Inhibition of biliary cholesterol and phospholipid secretion by cefmetazole. The role of vesicular transport and of canalicular events

Cava, Fernando; González, Julia García; González-Buitrago, José Manuel; Muriel, Carlos Muñiz; Jiménez, Rafael

doi:10.1042/bj2750591

Cited by 11 publications

(6 citation statements)

References 34 publications

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“…Studies with different species have shown that cholesterol and phospholipid biliary outputs increase in proportion to the increases in biliary bile acid secretion brought about by bile acid loads, 33,34 suggesting that biliary lipid secretion is tightly coupled to biliary secretion of bile acids. However, some organic anions, such as bilirubin, 12 certain antibiotics 13,35 , 36 and bile acid sulphates 37,38 have been reported to decrease cholesterol and phospholipid biliary excretion without affecting bile acid secretion. This uncoupling effect could be a consequence, as reported for ampicillin and bilirubin ditaurate, of aggregate formation with intracellular cholesterol and phospholipids, thereby inhibiting lipid transport from intracellular sources to bile 12,13 .…”

Section: Discussionmentioning

confidence: 99%

“…This uncoupling effect could be a consequence, as reported for ampicillin and bilirubin ditaurate, of aggregate formation with intracellular cholesterol and phospholipids, thereby inhibiting lipid transport from intracellular sources to bile. 12,13 Other drugs, such as cyclobutirol 15 or cefmetazole, 36 induce a parallel depression of both biliary lipids and enzymes of the plasma membrane, which suggests an effect at the level of the canalicular membrane and indicates that the fusion of repair vesicles and, thus, the input of cholesterol and phospholipids to the canalicular membrane is impaired. In our experiments, piperacillin induced a marked decrease in biliary phospholipid secretion, under both basal conditions and when biliary lipid output had been previously increased by an infusion of taurocholate, and the impairment in phospholipid secretion could not be reversed by additional administration of the bile acid.…”

Section: Discussionmentioning

confidence: 99%

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Choleresis and inhibition of biliary lipid secretion induced by piperacillin in the rat

González

Mauriz

Jiménez

et al. 2002

Clin Exp Pharma Physio

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1. The effects of the administration piperacillin on bile flow and biliary lipid secretion were studied in male Wistar rats. 2. Intravenous injection of piperacillin at doses ranging from 0.3 to 3.0 mmol/kg bodyweight led to an increase in its biliary concentration and excretion rate. Maximal biliary excretion was reached at a dose of 2.0 mmol/kg piperacillin. 3. Excretion of the antibiotic into bile was associated with a marked choleresis. A linear relationship was observed between bile flow and piperacillin excretion, 5.7 micro L bile being produced per micro mol piperacillin excreted into the bile. 4. Continuous i.v. infusion of piperacillin at 2.0 mmol/100 g per min did not result in significant changes in bile acid or cholesterol secretion, but biliary phospholipid secretion was markedly reduced. The inhibitory effect on phospholipid secretion was also present when biliary lipid output had been previously increased by an infusion of taurocholate (200 nmol/100 g per min). Addition of taurocholate did not reverse the impairment of phospholipid secretion induced by piperacillin. 5. These results indicate that acute administration of piperacillin in the rat induces a marked choleresis by stimulating bile acid-independent bile flow. The significant impairment in phospholipid secretion suggests a specific effect on intracellular supply and/or translocation across the canalicular membrane.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Choleresis and inhibition of biliary lipid secretion induced by piperacillin in the rat

González

Mauriz

Jiménez

et al. 2002

Clin Exp Pharma Physio

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“…In bosentanadministered rats, the biliary output of GSH was increased, but that of phospholipids was decreased; these changes were not observed in Mrp2-deficient rats (Fouassier et al, 2002). Similar phenomena were observed in rats administered ampicillin (Verkade et al, 1990), cefmetazole (Cava et al, 1991), bromosulfophthalein, and cefpiramide (Takikawa et al, 1993), although the doses of these drugs were much higher than those used in clinical conditions.…”

