Inhibitory effects of Triphala on CYP isoforms in vitro and its pharmacokinetic interactions with phenacetin and midazolam in rats

Context: Direct evidence of Triphala-drug interactions has not been provided to date. Objective: This study was aimed to determine the effects of Triphala on cytochrome P450 (CYP) isoforms and P-glycoprotein (P-gp) in vitro, and to investigate pharmacokinetic interactions of Triphala with CYP-probes in rats. Materials and methods: Effects of Triphala on the activities of CYP isoforms and P-gp were examined using human liver microsomes (HLMs) and Caco-2 cells, respectively. Pharmacokinetic interactions between Triphala and CYP-probes (i.e., phenacetin and midazolam) were further examined in rats. Results: Triphala extract inhibited the activities of CYP isoforms in the order of CYP1A2 > 3A4 > 2C9 > 2D6 with the IC50 values of 23.6 +/- 9.2, 28.1 +/- 9.8, 30.41 +/- 16.7 and 93.9 +/- 27.5 mu g/mL, respectively in HLMs. It exhibited a non-competitive inhibition of CYP1A2 and 2C9 with the Ki values of 23.6 and 30.4 mu g/mL, respectively, while its inhibition on CYP3A4 was competitive manner with the Ki values of 64.9 mu g/mL. The inhibitory effects of Tri-phala on CYP1A2 and 3A4 were not time-dependent. Moreover, Triphala did not affect the P-gp activity in Caco-2 cells. Triphala, after its oral co-administration at 500 mg/kg, increased the bioavailabilities of phenacetin and midazolam by about 61.2% and 40.7%, respectively, in rats. Discussion and conclusions: Increases observed in the bioavailabilities of phenacetin and midazolam after oral co -administration of Triphala in rats provided a direct line of evidence to show Triphala-drug interactions via in-hibition of CYP1A and CYP3A activities, respectively. These results, together with the lack of time-dependency of CYP 1A2 and 3A4 inhibition in vitro, suggested that the inhibitory effect of Triphala is primarily reversible.

Automated summary

This study aimed to investigate the interactions between Triphala and cytochrome P450 (CYP) isoforms and P-glycoprotein (P-gp) through in vitro and in vivo experiments. The results showed that Triphala inhibited the activities of CYP1A and CYP3A, and increased the bioavailabilities of phenacetin and midazolam in rats.