Inhibition of human liver cytochrome P450 2D6 (CYP6D2) by tetrahydropalmatine, protopine, and dehydrocorydaline and their oxidative metabolism

1. The inhibition and metabolism kinetics of tetrahydropalmatine (THP), protopine (PRO), and dehydrocorydaline (DHC), three major biologically active components of Corydalis yanhusuo W. T. Wang, which has been used for thousands of years in China, were evaluated in human liver microsomes (HLMs) to determine their potential for drug-drug interactions.2. THP acted as a mechanism-based inhibitor of cytochrome P450 2D6 (CYP2D6), with a K_inact of 0.053 min^-1 and a K_i of 0.26 µM. It was metabolized by HLMs with a K_m of 7.62 μM, V_max of 0.071 nmol/min/mg, and intrinsic clearance (C_Lint) of 9.27 × 10^-6 L/min/mg. The oxidative metabolism of THP involved CYP2C19, CYP3A4, CYP1A2, and CYP2D6.3. PRO was a mixed inhibitor (both competitive and non-competitive) of CYP2D6, with K_i of 0.023 µM and K_is of 0.042 µM. HLMs metabolized PRO with a Km of 3.99 μM, V_max of 0.033 nmol/min/mg protein, and C_Lint of 8.20 × 10^-6 L/min/mg. Its oxidative metabolism involved CYP2C19, CYP2D6, and CYP3A4.4. DHC was a weakly competitive inhibitor of CYP2D6 (K_i = 20.1 µM) and was no longer metabolized by HLMs.5. These findings indicate that CYP2D6 is a potential target for drug-drug interaction involving THP and PRO, whereas DHC exhibits minimal interaction potential.