| Autor: |
L C, Wienkers, C J, Wurden, E, Storch, K L, Kunze, A E, Rettie, W F, Trager |
| Rok vydání: |
1996 |
| Předmět: |
|
| Zdroj: |
Drug metabolism and disposition: the biological fate of chemicals. 24(5) |
| ISSN: |
0090-9556 |
| Popis: |
Kinetic studies demonstrate that two forms of human liver cytochrome P450 are responsible for the formation of (R)-8-hydroxywarfarin: a low-affinity enzyme (KM approximately 1.5 mM), previously identified as P4501A2; and a high-affinity enzyme (KM = 330 microM), now identified as P4502C19 on the basis of the following evidence. In crossover inhibition studies with P4501A2-depleted human liver microsomes between (R)-warfarin and (S)-mephenytoin, reciprocal competitive inhibition was observed. Apparent KM values for (S)-mephenytoin-4'-hydroxylation (52-67 microM) were similar to the determined Ki values (58-62 microM) for (S)-mephenytoin inhibition of (R)-8-hydroxywarfarin formation. Similarly, the apparent KM for (R)-warfarin 8-hydroxylation in furafylline-pretreated microsomes (KM = 289-395 microM) was comparable with the Ki values (280-360 microM) for (R)-warfarin inhibition of (S)-4'-hydroxymephenytoin formation. Inhibition studies with tranylcypromine, a known inhibitor of (S)-mephenytoin hydroxylase activity, and either substrate in three different microsomal preparations yielded nearly identical inhibitory constants: Ki = 8.7 +/- 1.6 microM for inhibition of (S)-4'-hydroxymephenytoin formation and 8.8 +/- 2.5 microM for inhibition of (R)-8-hydroxywarfarin formation. In addition, fluconazole, a potent inhibitor of (R)-warfarin 8-hydroxylation, Ki = 2 microM, was found to inhibit (S)-mephenytoin hydroxylation with an identical Ki (2 microM). Finally, a strong correlation between (S)-mephenytoin 4-hydroxylation and (R)-warfarin 8-hydroxylation activities in furafylline-pretreated microsomes was demonstrated in 14 human liver microsomal preparations (r2 = 0.97). |
| Databáze: |
OpenAIRE |
| Externí odkaz: |
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