Labetalol absorption kinetics: Rat small intestine and colon studies

Labetalol is a widely used drug for the management of hypertension, which is preferably administered by the oral route despite its low bioavailability. The objective of this study is to ascertain the mechanisms underlying its absorption as an approach to help in predicting the influence of dosage changes, possible drug-drug and drug-fruit juice interactions. Perfusion experiments have been performed in rats in two sites of absorption: the intestine and the colon. The nonlinearity of the process has been established by means of the assay of a wide range of concentrations (2-2000 µM). Fitting of the concentration versus time data allows the estimation of passive diffusion constant in the intestine (1.42 ± 0.05/h) and the colon (1.13 ± 0.06/h), Vm and Km of the input process (9.85 ± 4.98 µM/h, and 10.44 ± 26.16 µM, respectively) and Km of an efflux system (0.53 ± 1.16 µM) and Vm in both intestinal segments (2.60 ± 11.37 µM · /h in the intestine and 0.66 ± 1.38 µM · /h in the colon). The efflux carrier implicated is identified by means of several inhibition experiments, whose inhibition ability is mathematically estimated. Results suggest the p-glycoprotein as responsible for the efflux of labetalol.