TABLE 1

Characterization of human liver microsomes by CYP3A5 genotype, CYP3A4 and CYP3A5 protein content, and Vmax with VCR, TST, and ITZ as substrates

Metabolites for Vmax are in parentheses.

Liver
CYP3A5 Genotype
Protein Content
Vmax
VCR in Vitro/in Vivo Scaling
CYP3A4
CYP3A5
ITZ (OH-ITZ)
TST (6β-OH)
VCR (M1)
Km a
CLintb
 CLHc
pmol / mg pmol / min / mg μM ml / min
CYP3A5 high expressers
    IUL-40 *1 / *1 103.8 89.4 121.3 7244 1262 14.0 6070 823
    IUL-32 *1 / *3 20.9 18.2 18.1 1021 172 18.2 636 169
    IUL-41 *1 / *3 14.7 20.5 52.5 2886 467 26.2 1200 291
    IUL-42 *1 / *3 23.7 16.1 26.4 1518 302 25.1 813 210
    IUL-59 *1 / *3 36.3 14.7 51.6 3274 302 14.6 1400 328
    IUL-66 *1 / *3 24.4 20.6 32.7 2223 327 17.0 1300 310
    IUL-73 *1 / *3 96.1 20.1 147.0 6564 521 15.9 2220 461
    IUL-74 *1 / *6 10.7 26.2 13.5 1958 470 16.1 1970 424
    IUL-79 *1 / *3 11.2 13.6 15.4 1291 201 17.0 803 208
    IUL-85 *1 / *3 85.5 24.8 39.4 4013 393 20.7 1280 305
CYP3A5 low expressersd
    IUL-6 *3 / *3 19.0 0.8 33.8 3082 80 22.2 244 70
    IUL-49 *3 / *3 48.8 0.8 52.3 2511 68 23.8 193 56
    IUL-52 *3 / *3 14.8 0.0 8.4 1337 9 11.4 52 16
    IUL-55 *3 / *3 130.4 0.8 136.2 7260 245 29.8 555 150
    IUL-57 *1 / *3 40.6 0.8 41.1 3947 104 31.2 225 65
    IUL-65 *3 / *3 15.6 0.6 14.7 1139 18 10.7 115 34
    IUL-71 *1 / *7 10.9 1.1 41.9 2950 50 15.8 213 61
    IUL-72 *3 / *3 25.3 0.9 27.1 2100 40 20.6 132 38
    IUL-75 *3 / *3 78.2 2.3 108.2 4938 140 15.6 609 163
    IUL-78 *3 / *3 109.5 3.1 148.7 6993 198 19.2 695 183
    IUL-81 *3 / *3 71.7 2.0 65.2 3424 132 22.5 395 110
    IUL-86
*3 / *3
77.8
2.1
160.0
8851
288
23.0
844
217

  • ↵ a Corrected for microsomal binding to vincristine.

  • ↵ b Intrinsic clearance = CLint = Vmax · 1500 g liver · 45 mg microsomal protein/g liver/Km for a 70-kg man.

  • ↵ c Hepatic clearance = CLH = Q · fu,p/ρ · CLint/(Q + fu,p/ρ · CLint), where fu,p = 0.51, ρ = 1.2, and Q = 1500 ml/min for a 70-kg man.

  • ↵ d HLMs not selected randomly.