Posted by Rick on November 1, 2001, at 2:24:00
In reply to Re: modafinil and Serzone --- Krista » Rick, posted by Sunnely on October 30, 2001, at 23:56:27
I still come to the conclusion that Serzone is likely to potentiate modafinil, while modafinil is unlikely to have any significant effect on Serzone or mCPP.
Sorry about the misquote, but that doesn't change my conclusions, which I'm basing on Cephalon's June 2000 in-vitro analysis on modafinil's CYP450 effects, notably the following statement:
"Modafinil exhibited minimal capacity to inhibit any CYP enzyme, except CYP2C19"
If this is true, it is most likely that Serzone, as a powerful CYP3A4 inhibitor will decrease modafinil clearance (and yes, theoretically its own), while modafinil will have little if any accumulation effect on Serzone OR on mCPP. Thus, no risk of decreased Serzone effectiveness or added anxiety (unless it's produced by the modafinil).
From the "personal experiences" file, adding Serzone+Provigil enhanced the anti-anxiety benefits I get from Klonopin.
Rick
> > Anyway, Serzone is NOT an inducer of enzyme CYP3A4. Quite to the contrary, it is a potent *inhibitor* of CYP3A4.
>
> I don't believe I mentioned in my post that Serzone is an inducer of CYP3A4. In fact, I agree with you that it is a marked inhibitor of CYP3A4. However, Serzone is also a substrate of (metabolized by) CYP3A4 therefore, theoretically could inhibit its own metabolism (autoinhibition). One of Serzone's metabolites, mCPP, is a substrate of CYP2D6. Therefore, other co-administered drugs that either hasten the metabolism of Serzone to mCPP or inhibit the metabolism of mCPP via via CYP2D6, theoretically could lead to anxiety as mCPP is anxiogenic (induces anxiety). For example, combining Prozac or Paxil with Serzone may lead to increase anxiety via inhibition of CYP2D6 by Prozac or Paxil due to increase level of mCPP.
>
> > Since Provigil (modafinil) depends partly on CYP3A4 for its metabolism, the actual interaction effect is that Serzone's inhibition of this enzyme can increase the amount of Provigil (modafinil) in the bloodstream and slow down Provigil elimination.
>
> You're assumption is correct that Serzone could inhibit the metabolism of modafinil via CYP3A4. However, modafinil is also an inducer of CYP3A4 and therefore, theoretically could lead to increase metabolism of Serzone converting it to 3 metabolites, one of which is mCPP. Aside from being an inducer of CYP3A4, modafinil is also an inhibitor of CYP2C9 and CYP2C19 which could lead to another set of drug interactions depending on the affected drugs.
>
> On a related note, since modafinil partly depends on CYP3A4 for its metabolism and, at the same time induces this same cytochrome, theoretically it induces its own metabolism (autoinduction). This may not lead to clinically significant effect, however. One particular drug that is a good example of "autoinduction" is carbamazepine (Tegretol). In fact, after several weeks of Tegretol treatment, blood levels tend to drop and even may become subtherapeutic, due to autoinduction. Tegretol marekdly induces a number of cytochrome enzymes, hence the label "paninducer."
>
> > In fact, it's a great combo for many including myself. Provigil offset my Serzone+Klonopin induced fatigue completely, and (unexpectedly) added other welcome dimensions to my treatment at the same time.
>
> I agree. In fact, although only FDA-approved for the sleepiness of narcolepsy, modafinil is also used (off label) as an augmentation treatment to antidepressant and to alleviate psychotropic-induced sedation, among others.
>
> >
> > Rick
> >
> >
> > > Hi Krista,
> > >
> > > Modafinil (Provigil), a central nervous system stimulant which is FDA-approved for narcolepsy, induces the cytochrome P450 enzyme 3A4 (CYP3A4). Nefazodone (Serzone) is mainly dependent on this enzyme for its metabolism. The combination of Provigil and Serzone could lead to increased metabolism of Serzone (rapid formation of daughter compounds) ---- > decreased in Serzone blood level ---- > loss of Serzone effectiveness. Incidentally, one of Serzone's daughter compounds called mCPP (meta-chlorophenylpiperazine) is known to induce anxiety (anxiogenic). Theoretically, the rapid formation of mCPP could lead to anxiety and, this could become even more problematic if you belong to the 7-10% of Caucasian population who are genetically deficient of the cytochrome P450 enzyme that mainly metabolizes mCPP, CYP2D6. Provigil, being a psychostimulant itself, could further complicate this problem (i.e., anxiety, activation, insomnia).
> > >
> > > *******************************
> > >
> > > > I have been on Serzone for 6 months now and am not sedated but not exactly
> > > > awake. My doctor was thinking about adding modafinil. But I read a post on here that disturbed me about those two meds as a combo.
> > > > It was posted that Modafnil lowers a enzyme from the body that is needed to metabolize Serzone. I was just wondering if anyone knows this to be true. Or is there
> > > > a website where I can actually ask a doctor this question directly? I'd like to get a second opinion before I jump into taking the Modafinil.
> > > >
> > > > thanks
> > > > Krista
poster:Rick
thread:66507
URL: http://www.dr-bob.org/babble/20011025/msgs/82839.html