PXR mediated induction of CYP3A4, CYP1A2, and P‐gp by Mitragyna speciosa and its alkaloids

Kratom ( Mitragyna speciosa ), a native herb of Southeast Asia, is widely known for its psychoactive properties. Recent increase in the use of kratom as a recreational drug has increased the risk of its interaction with conventional drugs if taken concomitantly. A few reports are available related to the effects of kratom on the activity of cytochrome P450 enzymes (CYPs), but there are no reports of its effects on pregnane X receptor (PXR), a transcription factor that regulates the expression of CYPs and P‐glycoprotein (P‐gp). This study was carried out to evaluate the effects of a methanolic extract of kratom leaves, an alkaloid rich fraction and its 5 indole and 4 oxindole alkaloids on PXR activation and the resulting changes in the mRNA expression of PXR target genes (CYP3A4, CYP1A2, and P‐gp). A significant activation of PXR was observed by the extract (3‐fold), alkaloidal fraction (4‐fold) and all 9 alkaloids (4‐ to 6‐fold) that was associated with an increased mRNA expression which resulted into an increase in the activity of CYP3A4, CYP1A2, and P‐gp. These results indicate that high consumption of Mitragyna speciosa extract along with the conventional drugs may lead to potential herb–drug interactions due to its effects on PXR.