Table 4

Results of chemical inhibition studies of amitriptyline biotransformation by human liver microsomes and SUPERMIX at substrate concentrations of 1.5 and 15 μM

PathwayInhibitor (Concentration)Target CYPHuman LiversSUPERMIX
FDV at 1.5 μMFDV at 15 μMFDV at 1.5 μMFDV at 15 μM
N-Demethylationα-Naphthoflavone (1 μM)1A20.189  ± 0.090.23  ± 0.140.3790.277
(0.042–0.377)(0.058–0.503)
Sulfaphenazole (10 μM)2C90.112  ± 0.050.11  ± 0.070.1510.256
(0.024–0.192)(0.016–0.192)
Omeprazole (10 μM)2C190.453  ± 0.110.288  ± 0.080.6820.654
(0.294–0.614)(0.148–0.373)
S-Mephenytoin (500 μM)2C190.37  ± 0.160.292  ± 0.090.4250.296
(0.064–0.587)(0.115–0.377)
Quinidine (5 μM)2D60.056  ± 0.040.099  ± 0.030.3360.182
(0.005–0.156)(0.03–0.131)
TAO (100 μM)3A40.129  ± 0.120.307  ± 0.160.1780.268
(0–0.336)(0.091–0.529)
Ketoconazole (2.5 μM)3A40.405  ± 0.070.432  ± 0.110.4480.497
(0.316–0.531)(0.303–0.617)
E-10 hydroxylationQuinidine (5 μM)2D60.832  ± 0.060.624  ± 0.11.00.714
(0.723–0.939)(0.454–0.838)
TAO (100 μM)3A4N.D.0.271  ± 0.16N.D.0.372
(0.041–0.492)
Ketoconazole (2.5 μM)3A40.14  ± 0.080.227  ± 0.160.3720.501
(0.04–0.273)(0.056–0.432)

FDV is presented. Table entries are means ± S.D., with the range of values in parentheses. Data from CYP2C19 and 2D6 poor metabolizer livers were excluded in calculating means and range of values forN-demethylation; data from the CYP2D6 deficient liver was excluded for E-10 hydroxylation (n = 9 human livers forN-demethylation, n = 11 human livers for E-10 hydroxylation).

  • N.D., not determined.