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

Abstract

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.)

Coordinated defence and the liver

“…The highly effective combination is provided by CYP3A, SULT2A1, MRP2 and MDR1 at both intestinal and hepatic level. An excellent example of the efficacy of this system was provided by Dilger et al (2005) 2 who administered a single dose of the synthetic corticosteroid budesonide to healthy human volunteers and charted its concentration in peripheral blood. Remarkably, following a 5-day course of rifampicin which is a known inducer of CYP3A, virtually no budesonide could be detected in the systemic circulation following an oral dose.…”

Active Eosinophilic Esophagitis Is Associated with Impaired Elimination of Budesonide by Cytochrome P450 3A Enzymes

“…Concentrations of budesonide, 6β-hydroxybudesonide, and 16α-hydroxyprednisolone in plasma and urine were determined by validated liquid chromatography tandem mass spectrometry according to the principles of Good Laboratory Practice as described previously [12]. The lower limits of quantification in plasma (urine) were 0.1 ng/ml (0.5 ng/ml) for budesonide and 6β-hydroxybudesonide, and 0.5 ng/ml (2 ng/ml) for 16α-hydroxyprednisolone.…”

Medical Treatment of Primary Sclerosing Cholangitis: A Role for Novel Bile Acids and other (post-)Transcriptional Modulators?

“…In otherwise healthy gallstone patients undergoing cholecystectomy, rifampicin induced upregulation of UGT1A1 and MRP2 facilitating bilirubin elimination and increased CYP3A4 expression facilitating detoxification of bile acids 72 . Consistent with this, Dilger et al showed that in patients with early stage PBC and healthy controls, rifampicin markedly induced CYP3A metabolism as assessed by pharmacokinetic profiling of budesonide and its phase 1 metabolites in plasma and urine and urinary 6β-hydroxy cortisol 73 . The therapeutic bile acid ursodeoxycholic acid (UDCA) had no relevant effect on CYP3A metabolic activity 72,73 , but increased expression of the hepatocyte transporters BSEP, MDR3, and MRP4 by posttranscriptional mechanisms 72 .…”

“…Consistent with this, Dilger et al showed that in patients with early stage PBC and healthy controls, rifampicin markedly induced CYP3A metabolism as assessed by pharmacokinetic profiling of budesonide and its phase 1 metabolites in plasma and urine and urinary 6β-hydroxy cortisol 73 . The therapeutic bile acid ursodeoxycholic acid (UDCA) had no relevant effect on CYP3A metabolic activity 72,73 , but increased expression of the hepatocyte transporters BSEP, MDR3, and MRP4 by posttranscriptional mechanisms 72 . These complementary effects on transcriptional regulation of hepatobiliary enzymes and transporters suggest that the combined use of both agents might have synergistic beneficial effects in patients with non-obstructive cholestasis.…”