 d as follows: group A, glucose 5% (0.4 ml kg-1, i.p.) +3 h later olive oil (0.5 ml kg-1, oral); group B, DEM (0.4 ml kg-1, i.p.) +3 h later olive oil (0.5 ml kg-1, oral); group C, glucose 5% (0.4 ml kg-1, i.p.) +3 h later cyclosporin (50 mg kg-1, oral); group D, DEM (0.4 ml kg-1, i.p.) +3 h later cyclosporin (50 mg kg-1, oral). Cyclosporin alone increased bilirubin concentration from 1.0 +/- 0.6 mumol l-1 to 8.4 +/- 1.9 mumol l-1 (P < 0.05) without changing transaminases. In glutathione depleted rats cyclosporin caused a further elevation of serum bilirubin up to 23.4 +/- 5.5 mumol l-1. This was accompanied by a 50% increase of serum glutamic oxaloacetic transaminase (GOT). Cyclosporin alone significantly decreased creatinine clearance to 50% of controls (P < 0.05). Cyclosporin treatment following glutathione depletion resulted in a further decline of creatinine clearance to 22% of controls. DEM had no effect on kidney or liver function. In conclusion glutathione depletion increases the susceptibility to cyclosporin-induced liver and kidney injury. The results support the hypothesis that sufficient cellular glutathione concentrations may be important to prevent cyclosporin-induced hepato- and nephrotoxicity.

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Section: Discussionmentioning

confidence: 99%

Enhancement of cyclosporin A induced hepato‐ and nephrotoxicity by glutathione depletion

Inselmann

Lawerenz

Nellessen

et al. 1994

Eur J Clin Investigation

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“…It is well established that cyclosporin in high doses has cholestatic side effects [3), and from animal studies we know that cyclosporin reduces bile formation although no deterioration of liver biochemistry occurs [13,18,23). Our patients were on a low-dose regimen of cyclosporin, but a sideeffectofthisdrugmustbeconsideredasthecauseofthe impaired bile formation together with factors like the continuous immunological challenge to the graft and possible permanent injury during preservation and reperfusion.…”

Section: Discussionmentioning

confidence: 92%

The bile acid independent flow is reduced in the transplanted liver

Friman

Persson

Karlberg

et al. 1992

Transplant International

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Bile secretion is an important indicator of liver graft function. Reports on bile formation by the transplanted liver with stable function some months after operation are scarce. In this study bile flow, bile salt secretion rate (BSSR) and biliary clearance of polyethylene glycol (PEG) 900, a marker of canalicular bile flow, were studied in a group of liver-transplanted (LTX) patients (n = 8) 3-6 months after transplantation. A group of cholecystectomized patients with indwelling T-tubes (n = 6) served as a control group. Both groups were treated with oral ursodeoxycholic acid (500 mg/day). On the day of the study bile was drained for 6 h by gravity and four-hourly samples were used in the calculations. The relation between bile flow and BSSR analysed with linear regression showed a reduced bile acid independent flow in the livertransplanted group (0.11 ml/min) compared with the control group (0.20 ml/min). The relation between biliary clearance of PEG 900 and BSSR showed a significantly steeper slope for the cholecystectomized control patients (1.40 ml/Jlmol) compared with the liver-transplanted patients (0.30 mi/Jlmol). We conclude, that in spite of stable graft function with normal liver enzmyes, the transplanted liver has a reduced bile acid independent bile flow. The transplanted liver also has a reduced biliary clearance of PEG 900 indicating a reduced canalicular bile flow. The ~a use of this impaired bile formation could be due to the mfluence of the immunosuppressive drug cyclosporin, the result of damage to the liver during preservation and reperfusion or the continuous immunological challenge to the graft.

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“…The model of bile secretion studies in the rat is well validated [2]. The dose of cyclosporin used in the present study has been tested by Stone and coworkers [29]. The transplantation model has previously been tested in other kinds of studies but thus far not in bile secretion studies [20,21,31,38].…”

Section: Discussionmentioning

confidence: 99%

Influence of liver transplantation and cyclosporin on bile secretion – an experimental study in the rat

1995

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Bile secretion is reduced after liver transplantation. It has been suggested that this is due either to the effect of cyclosporin or to the damage to the liver graft during preservation and reperfusion. The aim of this study was to explore the influence of cyclosporin as well as of liver transplantation on bile secretion. Bile flow was studied in an experimental model in the rat. In syngeneic liver-transplanted animals, the bile flow was increased compared to the bile flow in the control group (1.29 +/- 0.09 ml/h vs 0.66 +/- 0.03 ml/h; P < 0.01), mainly due to an increased bile acid-independent flow (0.76 ml/h vs 0.50 ml/h; P < 0.01). The findings in the liver-transplanted rats contrasted with those in a group of nontransplanted animals treated with cyclosporin. Cyclosporin treatment resulted in a reduced bile acid-independent fraction (0.37 ml/h vs 0.50 ml/h, P < 0.05) of the bile flow, although no biochemical signs of hepatotoxicity were present. This reduction in the bile acid-independent fraction could, however, not be demonstrated when cyclosporin was given to a group of liver-transplanted rats, although a reduced total bile flow was recorded in the 1st hour measurements. In contrast to previous studies, we found that the cyclosporin vehicle (Cremophor EL), when administered chronically, induced a higher bile flow than that in the control rats. This effect was not seen in the transplanted rats. Our findings in this experimental rat model indicate that cyclosporin will influence and reduce bile secretion and bile acid secretion even if no other signs of liver dysfunction are present. On the other hand, the preservation and reperfusion in this model resulted in an increased bile flow, while bile acid secretion remained constant.

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Cyclosporin A-induced cholestasis

Cited by 87 publications

References 22 publications

Enhancement of cyclosporin A induced hepato‐ and nephrotoxicity by glutathione depletion

Enhancement of cyclosporin A induced hepato‐ and nephrotoxicity by glutathione depletion

The bile acid independent flow is reduced in the transplanted liver

Influence of liver transplantation and cyclosporin on bile secretion – an experimental study in the rat

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