PsychoTropical Research - Dr Ken Gillman, Serotonin Syndrome, Mirtazapine, Dual Action Drugs. Cytochrome P450 enzymes - 1A2 .

PsychoTropicalResearch, serotonin and serotonin syndrome research.

Cytochrome P450 enzymes - 1A2

Cytochrome P450 enzymes - 1A2

Introduction

Fluvoxamine is the only new antidepressant to inhibit cytochrome P450 1A2, thus far.

It inhibits 1A2 extremely potently.

Almost all patients treated with even low doses of fluvoxamine (only 50 mg/day) will reach population minimums for CYP1A2 activity (ie become 'PMs', poor metabolisers).

Fluvoxamine is also an extremely potent inhibitor of 2C19 and also significant inhibitor of 2C9 and 3A4; (but not of 2D6).

The use of fluvoxamine is thus fraught with risks because this potent cytochrome P450 blockade involves many other commonly used drugs. There are few clinical situations in which it represents a logical first or second choice treatment in primary care. In specialist practice interactions with neuroleptics, especially olanzapine and clozapine may cause serious problems.

1A2 Inhibitors

  • Fluvoxamine and -naphthoflavone.
  • sulconazole and tioconazole:- high-affinity inhibition= K(i), 0.4 microM
  • mexiletine, lidocaine, and (weaker) tocainide
  • Estrogen
  • some anti-psychotics especially clozapine
  • idrocilamide
  • phenylpropanolamine
  • bronchodilators (furafylline and theophylline)
  • quinolones (enoxacin)
  • moclobemide ? weak
  • flavones, a class of phytochemicals consumed in the human diet (found at high concentrations in 'Tofu") and psoralens

A wide range of flavonoids tested (isolated from Scutellariae radix) have all proved potent inhibitors of CYP1A2

Some small, but probably insignificant, consolation is that fluvoxamine seems not to significantly inhibit 2D6. It seems to have no effect on O-demethylation ratio (ODMR) of dextromethorphan in healthy volunteers (or patients) at steady state on fluvoxamine 100 mg/day.

Substrates

Cytochrome P450 1A2 metabolises several groups of compounds:--

  1. A number of important drugs, quinolone antibiotics
  2. Some compounds called pro carcinogens (e.g., arylamines in cigarette smoke),
  3. Endogenous hormones such as 17beta-estradiol.
  4. Melatonin
  5. Fluvoxamine itself (to inactive metabolites, and also via CYP2D6)
  6. Flavonoids in foods. Kaempferol, apigenin and naringenin and corresponding hydroxylated analogs quercetin, luteolin and eriodictyol; also hesperetin and tamarixetin and demethylated analogs eriodictyol and quercetin.

Important drugs

cimetidine, Zolmitriptan, theophylline, caffeine, tacrine, imipramine, haloperidol, pentazocine, phenacetin O-deethylation, propranolol, flecainide and estradiol and other drugs structurally related to these drugs. quinolone antibiotics

For instance:-- probably all the tertiary amine tricyclic antidepressants*** (clomipramine, amitriptyline, doxepin, dothiepin, but not secondary amines nortriptyline or desipramine) and also many neuroleptics like clozapine, olanzapine, chlorpromazine.

*** tertiary amine tricyclics are those with two methyl groups on the terminal nitrogen of the side chain. The primary step in metabolism is demethylation to secondary amines; viz amitriptyline is demethylated to nortriptyline

Inducers

  • Omeprazole
  • Carbamazepine
  • nicotine [nicotine may induce the activity of:- CYP1A2, CYP2B1/2B2 and CYP2E1]
  • Polycyclic aromatic hydrocarbons in tobacco smoke
  • highly inducible by the environmental contaminants dioxin and benzo[a]pyrene

Genetic polymorphism

Cytochrome P450 1A2 is genetically polymorphic.

A 16-fold variation of CYP1A2 activity has been shown in one study. With poor metabolisers (PMs) ~5% in a Chinese population. 1A2 activity of men was higher than that of women (median: 0.33 vs 0.23, P<0.001).

Clinical consequences

Fluvoxamine exhibits non-linear kinetics within the therapeutic dose range and the levels show large variations between subjects. The elimination half-life of fluvoxamine was 16 - 32 hrs

Caffeine levels are markedly elevated by even small doses of fluvoxamine; the most serious caffeine-related CNS effects include seizures and delirium. A dose of only 20 mg of fluvoxamine significantly inhibits caffeine (CYP1A2) metabolism.

Estrogen inhibits 1A2 and that reduces metabolism of caffeine. So exogenous estrogen given to post menopausal women may inhibit caffeine metabolism (but only by about 30%).

Induced metabolism of 1A2 because of cigarette smoking may have clinical consequence for some of these drugs.

"Fluvoxamine inhibited in a concentration-dependent manner the activity of all five cytochrome P450 (CYP) isoforms previously determined to be capable of catalyzing the demethylation of clozapine. Fluvoxamine inhibited CYP1A2 and 2C19 with the highest affinities (Ki values of 0.041 and 0.087 microM, respectively). The Ki values for CYP2C9 and 2D6 were 2.2 and 4.9 microM, respectively, whereas the Ki for CYP3A4 was 24 microM. Assuming a hepatic tissue concentration of fluvoxamine in the range of 4 to 7 microM under therapeutic conditions, a clinically significant inhibition of all but CYP3A4 is expected in relation to clozapine N-demethylation." The same would probably apply to similarly structured drugs: eg clomipramine, amitriptyline, doxepin, dothiepin, olanzapine, chlorpromazine.