M. S. Warren, C. Li, J. Baik, Y. Huang; Optivia Biotechnology Inc., Menlo Park, CA

BACKGROUND: Rifampicin (RIF) is known to cause liver injuries through blocking transporter-mediated hepatic bile salt (BS) excretion. Compared to using RIF alone, higher incidences of severe liver injuries were observed in HIV-infected tuberculosis patients taking RIF with protease inhibitors (PIs). This study aimed to elucidate potential hepatic transporter interactions that could contribute to such adverse drug reactions.
METHODS: Inhibitory potencies of RIF, lopinavir (LPV) and ritonavir (RTV) and their major metabolites on major hepatic BS transporters were tested for mechanistic assessment of their ability to block BS biliary excretion; PIs were tested for modulating P-gp mediated efflux and cellular retention of RIF and its metabolite desacetyl rifampicin (des-RIF); BS transcellular flux and intracellular accumulation were measured with cells expressing hepatic BS transporters, with and without P-gp, treated with RIF/des-RIF alone or together with PIs.
RESULTS: 1) RIF and des-RIF are potent inhibitors of BSEP but not NTCP, whereas LPV and RTV inhibit both; 2) P-gp attenuated BSEP inhibition by RIF and des-RIF through reducing their intracellular concentrations by 5- to 13-fold; 3) LPV/RTV at clinical concentrations aggravated the inhibitory effects of RIF/des-RIF on BS transport through additive, direct inhibition of NTCP and BSEP, and indirectly through inhibiting P-gp, which led to increased RIF/des-RIF intracellular concentrations for more BSEP inhibition.
CONCLUSION: Hepatic P-gp may attenuate rifampicin’s liver toxicity through reducing its hepatocellular concentration; protease inhibitors could aggravates rifampicin’s liver toxicity directly through further inhibiting bile salt transporters and indirectly through increasing rifampicin’s liver level.