Implication of biopharmaceutics and pharmacokinetics of rifampicin in variable bioavailability from solid oral dosage forms.

Rifampicin is one of the oldest and most effective chemotherapeutic agents available for the treatment of tuberculosis but exhibits variable bioavailability from separate and fixed dose combination formulations, which has been identified as a major bottleneck in the effective treatment of tuberculosis. In this investigation, physico-chemical characterization, single dose pharmacokinetic studies and the permeability of rifampicin under physiological conditions in the rat were studied to trace the possible reasons for its variable absorption. Rifampicin exhibits very high solubility in acidic and basic pH, corresponding to the pH of the stomach and distal intestine, respectively, whereas it is moderately soluble at the jejunal pH. From single-dose pharmacokinetic studies and permeability characterization, rifampicin is a highly permeable molecule and thus according to BCS, it is a borderline class II drug. This investigation has ruled out the possibility of intrinsic solubility, effective permeability, drug decomposition, presystemic metabolism and interaction with other antituberculosis drugs as direct factors responsible for the variable bioavailability of rifampicin. However, it was found that the rate of dissolution in association with pH and the concentration-dependent absorption of rifampicin affects the in vivo performance of the dosage forms. In addition, this is the first report of methodology for correcting inlet concentration for permeability calculations of a chemically unstable molecule. Copyright (c) 2005 John Wiley & Sons, Ltd.