Abstract
Ganoderic acid B is an important bioactive ingredient isolated from Ganoderma lucidum, and exhibits various pharmacological activities. To investigate the influence of Ganoderic acid B towards the therapeutic window of trifluoperazine (TFP). In vitro human liver microsomes (HLMs) incubation system was used to determine the inhibition of Ganoderic acid B towards the glucuronidation of trifluoperazine (TFP). Ganoderic acid B exerted concentration-dependent inhibition towards the glucuronidation of TFP. Furthermore, Dixon plot was used to determine the inhibition type. The intersection point was located in the second quadrant in Dixon plot, indicating the competitive inhibition of Ganoderic acid B towards TFP glucuronidation. Through fitting the data using competitive nonlinear fitting equation, the inhibition kinetic parameter was calculated to be 56.7 uM. All this data indicated the potential influence of Ganoderic acid B-containing herbs towards therapeutic window of TFP. Given that the glucuronidation reaction of TFP is the probe reaction of UGT1A4, the data obtained from the present study also indicated the potential influence of Ganoderic acid-containing herbs towards the therapeutic window of drugs mainly undergoing UGT1A4-mediated metabolism.
Highlights
Ganoderma lucidum, a well-known traditional Chinese medicine, has been utilized for longevity and treatment of multiple diseases in Asia for many years[1]
The present study aims to investigate the inhibition of Ganoderic Acid B towards the metabolism of TFP
Multiple concentrations of Ganoderic acid B were used to screen the inhibition potential of Ganoderic acid B towards TFP glucuronidation, and the results showed that 0, 20, 40, 60 and 100 uM of Ganoderic acid B inhibited the glucuronidation activity of TFP by 0, 26.6%, 44.1%, 52.9%, and 66.9%, respectively (Fig. 1)
Summary
A well-known traditional Chinese medicine, has been utilized for longevity and treatment of multiple diseases in Asia for many years[1]. The oxygenated lanostane-type triterpenoids isolated from Ganoderma lucidum, have been reported to exhibit multiple biochemical and pharmacological activities, such as anti-tumor[2,3], cardioprotective. The inhibition of compounds towards the activity of drug-metabolizing enzymes (DMEs) is another reason for drugs-induced adverse effects. The anti-tumor drug noscapine exhibits significant inhibitory effects towards CYP3A4 and CYP2C9-catalyzed warfarin metabolism, and induces clinical noscapine-warfarin interaction[7]. Conclusion: All this data indicated the potential influence of Ganoderic acid B-containing herbs towards therapeutic window of TFP. Given that the glucuronidation reaction of TFP is the probe reaction of UGT1A4, the data obtained from the present study indicated the potential influence of Ganoderic acid-containing herbs towards the therapeutic window of drugs mainly undergoing UGT1A4-mediated metabolism
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