cqvip: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. The refore, we compared the induction potential of UDCA with that of the prototypica l 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 p rofiling of oral budesonide (3 mg) was performed by determination of budesonide and phase I metabolites (6β - hydroxybudesonide, 16α - hydroxyprednisolone) in plasma and urine at baseline and at the end of each treatment. In parallel, u rinary 6β - hydroxycortisol, a validated marker of CYP3A induction, was determ ined. UDCA did not affect biotransformation of budesonide and urinary excretion of 6α - hydroxycortisol either in patients or in healthy volunteers. Ratios of areas under plasma concentration- time curves (AUC0- 12h during UDCA/AUC0- 1 2h before UDCA) of both metabolites were not higher than those of budesonide its elf. In contrast, administration of rifampicin markedly induced CYP3A metabolism , resulting in abolished budesonide plasma levels and high urinary excretion of 6β - hydroxycortisol. Metabolite formation was enhanced by rifampicin, but not by UDCA (e.g., AUC16α - hydroxyprednisolone/ AUCbudesonide in patients: basel ine, 8.6 ± 3.9; UDCA, 10.7 ± 7.1; rifampicin, 527.0 ± 248.7). In conclusio n, UDCA is not a relevant inducer of CYP3A enzymes in humans.
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