Carebastine

To investigate the reported differences in catalytic activities of cytochromes P450 (CYP or P450) 3A4 and 3A5, molecular docking studies were conducted of the interactions of 13 compounds with active sites of the reported three-dimensional structure of CYP3A4 and the modeled structure of CYP3A5. The primary sequence of human CYP3A5 was aligned with that of human CYP3A4 (1TQN) using threedimensional modeling software. Docking simulations were carried out after the energy of the CYP3A4 and CYP3A5 structures had been minimized. Kinetic parameters for the substrate oxidations were taken from the literature. Among the substrates that are preferably metabolized by CYP3A4, including carebastine, itraconazole, haloperidol, and fluvastatin, the former three compounds were found to closely dock to the heme region of CYP3A4 but not to that of CYP3A5. The ligand-CYP3A5 interaction energies (U values) for vincristine, R- and S-verapamil, and β-endosulfan were considerably lower than the corresponding ligand-CYP3A4 interaction energies; these substrates also had lower reported Michaelis constants (km) for CYP3A5 than for CYP3A4. Despite higher CYP3A5 km values for α-endosulfan and estradiol, the CYP3A5 U value for estradiol was lower than that for CYP3A4. No marked differences of U values between CYP3A4 and CYP3A5 were observed for midazolam and triazolam, and comparable km values for the oxidations of these two substrates have been reported for CYP3A4 and CYP3A5. Molecular docking simulation could partly explain the differences of the affinities (km) of the substrates for CYP3A4 and CYP3A5 based on the accessibility of substrates to the heme moiety of CYP3A molecules.