TABLE 4.
Impact of CYP3A5 expression on the inhibition of MDZ and TST metabolism in HLM by KTZ and ITZ
Data are presented as the mean ± S.D. (n = 3 determinations).
| CYP3A5 Genotype | HLM Preparation | IC50 |
|||
|---|---|---|---|---|---|
| MDZa |
TSTb |
||||
| + KTZ | + ITZ | + KTZ | + ITZ | ||
| nM | nM | nM | nM | ||
| *1/*1 | HL739 | 35.8 ± 3.8 | 108 ± 24 | 31.5 ± 4.8 | 85.4 ± 10.5 |
| HL867 | 34.3 ± 3.2 | 111 ± 15 | 19.7 ± 3.8 | 120 ± 12 | |
| HL47 | 30.7 ± 4.0 | 123 ± 21 | 29.1 ± 2.7 | 111 ± 11 | |
| Mean ± S.D. | 33.6 ± 2.6* | 114 ± 8* | 26.8 ± 6.3 | 105 ± 18* | |
| *1/*3 | HL150 | 132 ± 13 | 1133 ± 782 | 308 ± 52 | 513 ± 105 |
| HL125 | 11.8 ± 1.5 | 161 ± 27 | 53.9 ± 3.8 | 158 ± 14 | |
| HL167 | 24.3 ± 2.2 | 176 ± 13 | 64.2 ± 6.6 | 195 ± 15 | |
| Mean ± S.D. | 56.1 ± 66.3 | 490 ± 557 | 142 ± 144 | 289 ± 195* | |
| *3/*3 | HL152 | 6.92 ± 1.12 | 47.3 ± 8.5 | 25.8 ± 3.8 | 20.0 ± 2.3 |
| HL143 | 12.9 ± 2.0 | 83.0 ± 5.9 | 27.1 ± 5.5 | 21.6 ± 1.7 | |
| HL131 | 11.5 ± 1.0 | 53.3 ± 7.4 | 10.2 ± 1.1 | 46.7 ± 4.2 | |
| Mean ± S.D. | 10.4 ± 3.1 | 61.2 ± 19.1 | 21.0 ± 9.4 | 29.4 ± 15.0 | |
HL, human liver.
a
Initial concentration of MDZ was 1 μM.
b
Initial concentration of TST was 10 μM.
*
P < 0.05, significantly different from the IC50 obtained with HLM of a liver genotyped CYP3A5*3/*3.