In order to develop a novel strategy to alleviate the inherent hepatotoxicity of antidepressant trazodone (TZ), Cucurbit[7]uril (CB[7]) was adopted as pharmaceutical excipients and was studied for its capability to reduce the hepatotoxicity of TZ via supramolecular encapsulation. CB[7] was found to form strong 1:1 host-guest complexes with TZ and its metabolite m-chlorophenyl piperazine (mCPP), with binding constants of 1.50 (0.13) x 10(6) M-1 and 6.90 (+/- 0.49) x 10(5) M-1, respectively. The supramolecular complexations were examined by H-1 NMR and UV-visible spectroscopic titration, ESI-MS and ITC. In the presence of 0.5 mM CB[7], the IC50 values of TZ and mCPP on a human normal liver cell line L02 were increased from 215.5 +/- 3.3 mu M to 544.1 +/- 51.2 mu M, and from 166.8 +/- 3.8 mu M to 241.7 +/- 6.8 mu M, respectively. Evaluation on a zebrafish model demonstrated that CB[7] (0.1 mM) significantly alleviated the TZ induced liver toxicity, as shown by the level of liver degeneration, liver size and yolk sac retention. Our study may provide a supramolecular strategy to alleviate the hepatotoxicity induced by TZ and its metabolite mCPP, and this strategy may be extendable to other drugs that have inherent hepatotoxicity or other adverse effects.