4.5 Article

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

期刊

HELIYON
卷 8, 期 6, 页码 -

出版社

ELSEVIER SCI LTD
DOI: 10.1016/j.heliyon.2022.e09764

关键词

Pharmacokinetic interaction; Triphala extract; Cytochrome P450; P-glycoprotein; Phenacetin; Midazolam

资金

  1. National Research Council of Thailand [N41D640036]

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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.
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.

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