Pharmacokinetics and first-pass effect of bromhexine in rats

The pharmacokinetics and first-pass effect of bromhexine (BH) were studied in rats. Upon i.v. administration of 0.3 and 1 mg/kg of BH hydrochloride to normal rats, the plasma concentrations followed a biexponential curve, with slower terminal elimination (t1/2 beta = 8.9-11 h). In bile duct cannulated rats, the plasma concentration-time profile was similar to that of normal rats and the bile excreted within 30 h contained only 1.5 +/- 1.2% of the dose as intact and conjugated BH. These results suggest that a slower terminal elimination of BH after i.v. injection is due to a relatively small plasma clearance and large distribution volume rather than the enterohepatic recycling of the drug. Renal clearance of BH was negligible since urinary excretion of intact BH for 24 h after i.v. injection did not exceed 1% of the dose. After oral administration of BH, the systemic availability ranged only 1.8-3.9% based on i.v. and oral data, showing the poor bioavailability of oral BH. The first-pass effect of BH was measured by comparing the area under plasma concentration-time curve (AUC) after i.v., oral or hepatic portal (h.p.v.) administration of the drug. The AUC following h.p.v. dosing was only one-tenth of that obtained following i.v. administration and the AUC after oral dose was a quarter of that after h.p.v. administration. The hepatic extraction ratio was estimated to be 0.92. A low bioavailability after oral BH was explained by both hepatic and intestinal first-pass clearance, but mainly due to hepatic extraction.