Inhibition of human liver microsomal cytochrome P450 activities by adefovir and tenofovir.

Adefovir (PMEA) and tenofovir (PMPA) and their prodrugs, adefovir dipivoxil (bisPOM-PMEA) and tenofovir disoproxil (bisPOC-PMPA), were subjected to a detailed study of their potential to inhibit the activities of human liver microsomal cytochromes P450 (CYP). The inhibition of marker enzyme activities of CYP1A2, CYP2A6, CYP2B6, CYP2C9, CYP2D6, CYP2E1 and CYP3A4 was examined with high-performance liquid chromatography (HPLC) or spectroscopic (fluorescence, luminescence) detection. Adefovir and adefovir dipivoxil did not significantly influence activities of most CYP enzymes. The activity of CYP3A4 was inhibited by adefovir dipivoxil at concentrations over 100 microM. Adefovir and its prodrug inhibited CYP2C9 at concentrations below 100 microM; inhibition by adefovir was of the uncompetitive (at the lower inhibitor concentrations) or of the competitive nature with a Ki = 420 microM. Tenofovir and tenofovir disoproxil influenced the activity of CYP2C9, and competitive inhibition was found with Ki = 580 and 395 microM, respectively. Tenofovir disoproxil was shown to inhibit microsomal CYP2E1 activities by a mixed-type inhibition with Ki values at about 140 microM. The results indicate the possibility of an influence of the compounds tested on the respective CYP activities when used at high doses.