Posted by Sunnely on February 28, 2002, at 8:16:57
In reply to Serzone and CYP3A4 inhibition, posted by Jim86 on February 24, 2002, at 21:18:53
Typically, inhibition of CYP450 enzymes is competitive and dependent on the relative affinities of the compounds for the enzyme. Because the inhibition is competitive, once an inhibitor is introduced, inhibition is immediate. Removing the inhibitor will quickly negate the inhibition, and enzyme activity will return to normal levels within a few days, the time dependent on the half-life of the inhibitor. One exception to this quick reversal, however, is the reversal of fluoxetine. Fluoxetine (and its active metabolite, norfluoxetine) has a long half-life, approximately 5-14 days. When fluoxetine is removed, a 4-to-8-week washout period elapses before enzyme activity return to normal.
With regard to Serzone, it is extensively metabolized in the liver to 3 active metabolites - hydroxynefazodone, triazoledione, and mCPP. At steady state blood level (i.e., amount administered is equal to the amount eliminated in 24 hours, provided all factors remaining constant), Serzone's half-life is dependent on dose, varying from 2 hours at 100 mg per day to 4-5 hours at 600 mg per day. Therefore, if you are taking 600 mg/day, it would take approximately 2 days (give or take a few hrs) to remove almost 100% of Serzone's CYP3A4 inhibition. (The general rule is, it takes approximately 5 half-lives to reach steady state and the same number of half-lives, once stopped, to eliminate >90% of the compound from the system, provided all other factors remain constant.)
FYI, while the effect of CYP450-enzyme inhibition is felt immediately (i.e., increased side effects), CYP450-enzyme effect due to induction is gradual (i.e., loss of efficacy). For example, carbamazepine (Tegretol) which induces itself, may require upward dosing after a few weeks from reaching steady state due to falling blood levels.
> Does anyone know how long after taking a dose of Serzone the CYP3A4 enzyme in the liver is inhibited? Also, if you have been on serzone for a while (more than a year), how long must you discontinue taking it for the CYP3A4 enzyme to return to normal functioning (i.e., not be inhibited any more) ?
>
> Thanks a lot!
poster:Sunnely
thread:95362
URL: http://www.dr-bob.org/babble/20020222/msgs/95806.html