Inhibitory effects of Triphala on CYP isoforms in vitro and its pharmacokinetic interactions with phenacetin and midazolam in rats
Issued Date
2022-06-01
Resource Type
ISSN
24058440
Scopus ID
2-s2.0-85132505582
Journal Title
Heliyon
Volume
8
Issue
6
Rights Holder(s)
SCOPUS
Bibliographic Citation
Heliyon Vol.8 No.6 (2022)
Suggested Citation
Nontakham J., Siripong P., Sato H., Chewchinda S., Arunrungvichian K., Yahuafai J., Goli A.S., Sato V.H. Inhibitory effects of Triphala on CYP isoforms in vitro and its pharmacokinetic interactions with phenacetin and midazolam in rats. Heliyon Vol.8 No.6 (2022). doi:10.1016/j.heliyon.2022.e09764 Retrieved from: https://repository.li.mahidol.ac.th/handle/20.500.14594/87554
Title
Inhibitory effects of Triphala on CYP isoforms in vitro and its pharmacokinetic interactions with phenacetin and midazolam in rats
Author's Affiliation
Other Contributor(s)
Abstract
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 μg/mL, respectively in HLMs. It exhibited a non-competitive inhibition of CYP1A2 and 2C9 with the Ki values of 23.6 and 30.4 μg/mL, respectively, while its inhibition on CYP3A4 was competitive manner with the Ki values of 64.9 μg/mL. The inhibitory effects of Triphala 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 inhibition 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.