Effect of chlorpromazine on the function of the perfused isolated liver

Kendler, J.; Bowry, Subhash; Seeff, Leonard B.; Zimmerman, Hyman J.

doi:10.1016/0006-2952(71)90244-9

Cited by 33 publications

(13 citation statements)

References 16 publications

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“…Impaired hepatic blood flow is another possibility. It was apparently not the cause of cholestasis in the isolated perfused rat liver (Kendler et al 1971;Tavoloni et al 1976). The beneficial effect of TC seen in the present study is not attributable to a restoration in blood flow.…”

Section: Discussionmentioning

confidence: 95%

Taurolithochoiic acid and chlorpromazine cholestasis in the rhesus monkey

Strasberg¹,

Kay²,

Ilson³

et al. 1979

Can. J. Physiol. Pharmacol.

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Taurolithocbolic acid and chldarprornaajne ckolestasis in the rkesus monkey. Can. J. Physiol. Plaarmacol. 54, 1138-1 147.Taurolithocholic acid (TLC) and clhlorprdamaziine (CPZ) ckolestasis were studied in reversible primate models in order to determine the level of injury, changes in canalicular permeability, and the effects of taurocholic acid (TC) on the production of cholestasis. TLC produced dose-dependent cholestasis. Reductions in bile acid secretion rate and concentration, larger decreases in [ldC]erythritol clearance than in total bile flow, and increased bicarbonate concentration in bile indicated that the cholestasis was canalicular in origin. TC prevented cholestasis; it also caused an increased secretion s f TLC in bile, but the TLC:TC concentration ratio was unchanged, providing evidence that TC is beneficial because it hastens excretion sf TLC from the liver cell in micelles. Permeability to [ Wlinulin was increased during the recovery period. CPZ caused reductions in bile flow, bile acid secretion rate, and [14C]erythritol clearance, and almost comanpletely eliminated biliary bicarbonate secretion, suggesting a mixed canalicular and ductlalar form of cholestasis. When TC was given with CPZ, no reductions iia bile acid secretion rate or [I4C]erythritol clearance were found but bicarbonate secretion was n-aarkedly reduced, bicarbonate concentration diminished, and bile acid concentration increased, i.e., TC protected against the canalicular component of CPZ chslestasis and unmasked the ductular component. Permeability to inulin was increased in three of four animals. TLC clholestasis occurs predominately at the canalicular level, whereas CPZ probably aflects bile Wow at the ductular level as well. TC protects the hepatocyte against the effects of both agents. STRASBERG, S. M., KAY, R. M., IESON, R. G., PETRUNKA, @. N., et PALOHEHMO, J. E. 1979-Taaarolithocholic acid and chlorpromazine cholestasis in the rhesus monkey. Can. J. Physiol. Pharmacol. 5'7, 1138-1 147.On a Ctudik la cholestase due 8 B'acide taurolithoclholique (TLC) et B la chlo~promaaine (CPZ) sur des modkles rkversibles utilisant des primates, dans le but de determiner le degre de blessure, les changements de perrnCabilit6 canaliculaire ainsi que les effets de l'acide taurocholique (TC) sur la production d9une clholestase. TLC produit une cholestase dose-dependante. Des diminutions du taux de skrCtion et de la concentration en acide biliaire, des rCductions de l'elirnlnation du [14C]6rythritol qui sont plus importantes que celles du d6bit total de bile et une concentration accrue en bicarbonate dans la bile, indiqusnt que les cholestases sont d'origine canaliculaire. TC prCvient la cholestase et cause une secretion accure de TLC dans la bile; par contre. le rapport des concentrations TLC:TC demeure inchaiagk, ce qui eonstitue la preuve que TC est bknefique car il acckl&re l'excr6tion d'acide taurolithocholique des cellules hepatiques vers Ies micelles. La permCabilit6 la [3H]inuline augmente au cows de la pCriode de rdcuperation. CPZ caus...

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Section: Discussionmentioning

confidence: 95%

Taurolithochoiic acid and chlorpromazine cholestasis in the rhesus monkey

Strasberg¹,

Kay²,

Ilson³

et al. 1979

Can. J. Physiol. Pharmacol.

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“…This was not unexpected, since neither chronic nor acute administration of CPZ to rats has previously resulted in a cholestatic syndrome (1,14,21), and there appear to have been no reports of EE-induced cholestasis in experimental animals. Both drugs have been shown to reduce bile flow in the isolated perfused rat liver (12,13); however, this may be due to the direct cytotoxic effect which can be demonstrated in other in vitro liver preparations (7)(8)(9)31). Neither drug poten tiated the cholestatic effects of intravenously administered bile salts, nor could the interac tion of EE be differentiated from that of the supposedly less cholestatic EB.…”

Section: Discussionmentioning

confidence: 92%

Effect of Chlorpromazine and Erythromycin on Bile Salt-Induced Cholestasis in the Rat

Drew¹,

Priestly²

1979

Pharmacology

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The effects of subacute administration of chlorpromazine HCl (CPZ), erythromycin base and erythromycin estolate on the cholestatic response to intravenous taurolithocholate (TLC) and taurochenodeoxycholate (TCDC) in the rat were investigated. All three enhanced the recovery of bile flow after TCDC but not after TLC. Erythromycin base and estolate enhanced bile flow recovery after TCDC and potentiated the increase of plasma 5’-nucleotidase, as did CPZ. Neither erythromycin estolate nor CPZ precipitated a cholestatic response in rats maintained for 9–13 days on a diet supplemented with 0.05% lithocholic acid. It is concluded that the interaction of CPZ and erythromycins with bile salts is not based on the cholestatic properties of the drugs, and hence is not a practical way of distinguishing cholestatic from non-cholestatic drugs.

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“…sitivity to that drug, have led us (7)(8)(9)(10) to suggest that this form of drug-induced hepatic injury is the result of slight intrinsic toxilcity which when coupled with generalized hypersensitivity leads to clinically evitden t liver disease.…”

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confidence: 97%

“…Phenothiazine derivatives have been found to lead to injury of ralbbit liver slices (3) and Chang cells (1,2), and to lead to impaired function of the ex vivo perfused liver ( 10,11). Previous studlies have shown that perfusion of the isolated liver with erythromycin derivatives also leads to inhibition of bile production and to impaired bromsullfophthalein excretion ( 12 ) .…”

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confidence: 99%