Vildagliptin Affects the Metabolism of Anti-Colon Cancer Drugs Catalyzed by Cytochrome P450 (CYP) 2B6

Many clinical drugs have been used to treat colon cancer which has become one of the top reasons to threaten the health of human body, such as cyclophosphamide, ifosfamide, and tamoxifen. Cytochrome P450 (CYP) 2B6 has been demonstrated to be the major drug-metabolizing enzyme (DME) involved in the metabolic elimination of anti-colon cancer drugs. With the increased incidence of type 2 diabetes (T2D), the clinical utilization of vildagliptin become more and more popular. This study aims to evaluate the inhibition behaviour of vildagliptin on the activity of CYP2B6, trying to indicate potential drugdrug interaction between vildagliptin and anti-colon cancer drugs. The combination of in silico docking and in vitro determination was used. Vildagliptin can be well docked into the activity cavity of CYP2B6. The amino acids residues in the activity cavity binding with vildagliptin contained Ile-101, Tyr-102, Ile114, Phe-115, Leu-196, Lys-197, Met-198, Leu-201, Tyr-203, Gln-204, Ser-207, Ser-210, Thr-305, Leu-362, Leu-363, Gly-366, Val-367, Pro-368, Cys-436, Val-477, Gly-478, Lys-479, and Ile-480. One hydrogen bond was formed between vildagliptin and the amino acids residues in the activity cavity, and the length of the hydrogen bond was 2.8 nm. The hydrophobic interaction also significantly contributed to the strong binding of vildagliptin with the activity cavity of CYP2B6, and the amino acids residues involved in the hydrophobic interaction contained Ile101, Phe206, Ser210, Phe297, Tyr305, Leu362, Leu363, Val367, Val477, Gly478, Lys479, and Ile480. Furthermore, to demonstrate the inhibition potential of vildagliptin on the activity of CYP2B6, in vitro HLMs-catalyzed metabolism of bupropion was used, and the results showed that 100 mu M of vildagliptin inhibited approximately 60% activity of CYP2B6. In conclusion, all these results demonstrated strong drug-drug interaction between vildagliptin and drugs used to treat colon cancers.