Pharmacokinetics and Pharmacodynamic Action of Budesonide in Early– and Late–Stage Primary Biliary Cirrhosis

Hempfling, W.; Grünhage, F; Dilger, Karin; Reichel, Christoph; Beuers, Ulrich; Sauerbruch, Tilman

doi:10.1053/jhep.2003.50266

Cited by 147 publications

(95 citation statements)

References 28 publications

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“…Our previous pharmacokinetic study with budesonide revealed that budesonide should not be administered in late-stage PBC because of unpredicted side effects. 27 Rifampicin is used as second-line therapy for controlling pruritus in PBC. [36][37][38] It is a potent inducer of intestinal and hepatic CYP3A via activation of the pregnane X receptor/steroid and xenobiotic receptor.…”

Section: Discussionmentioning

confidence: 99%

“…Thereafter, each patient was treated with UDCA capsules (15 mg/kg daily, divided into a morning and an evening dose) for 3 weeks (days 2-22) and subsequently with rifampicin dragées (600 mg/d, evening dose) for 1 week (days [23][24][25][26][27][28][29]. Administration of 3 mg budesonide was repeated on study days 22 and 29.…”

Section: Methodsmentioning

confidence: 99%

“…Sample size calculation was based on the coefficient of variation of the budesonide AUC in a previous study of patients with PBC stages I-II. 27 The effect of UDCA and rifampicin on CYP3A metabolism was analyzed by use of the software package GraphPad Instat (Version 3.05, GraphPad Software, Inc., San Diego, CA). Differences between patients and healthy volunteers at baseline were tested for significance by the Mann-Whitney U test.…”

Section: Methodsmentioning

confidence: 99%

“…We analyzed CYP3A metabolism by (1) CYP3A-dependent 25 pharmacokinetics of oral budesonide, a glucocorticosteroid recently being suggested for combined medical treatment of early-stage PBC, 26,27 and by (2) urinary 6␤-hydroxycortisol, a noninvasive, validated marker of CYP3A induction. 28 (2) an alkaline phosphatase or ␥-glutamyltransferase level of more than 1.5-fold the upper limit of normal at initial diagnosis, and (3) histologically proven noncirrhotic liver disease compatible with PBC stages I-II within 5 years before inclusion and no morphological signs of portal hypertension on abdominal ultrasound at study entry.…”

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confidence: 99%

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No relevant effect of ursodeoxycholic acid on cytochrome P450 3A metabolism in primary biliary cirrhosis

et al. 2005

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Induction of cytochrome P450 3A (CYP3A) has been suggested as a mechanism of action of ursodeoxycholic acid (UDCA) in cholestasis. CYP3A is of key importance in human drug metabolism, being involved in presystemic extraction of more than 50% of all drugs currently available and of various endogenous compounds. Therefore, we compared the induction potential of UDCA with that of the prototypical inducer rifampicin in a human model study with the CYP3A substrates budesonide and cortisol. Twelve patients with early-stage primary biliary cirrhosis and eight healthy volunteers were treated with UDCA (15 mg/kg daily) for 3 weeks and subsequently with rifampicin (600 mg/d) for 1 week. Extensive pharmacokinetic profiling of oral budesonide (3 mg) was performed by determination of budesonide and phase I metabolites (6␤-hydroxybudesonide, 16␣-hydroxyprednisolone) in plasma and urine at baseline and at the end of each treatment. In parallel, urinary 6␤-hydroxycortisol, a validated marker of CYP3A induction, was determined. UDCA did not affect biotransformation of budesonide and urinary excretion of 6␤-hydroxycortisol either in patients or in healthy volunteers. Ratios of areas under plasma concentration-time curves (AUC 0-12 h during UDCA/AUC 0-12 h before UDCA) of both metabolites were not higher than those of budesonide itself. In contrast, administration of rifampicin markedly induced CYP3A metabolism, resulting in abolished budesonide plasma levels and high urinary excretion of 6␤-hydroxycortisol. Metabolite formation was enhanced by rifampicin, but not by UDCA (e.g., AUC 16␣-hydroxyprednisolone /AUC budesonide in patients: baseline, 8.6 ؎ 3.9; UDCA, 10.7 ؎ 7.1; rifampicin, 527.0 ؎ 248.7). In conclusion, UDCA is not a relevant inducer of CYP3A enzymes in humans. (HEPATOLOGY 2005;41:595-602.)

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Section: Discussionmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

mentioning

confidence: 99%

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No relevant effect of ursodeoxycholic acid on cytochrome P450 3A metabolism in primary biliary cirrhosis

et al. 2005

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“…However, it should be noted that transaminitis in PBC may in part be a feature of hepatocyte injury from the effects of cholestasis. Of note, portal vein thrombosis has been reported as a complication in up to 29% of patients with advanced liver fibrosis [Hempfling et al 2003], precluding budesonide use in patients with cirrhosis. Due to concerns over side effects, evidence supporting the benefit of prednisolone is lacking, and although some restitution in serum and histological markers of liver inflammation has been documented [Mitchison et al 1992], these findings have not translated into improved patient outcomes.…”

Section: Alternative and Adjuvant Therapiesmentioning

confidence: 99%

Treatment of autoimmune liver disease: current and future therapeutic options

Trivedi

Hirschfield

2013

Therapeutic Advances in Chronic Disease

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Autoimmune liver disease spans three predominant processes, from the interface hepatitis of autoimmune hepatitis to the lymphocytic cholangitis of primary biliary cirrhosis, and finally the obstructive fibrosing sclerotic cholangiopathy of primary sclerosing cholangitis. Although all autoimmune in origin, they differ in their epidemiology, presentation and response to immunosuppressive therapy and bile acid based treatments. With an ongoing better appreciation of disease aetiology and pathogenesis, treatment is set ultimately to become more rational. We provide an overview of current and future therapies for patients with autoimmune liver disease, with an emphasis placed on some of the evidence that drives current practice.

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