Section: Discussionmentioning

confidence: 52%

Ticlopidine, a Cholestatic Liver Injury-Inducible Drug, Causes Dysfunction of Bile Formation via Diminished Biliary Secretion of Phospholipids: Involvement of Biliary-Excreted Glutathione-Conjugated Ticlopidine Metabolites

et al. 2012

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The antiplatelet drug, ticlopidine (TIC), reportedly causes cholestatic liver injuries. The present study analyzed the effect of TIC on bile formation, revealing that the biliary secretion of phospholipids was significantly decreased in TIC-administered Sprague Dawley (SD) rats. However, the effect of TIC on biliary phospholipids was not observed in SD rats pretreated with diethylaminoethyl diphenylpropylacetate that inhibits cytochrome P450s (P450), or in Eisai hyperbilirubinemic rats (EHBR) lacking functional multidrug resistance-associated protein 2 (MRP2/ABCC2). These results suggest that glutathione-conjugated TIC metabolites (TIC-SGs), which were formed in the liver after P450s-mediated metabolism and were excreted extensively into bile by MRP2, mediated the observed alterations of the bile composition. Administration of TIC caused significant liver injuries in SD rats, with decreased biliary phospholipids, but not in EHBR, consistent with the in vitro observation that phospholipid-bile acid-mixed micelles moderated the cytotoxic effects of bile acids. Further analyses revealed that TIC-SGs did not directly inhibit multidrug resistance 3 P-glycoprotein (MDR3/ ABCB4)-mediated phosphatidylcholine efflux in vitro. Because the diminished biliary secretion of phospholipids with TIC administration was restored by taurocholate infusion in SD rats, the decreased biliary concentration of bile acids, due to the stimulation of bile acid-independent bile flow driven by TICSGs, might have indirectly attenuated phospholipid secretion. In conclusion, extensive biliary excretion of TIC-SGs decreased the biliary secretion of phospholipids, which might have increased the risk of TIC-induced cholestatic liver injury.

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“…Cefmetazole choleresis, as a doserelated phenomenon partly dependent on the osmotic properties of the compound excreted into bile, has been previously reported (Gonzhlez et al 1989;Cava et al 1991). The smaller increase in bile flow found in diabetic animals could be explained on the basis of the reduced excretion of cefmetazole, with no different choleretic capacity than the controls.…”

Section: Discussionmentioning

confidence: 68%

Effects of Diabetes on Disposition and Hepatic Handling of Cefmetazole in Rats

Barrientos¹,

González²,

Tuñón³

et al. 1993

Clin Exp Pharma Physio

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1. The effects of streptozotocin-induced diabetes on disposition and hepatic handling of cefmetazole, a broad-spectrum cephalosporin, were investigated in rats. 2. Male Wistar rats were pretreated with streptozotocin (60 mg/kg, i.p.) to induce uncontrolled diabetes. Fourteen days later bile flow was significantly reduced (12%) and bile acid secretion was significantly enhanced (87%) when compared with control animals. 3. Following intravenous injection of cefmetazole at a dose of 200 mumol/kg, maximal and cumulative biliary excretion of the antibiotic were significantly impaired in streptozotocin-treated animals (27 and 22%, respectively). 4. Cefmetazole excretion into bile was accompanied by marked choleresis. The magnitude of bile flow increase was larger in control animals. 5. Total systemic clearance of the antibiotic was reduced (36%) and mean half-life for the fast and slow phases of disposition increased (136 and 48%, respectively) in diabetic rats. 6. These changes were probably due to the diabetic condition of the animals because insulin treatment resulted in almost complete correction.

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Inhibition of biliary cholesterol and phospholipid secretion by cefmetazole. The role of vesicular transport and of canalicular events

Cited by 11 publications

References 34 publications

Choleresis and inhibition of biliary lipid secretion induced by piperacillin in the rat

Choleresis and inhibition of biliary lipid secretion induced by piperacillin in the rat

Ticlopidine, a Cholestatic Liver Injury-Inducible Drug, Causes Dysfunction of Bile Formation via Diminished Biliary Secretion of Phospholipids: Involvement of Biliary-Excreted Glutathione-Conjugated Ticlopidine Metabolites

Effects of Diabetes on Disposition and Hepatic Handling of Cefmetazole in Rats

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