The regulatory effects of mitragynine on P-glycoprotein transporter.

Abduraman, Muhammad Asyraf; Amanah, Azimah; Hamid, Shahrul Bariyah Sahul; Abdullah, Mohammad Farris Iman Leong; Sulaiman, Shaida Fariza; Tan, Mei Lan

Objectives Kratom preparation containing Mitragyna speciosa Korth plant is frequently used as a recreational drug. Mitragynine, a major alkaloid isolated from M. speciosa , is often detected concurrently with other drugs during forensic analysis, indicating a safety concern. P-glycoprotein (P-gp) is a multidrug transporter. Modulation of P-gp transport activity by drugs or herbal compounds in the brain may lead to drug-herb interactions, resulting in neurotoxicity. We aim to determine the effects of mitragynine on the P-gp regulation and possible neurotoxicity. Methods The effects of mitragynine on the P-gp regulation were investigated in human brain capillary endothelial cells (hCMEC/D3) using molecular docking and dynamic simulation and an optimized bidirectional transport assay, respectively. Repeated-dose treatment and neurotoxicity assessment were carried out using a blood–brain barrier model and polimerase chain reaction (PCR) array. Key findings Mitragynine inhibits the P-gp transport activity via binding onto the nucleotide-binding domain site and forms a stable interaction with the P-gp protein complex. Nontoxic concentrations of mitragynine (<4 μM) and substrate drugs (0.001 μM) in the cells significantly enhanced endothelial cell permeability and elicited signs of neurotoxicity in PC-12 cells. Conclusions Mitragynine is likely a P-gp inhibitor, hence concurrent administration of kratom products with P-gp substrates may lead to clinically significant interactions and neurotoxicity.

MEMBRANE permeability (Biology); DRUG-herb interactions; DRUG abuse; DRUG interactions; ENDOTHELIAL cells

Journal of Pharmacy & Pharmacology, 2025, Vol 77, Issue 2, p321

0022-3573

Academic Journal

10.1093/jpp/rgae131