Oral bioavailability and enterohepatic recirculation of otilonium bromide in rats.

This study was conducted to examine the oral bioavailability and the possibility of enterohepatic recirculation of otilonium bromide in rats. A sensitive LC/MS/MS assay (LLOQ 0.5 ng/mL) was developed for the determination of otilonium and applied to i.v. and oral administration studies in bile duct cannulated (BDC) and non-BDC rats. After i.v. injection to BDC rats (1 mg/kg as otilonium), average t1/2, CL, Vz and AUC were 7.9 ± 1.9 h, 8.7 ± 3.1 mL/min/kg, 5.7 ± 1.4 L/kg and 2,088 ± 676 ng·h/mL, respectively, and these values were comparable to those found in non-BDC rats. The percentages of i.v. dose excreted unchanged in bile and urine in BDC rats were 11.6 ± 3.0 and 3.1 ± 0.7%, respectively. Upon oral administration to non-BDC rats (20 mg/kg as otilonium), t1/2, Cmax, Tmax and AUC were 6.4 ± 1.3 h, 182.8 ± 44.6 ng/mL, 1.9 ± 1.6 h and 579 ± 113 ng·h/mL, respectively. The absolute oral bioavailability was low (1.1%), while the drug was preferentially distributed to gastrointestinal tissues. A secondary peak was observed in the serum concentration-time profiles in non-BDC rats following both i.v. and oral administration, indicating that otilonium bromide was subject to enterohepatic recirculation.