A cocrystal for effectively reducing the hepatotoxicity of ethionamide

Abstract Although ethionamide (ETH) has proven highly effective for multidrug-resistant tuberculosis treatment, the severe hepatotoxicity limits the clinical application of ETH, making it still just a second-line drug to cure critical TB patients. In this paper, a cocrystal of ETH with natural hepatoprotective ingredient baicalein (BAI) was developed, as an exciting attempt to restrain the toxicity of ETH by crystal engineering technique. The structure of the ETH-BAI cocrystal was confirmed by single crystal X-ray diffraction, and further characterized by powder X-ray diffractionand differential scanning calorimetry. Meanwhile, the solubility behavior, pharmacokinetics and toxicity of the cocrystal were systematically evaluated. The bioavailability of ETH in the cocrystal was enhanced by1.83 times due to the sustained release of cocrystal. The dissolution rate, maximum solubility and oral bioavailability of BAI in the cocrystal were increased by 8.71, 10.40 and 6.00 times than coarse BAI, respectively. The hepatoprotectiveness of BAI in cocrystal was obviously optimized because of the improved pharmacological properties. The in vivo hepatotoxicity studies demonstrated that the ETH-BAI cocrystal almost removed the severe liver toxicity of ETH. These findings provide a new way for developing high efficiency and low-toxicity antituberculosis drug formulations.