PsychoTropical Research - Dr Ken Gillman, Serotonin Syndrome, Mirtazapine, Dual Action Drugs. Cytochrome P450 enzymes - 2C9.

PsychoTropicalResearch, serotonin and serotonin syndrome research.

Cytochrome P450 enzymes - 2C9

Cytochrome P450 enzymes - 2C9

Inhibitors

Fluvoxamine is a potent inhibitor of CYP2C9 and extremely for 2C19 and 1A2).

Fluoxetine may also cause significant interactions.

Inhibitor constants

  • Ki of fluvoxamine ~13 microM-- potent enough to be clinically significant at usual doses
  • Fluoxetine ~87.0 microM-- weaker and ? not often clinically significant except in higher doses.
  • sulfa-phenazole (-diazine, methizole, methoxazole)
  • sulconazole K(i), 0.01 microM = high affinity
  • Ketoconazole
  • trimethoprim, chloramphenicol
  • cimetidine
  • amiodorone
  • phenylbutazone
  • valproate
  • gemfibrozil

Substrates

  • Phenytoin
  • warfarin
  • tolbutamide
  • torasemide
  • Many NSAIDs:--diclofenac and ibuprofen other 'profens, mefenamic acid, naproxen, piroxicam, tenoxicam etc.
  • losartan
  • amitriptyline
  • fluoxetine
  • propofol (anesthetic)

Inducers

  • barbiturates
  • carbamazepine
  • ethanol
  • rifampicin
  • colchicine

Genetic polymorphism

Genetic polymorphism of 2C9 means the half-life of tolbutamide varies between subjects from 2.9 up to 25 hours, and in one very poor metaboliser was 37 hrs (probable frequency of this poor metaboliser variant is <1%). Maintenance doses of warfarin are significantly related to 2C9 genotype.

The frequencies of CYP polymorphisms in one study were:- 2C9*2,15.7%; 2C9*3 15.0%. CYP polymorphisms were less common in African Americans (15.2%) than Caucasians 39.2% (p = 0.05).

Clinical consequences

Fluvoxamine at the low dose of only 75 mg per day has a significant effect on tolbutamide levels; thus demonstrating it is a moderate inhibitor of 2C9 in vivo. Phenytoin intoxication has occurred with fluvoxamine (concentration of phenytoin increased from 16.6 to 49.1 mcg/m). This suggests significant inhibition of both CYP2C9 and 2C19 by fluvoxamine.

Fluoxetine at the higher dose of 40 mg per day has a significant effect on Phenytoin levels. The risk of a SSRI-phenytoin interaction is highest with fluoxetine and norfluoxetine, and less likely with sertraline and paroxetine (which do have weak 2C9 inhibitor activity).

Warfarin is racemic mixture. Cytochrome P-450 2C9 seems to be the principle enzyme that terminates the anticoagulant effect (ie is the rate limiting step). CYP1A2 and CYP2C19 and 3A4 may also play a smaller part, perhaps more so in those subjects who are poor metabolisers via 2C9.

Genetic polymorphisms of CYP2C9 impairing warfarin metabolism occur in ~35% of patients, and are associated with increased warfarin sensitivity. Studies show an increased plasma level and decreased clearance with variant CYP2C9 alleles. Maintenance doses of warfarin are significantly related to 2C9 genotype.

Fluvoxamine is likely to convert most patients to poor metaboliser status at usual doses of 100 mg per day for 2C9 (and 1A2). Theory indicates other selective serotonin reuptake inhibitors are unlikely to have much effect on 2C9. Warfarin levels are very sensitive to changes in 2C9, so a small change can alter the INR even though none of the SSRIs (bar fluvoxamine and fluoxetine) potently block 2C9.

As is the case for most cytochrome P450 enzyme inhibition scenarios involving selective serotonin reuptake inhibitors citalopram and sertraline are the safest bet. The other three selective serotonin reuptake inhibitors, fluoxetine, paroxetine and fluvoxamine all have potentially problematic and serious cytochrome P450 interactions. They are therefore best avoided as much as possible by those not fully conversant with the latest data concerning interactions.

At a slightly deeper and more theoretical level it is useful to understand that blockade of 1A2 by fluvoxamine converts people to a phenotypic poor metaboliser status. Since approximately 30% of people have the allelic variant which makes them genotypic poor metabolisers and therefore “sensitive” to Warfarin one can argue there isn’t much difference. Indeed if someone was going to remain on a constant dose of fluvoxamine sufficient to properly inhibit 1A2 then adjustment of Warfarin dose might be made easier because they’d be permanent slow metabolisers and get a constant INR on a minimal Warfarin dose. The same argument can be advanced for paroxetine and fluoxetine; if everyone was converted to a poor metaboliser by such drugs then there’d be less problem with adjusting dosage the necessity for which is created by the wide genetic variation in the rate of metabolism.

Obviously, in practice such techniques are generally impractical and potentially risky but never the less in special circumstances it’s appropriate to understand that, providing the subjects metaboliser status doesn’t change, then it is quite safe to use such techniques with appropriate monitoring of blood levels be that TCAs or INR with Warfarin.