Pharmacokinetics and pharmacodynamic action of budesonide after buccal administration in healthy subjects and patients with oral chronic graft-versus-host disease.

Buccal administration of budesonide (mouthwash) may be effective as a topical add-on therapy in patients with oral chronic graft-versus-host disease (cGVHD). Safety of approved oral budesonide is based on high intestinal and hepatic extraction by cytochrome P450 3A (CYP3A) enzymes. The purpose of this study was to evaluate the presystemic extraction and pharmacodynamic action of buccal budesonide. Oral budesonide (3 mg) was taken as reference to which various single and multiple dose regimens of buccal budesonide were compared. Budesonide and the 2 main CYP3A-dependent metabolites (6beta-hydroxybudesonide, 16alpha-hydroxyprednisolone) were analyzed in blood and urine along with the drug's effect on endogenous cortisol in 12 healthy subjects and 7 patients with oral cGVHD. We assessed CYP3A-dependent metabolites in both healthy subjects and patients after buccal budesonide. Whereas systemic exposure to budesonide was markedly lower in healthy subjects after the mouthwash compared to oral dosing (mean relative bioavailability 18%-36%), the systemic concentrations thereafter in patients were as high as those after the identical dose of oral budesonide. Reduced buccal CYP3A activity (lower inactivation of budesonide) in patients contributed to this remarkable difference. Endogenous cortisol was suppressed in some patients during 1 week of continuous treatment with buccal budesonide (3 x 3 mg per day). We are the first to report the biotransformation of budesonide via CYP3A enzymes after buccal drug administration. Only 2% of a buccal dose of budesonide achieves systemic circulation in healthy individuals; that fraction is 10% in patients with oral cGVHD, probably because of alterations in drug uptake and metabolization.