Drug-induced cholestasis

Padda, Manmeet; Sanchez, Mayra; Akhtar, Abbasi J.; Boyer, James L.

doi:10.1002/hep.24229

Cited by 318 publications

(314 citation statements)

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“…Furthermore, only TER significantly induced the expression of CYP7A1, a rate-limiting enzyme in the biosynthesis of bile acid, by approximately 6-fold in human hepatocytes ( Figure 2B). Many drugs disrupt homeostatic mechanisms by directly inhibiting bile acid transporters, such as NTCP or BSEP, leading to bile acid-induced hepatotoxicity [28][29][30] . Our results implied TER may have similar impacts on the homeostasis of bile acid.…”

Section: Discussionmentioning

confidence: 99%

Inhibition of hepatic cytochrome P450 enzymes and sodium/bile acid cotransporter exacerbates leflunomide-induced hepatotoxicity

Wang

et al. 2016

Acta Pharmacol Sin

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Aim: Leflunomide is an immunosuppressive agent marketed as a disease-modifying antirheumatic drug. But it causes severe side effects, including fatal hepatitis and liver failure. In this study we investigated the contributions of hepatic metabolism and transport of leflunomide and its major metabolite teriflunomide to leflunomide induced hepatotoxicity in vitro and in vivo. Methods: The metabolism and toxicity of leflunomide and teriflunomide were evaluated in primary rat hepatocytes in vitro. Hepatic cytochrome P450 reductase null (HRN) mice were used to examine the PK profiling and hepatotoxicity of leflunomide in vivo. The expression and function of sodium/bile acid cotransporter (NTCP) were assessed in rat and human hepatocytes and NTCP-transfected HEK293 cells. After Male Sprague-Dawley (SD) rats were administered teriflunomide (1,6, 12 mg • kg, ig) for 4 weeks, their blood samples were analyzed. Results: A nonspecific CYPs inhibitor aminobenzotriazole (ABT, 1 mmol/L) decreased the IC 50 value of leflunomide in rat hepatocytes from 409 to 216 μmol/L, whereas another nonspecific CYPs inhibitor proadifen (SKF, 30 μmol/L) increased the cellular accumulation of leflunomide to 3.68-fold at 4 h. After oral dosing (15 mg/kg), the plasma exposure (AUC 0-t ) of leflunomide increased to 3-fold in HRN mice compared with wild type mice. Administration of leflunomide (25 mg • kg -1 • d -1 ) for 7 d significantly increased serum ALT and AST levels in HRN mice; when the dose was increased to 50 mg • kg, all HRN mice died on d 6. Teriflunomide significantly decreased the expression of NTCP in human hepatocytes, as well as the function of NTCP in rat hepatocytes and NTCP-transfected HEK293 cells. Four-week administration of teriflunomide significantly increased serum total bilirubin and direct bilirubin levels in female rats, but not in male rats. Conclusion: Hepatic CYPs play a critical role in detoxification process of leflunomide, whereas the major metabolite teriflunomide suppresses the expression and function of NTCP, leading to potential cholestasis.

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Section: Discussionmentioning

confidence: 99%

Inhibition of hepatic cytochrome P450 enzymes and sodium/bile acid cotransporter exacerbates leflunomide-induced hepatotoxicity

Wang

et al. 2016

Acta Pharmacol Sin

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“…Among DILI, cholestatic and mixed cholestatic hepatocellular injuries are often severe manifestations of drug toxicity (Padda et al, 2011). In order to predict and understand the mechanisms underlying drug hepatotoxicity, in vivo and in vitro model systems are used.…”

Section: Introductionmentioning

confidence: 99%

Role of Multidrug Resistance Protein 3 in Antifungal-Induced Cholestasis

et al. 2016

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Drug-induced liver injury is an important clinical entity resulting in a considerable number of hospitalizations. While drug-induced cholestasis due to the inhibition of the bile salt export pump (BSEP) is well investigated, only limited information on the interaction of drugs with multidrug resistance protein 3 (MDR3) exists and its role in the pathogenesis of drug-induced cholestasis is poorly understood. Therefore, we aimed to study the interaction of drugs with MDR3 and the effect of drugs on canalicular lipid secretion in a newly established polarized cell line system that serves as a model of canalicular lipid secretion. LLC-PK 1 cells were stably transfected with human Na 1 -taurocholate cotransporting polypeptide, BSEP, MDR3, and ABCG5/G8 and grown in the Transwell system. Apical phospholipid secretion and taurocholate transport were assayed to investigate the effect of selected drugs on MDR3-mediated phospholipid secretion as well as inhibition of BSEP. The established cell line displayed vectorial bile salt transport and specific phosphatidylcholine secretion into the apical compartment. The antifungal azoles, posaconazole, itraconazole, and ketoconazole, significantly inhibited MDR3-mediated phosphatidylcholine secretion. In contrast, amoxicillin clavulanate and troglitazone did not interfere with MDR3 activity. Drugs interfering with MDR3 activity did not display a parallel inhibition of BSEP. Our in vitro model for MDR3-mediated phospholipid secretion facilitates parallel screening for MDR3 and BSEP inhibitors. Our data demonstrate that the cholestatic potential of certain drugs may be aggravated by simultaneous inhibition of BSEP and MDR3.

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“…The presented case was notable for a period of prolonged hypotension shortly before SC-CIP was diagnosed on imaging, as well as mechanical ventilation with PEEP. Medications currently known to cause cholestasis with bile duct injury or sclerosing cholangitis-like cholestasis (19) were not administered to the patient during his hospitalization.…”

Section: A B a Bmentioning

confidence: 99%