Inhibitory and inductive effects of Bacopa monnieri standardized extract and its constituents on human liver cytochrome P450

Abstract

Bacopa monnieri (L) Wettst. (B. monnieri) has been beneficial for neuropharmacological disorders treatment. Herb-drugs interaction (HDIs) could occur due to inhibition or induction potential of drug metabolism enzymes. It could alter the pharmacokinetics and lead to toxicity or therapeutic failure. Currently, there are a few studies that reported B. monnieri extract could inhibit drug-metabolizing enzymes using rat liver microsome and human recombinant Cytochrome P450 (rCYPs). Those results align with an in vivo study that reported B. monnieri extract relatively inhibits CYP2C and 3A in rats after co-administration of B. monnieri extract and amitriptyline. However, no study regarding the inhibition potential on CYPs system using human liver microsome (HLMs) has been conducted. In addition, the induction potential of B. monnieri extract is still unclear. To achieve this purpose, the extract's inhibition, and the induction effect of the extract on CYP isoforms were evaluated using the in vitro gold standard models i.e., the pooled HLMs and primary human hepatocytes, respectively.

As the results, B. monnieri extract demonstrates strongly inhibit CYP2C19 activity with IC50 values of 17.68 µg/mL, and moderate inhibit CYP1A2, 2B6, and 2C9 with IC50 values of 75.98, 59.69, and 47.72 µg/mL, respectively. Whereas this extract showed weak inhibition potential on CYP3A4 with IC50 values of 101.40 µg/mL. To solve the puzzle of inhibition mode of B. monnieri extract and bacopaside I which is assumed as a major bioactive compound derived from the pharmacological activity, the Lineweaver–Burk plots were conducted, and the secondary plots of Lineweaver-Burk plots were conducted to determine the inhibition constant (Ki) values. The results found that B. monnieri extract could inhibit CYP1A2 with competitive mode (Ki = 48.06 µg/mL) and inhibit CYP2B6, 2C9, and 2C19 (Ki = 5.16, 19.93, and 3.04 µg/mL, respectively) with mixed-type inhibition. In addition, the CYP2B6 was competitively inhibited by bacopaside I with Ki values of 7.02 µg/mL. Whereas this saponin glycoside could inhibit the CYP2C9 and CYP2C19 enzyme activity with mixed type inhibition (Ki = 25.92 and 13.25 µg/mL, respectively). Consequently, B. monnieri extracts also significantly enhanced the enzyme activity and mRNA expression of CYP1A2, and 2B6. In addition, the bacopaside I showed moderate inhibit CYP2B6 and CYP2C9 activity while others phytochemical compounds did not inhibit any CYPs isoform. Although in in vitro results demonstrated the inhibition and induction potential on the CYPs system, at oral administration of 300 mg/day B. monnieri extract, which is a recommended dose, may not produce HDIs.

Since the predicted fraction absorbed of five major bioactive compounds did not exceed 20% and oral bioavailability was equal to 6.2% in humans after orally receiving 10 mg of isolated compounds. Besides, consuming the B. monnieri extract might not produce hepatotoxicity. Because of the cell viability are still over 75% when treated with B. monnieri extract at high concentration in primary human hepatocyte. However, oral intake of simultaneous medications and B. monnieri extract should be done with caution. It cannot conclude from the present study whether B. monnieri extract has been a cause of herb-drug or herb-herb interactions in humans.

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