Differentiating mucosal and hepatic metabolism of budesonide by local pretreatment with increasing doses of ketoconazole in the proximal jejunum

Many drugs undergo first-pass metabolism both in the gut mucosa and the liver, but little is known about the relative efficiency of these two pathways. The objective of this study was to differentiate between mucosal and hepatic metabolism using budesonide as a probe. After a light breakfast, budesonide, 3 mg, was infused locally in the proximal jejunum of eight healthy men on seven occasions, on six occasions after administering the CYP3A4 inhibitor ketoconazole 5 min before in the same jejunal position. The dose range of local inhibitor was 1–128 mg, the highest dose also preceded by an oral dose of 200 mg given 12 h earlier. Simultaneously with intrajejunal budesonide, deuterium-labelled budesonide (0.2 mg) was administered intravenously. Pharmacokinetics of unlabelled and labelled budesonide in plasma was evaluated after LC–MS/MS analysis. Bioavailability of budesonide without inhibition was 27(12–42)%. All ketoconazole doses increased budesonide bioavailability. However, systemic clearance of labelled budesonide was unaffected by ketoconazole doses up to 16 mg but decreased significantly at doses of 64 mg and above. At the two highest doses (128 mg and above) bioavailability approached 100%, showing that budesonide was completely absorbed from jejunum. Ketoconazole doses up to 16 mg appeared to inhibit only mucosal enzymes, while higher doses inhibited also hepatic metabolism. Applying sigmoid Emax-models of the mean inhibitions in mucosa and liver indicated that, in this study performed under fed conditions, their uninhibited extraction ratios of budesonide were approximately 0.32 and 0.60, respectively. Ketoconazole doses that inhibited half the metabolism were estimated at about 1 mg in the mucosa and about 50 mg in the liver. In conclusion, this study gave a rough estimate of the relation between mucosal and hepatic first-pass metabolism of budesonide.