Differential inhibition of rat and human hepatic cytochrome P450 by Andrographis paniculata extract and andrographolide

The inhibitory effect of Andrographis paniculata extract (APE) and andrographolide (AND), the most medicinally active phytochemical in the extract, on hepatic cytochrome P450s (CYPs) activities was examined using rat and human liver microsomes. For this purpose, CYP1A2-dependent ethoxyresorufin-O-deethylation, CYP2B1-dependent benzyloxyresorufin-O-dealkylation, CYP2B6-dependent bupropion hydroxylation, CYP2C-dependent tolbutamide hydroxylation, CYP2E1-dependent p-nitrophenol hydroxylation and CYP3A-dependent testosterone 6β-hydroxylation activities, were determined in the presence and absence of APE or AND (0–200 μM). APE inhibited ethoxyresorufin-O-deethylation activity in rat and human liver microsomes, with apparent Ki values of 8.85 and 24.46 μM, respectively. In each case, the mode of inhibition was noncompetitive. APE also inhibited tolbutamide hydroxylation both in rat and human microsomes with apparent Ki values of 8.21 and 7.51 μM, respectively and the mode of inhibition was mixed type. In addition, APE showed a competitive inhibition only on CYP3A4 in human microsomes with Ki of 25.43 μM. AND was found to be a weak inhibitor of rat CYP2E1 with a Ki of 61.1 μM but did not affect human CYP2E1. In conclusion, it cannot be excluded from the present study that APE could cause drug–drug interactions in humans through CYP3A and 2C9 inhibition.