Table 4

Individual enzyme kinetic parameters for terbinafine metabolism

PathwayCYPRecombinant EnzymesPrediction of CYP Contribution to Human Liver Microsomal Values
KmVmaxVmax/KmVmaxCIint
μM nmol/h/nmol CYP (nmol/h/mg protein) ml/h/nmol CYP nmol/h/mg protein ml/h/mg protein
All1A27.6416.7  (77.1)55.08.61.13
2B618.096.7  (12.4)5.4
2C815.3268.2  (134.1)17.510.30.67
2C915.3244.0  (135.4)15.933.92.21
2C193.9816.5  (291.5)209.41.30.32
3A417.6683.9  (67.7)38.917.81.01
∑5.34
Side-chain oxidation OL+CA+DOL1A278.8141.2  (26.1)1.22.90.04
2B623.921.3  (2.7)0.9
2C826.449.5  (24.8)1.91.90.07
2C938.29.3  (5.2)0.21.30.03
2C1910250.8  (89.5)25.30.40.04
∑0.18
N-Demethylation D+DOL+DHDs1A214.5163.6  (30.3)11.33.40.23
2B618.253.0  (6.8)2.9
2C813.6123.8  (61.9)9.14.80.35
2C914.3149.2  (82.8)10.420.71.45
2C197.5317.0  (113.2)42.30.50.07
3A419.690.5  (9.0)4.62.40.12
∑2.22
Deamination NAL+NM+NA1A219.330.2  (5.6)1.60.60.03
2B635.019.5  (2.5)0.6
2C824.830.7  (15.4)1.21.20.05
2C9125.425.6  (14.2)0.23.60.03
2C191.653.9  (19.2)33.70.10.05
3A417.5401.9  (39.8)23.010.50.60
∑0.76
Dihydrodiols DHDs+D-DHDs1A28.9273.5  (50.6)30.75.60.63
2B612.310.2  (1.3)0.8
2C93.232.4  (18.0)10.14.51.40
∑2.03

Michaelis-Menten parameters (Km,Vmax) and enzyme efficiency (Vmax/Km) were determined from recombinant baculovirus/insect cell microsomes expressing active human CYP. Relative activity factors were used to predict isoenzyme specific velocity (Vmax) and in vitro intrinsic metabolic clearance (CIint) in human liver microsomes.

  • ∗ No specific relative activity factor available.