Speaker
Description
Background: The analgesic effects of opioids are mediated through four known receptors: mu (MOR), kappa (KOR), delta (DOR), and opioid receptor-like 1 (ORL-1). Of opioid analgesics, mu-opioid agonists (MOAs) are the most commonly used. 2-hydroxytriazolo[4,5-b]pyridine was synthesized as a potential MOA. Pyridines inhibit P-glycoprotein and can reverse multidrug resistance in cancer cells. They are also known to inhibit rodent Cyp3a enzymes (Black et al.: J. Biol. Chem. 269 (1964) 1238).
Methods: We tested whether 2-hydroxytriazolo[4,5-b]pyridine inhibits cytochrome P450 3A4 (CYP3A4) and the P-glycoprotein transporter using human liver microsomes and MDCKII cells overexpressing human P-glycoprotein (ABCB1). Midazolam served as the CYP3A4 substrate; digoxin was used in transport assays.
Results: The compound efficiently inhibited P-glycoprotein but not CYP3A4, with IC50 values of 0.03 μM and 25.2 μM, respectively. CYP3A4 inhibition appeared to be mechanism-based (irreversible).
Conclusions: 2-hydroxytriazolo[4,5-b]pyridine is a potent P-glycoprotein inhibitor. Given CYP3A4's role in metabolizing over half of marketed drugs, high doses may also lead to CYP3A4 inhibition with implications for drug–drug interactions.
Acknowledgments:
Supported by the University Agency, grant No. 1234.
