|
|
Publication
|
| Research Title |
The “albumin effect” on in vitro kinetics of various cytochrome P450-catalyzed reactions: in vitro to in vivo extrapolation |
| Date of Distribution |
5 September 2010 |
| Conference |
| Title of the Conference |
9th International ISSX Meeting |
| Organiser |
International Society for the Study of Xenobiotics |
| Conference Place |
Istanbul Lutfi Kirdar Convention and Exhibition Center |
| Province/State |
Istanbul, Turkey |
| Conference Date |
4 September 2010 |
| To |
8 September 2010 |
| Proceeding Paper |
| Volume |
- |
| Issue |
- |
| Page |
59 |
| Editors/edition/publisher |
Heyo Kroemer |
| Abstract |
The addition of bovine serum albumin (BSA) to in vitro incubations improves estimation of kinetic parameters, intrinsic clearance (CLint) to in vivo clearance, mainly via a reduction of the Km for drugs metabolized by cytochrome P450 2C9 (CYP2C9). The universal effect of BSA on other CYP isozymes, however, is unclear. The aims of this study were to characterize the effect of BSA on kinetics of specific pathways for CYP2C8, 2C19, 2E1, and 3A4 whether the inclusion of BSA could improve the prediction of in vivo clearance from in vitro kinetics data. Using human liver microsomes as an enzyme source; 6alpha-hydroxypaclitaxel, 5-hydroxyomeprazole, 6-hydroxychlorzoxazone and omeprazole sulfone formations were used as markers for CYP2C8, 2C19, 2E1, and 3A4 activity. In the presence of 2% BSA, the mean CLint for paclitaxel 6alpha-hydroxylation was significantly increased by decreasing Km with a minor effect on mean Vmax. In the presence of 2% BSA, the mean Km1 and Vmax1 for omeprazole 5-hydroxylation were decreased which resulted in increases in the mean CLint1. BSA decreased CLint for chlorzoxazone 6-hydroxylation mainly via an increase of the Km. The mean Km and Vmax for CYP3A4-mediated omeprazole sulfoxidation were significantly increased in the presence of 2% BSA and therefore the mean CLint was not significantly changed. Taken together, extrapolation of CLint values for CYP2C8-mediated paclitaxel 6alpha-hydroxylation in the presence of 2% BSA were more predictable as compared to in vivo clearance. In conclusion, the effect of albumin on individual CYP isoforms was variable; the use of BSA to improve prediction of in vivo intrinsic clearance seems to be possible with only CYP2C8. BSA showed a minor effect on the CYP2C19-mediated omeprazole 5-hydroxylation whereas it had no effect on CYP2E1-mediated chlorzoxazone 6-hydroxylation and 3A4-mediated omeprazole sulfoxidation for improving clearance prediction. |
| Author |
|
| Peer Review Status |
มีผู้ประเมินอิสระ |
| Level of Conference |
นานาชาติ |
| Type of Proceeding |
Abstract |
| Type of Presentation |
Poster |
| Part of thesis |
true |
| ใช้สำหรับสำเร็จการศึกษา |
ไม่เป็น |
| Presentation awarding |
false |
| Attach file |
|
| Citation |
0
|
|
|
|
|
|
|
|
|
Journal Publication
ไทย