METABOLISM OF THE TRICYCLIC ANTIDEPRESSANT AMITRIPTYLINE BY CDNA-EXPRESSED HUMAN CYTOCHROME-P450 ENZYMES

The metabolism of amitriptyline was studied in vitro using cDNA-expres sed human cytochrome P450 (CYP) enzymes 1A2, 3A4, 2C9, 2C19, 2D6 and 2 E1. CYP 2C19 was the most important enzyme with regard to the demethyl ation of amitriptyline, the quantitatively most important metabolic pa thway. CYP 1A2, 3A4, 2C9 and CYP 2D6 also participated in the demethyl ation of amitriptyline. CYP 2D6 was the sole enzyme mediating the hydr oxylation of amitriptyline, and (E)10-OH-amitriptyline was exclusively produced. CYP 2E1 did not metabolize amitriptyline. Concerning the qu antitative relations, CYP 2C19 and 2D6 exhibited high affinities with K-m values in the range of 5-13 mu mol/l, whereas the affinities of 1A 2, 3A4 and 2C9 were somewhat lower with K, values ranging from 74 to 9 2 mu mol/l. CYP 2C19 displayed the highest reaction capacity per mole with V-max equal to 475 mol h(-1) (mol CYP)(-1). The other enzymes had V-max values in the range of 90-145 mol h(-1) (mol CYP)(-1). Allowing for the typical relative distribution of amounts of CYP enzymes in th e liver, a simulation study suggested that, at therapeutic doses, on a verage about 60% of the metabolism depended on CYP 2C19. At toxic dose s, CYP 2C19 is expected to be saturated, and CYP 3A4 may now play a do minant role in the metabolism.