PsychoTropical Research - Dr Ken Gillman, Serotonin Syndrome, Mirtazapine, Dual Action Drugs.Cytochrome P450 enzymes - 2D6.

PsychoTropicalResearch, serotonin and serotonin syndrome research.

Cytochrome P450 enzymes - 2D6

Cytochrome P450 enzymes - 2D6

Inhibitors

Potent inhibitors are likely to cause serious or dangerous interactions in some circumstances, especially because some of these drugs have a narrow therapeutic margin.

Of the selective serotonin reuptake inhibitor antidepressants, and the other new antidepressants to date, only fluoxetine and paroxetine are potent inhibitors of CYP450 2D6.

miconazole K(i), 0.70 microM; sulconazole K(i), 0.40 microM) = high affinity
metoclopramide
quinidine
ticlopidine
ritnavir
moclobemide ? weak
risperidone ? weak.

Substrates

CYP450 2D6 plays a significant part in inactivating the following drugs (along with, in varying proportions, 1A2, 2C9, 3A4):--

  • paroxetine
  • venlafaxine (and partly 2C19)
  • most of the tricyclic antidepressants
  • dextromethorphan, dextropropoxyphene, codeine, (R)-methadone
  • beta-blockers
  • colchicine
  • some neuroleptics, including risperidone and sertindole
  • anti-histamines.

Genetic polymorphism

About 8% of the Caucasian population are genetically ‘deficient’ in 2D6 which renders them poor metabolisers and liable to develop considerably elevated blood levels with all drugs that are dependent on 2D6 for their elimination.

For the tricyclic antidepressants nortriptyline and desipramine 2D6 is the main metabolic pathway. The 8% of Caucasians who are ‘deficient’ in 2D6 and will have high blood levels (they are referred to as ‘poor metabolisers’ -PMs). Some people are very rapid ‘extensive’ metabolisers -EMs.

The actual numbers are easy to remember since a typical dose of 100 mg of desipramine gives a steady state level of about 100 µg/L (measured 12 hours after the last dose); a ratio of 1:1 . An EM may have a level as low as 15 µg/L; a ratio of 0.15:1 while for a PM the blood level may be up to 1200 µg/L, a ratio of 12:1 .

In one Colombian sample, ~ 90% of the individuals were normal metabolizers, 7% were poor metabolizers, and 2% were ultrarapid metabolizers.

Clinical consequences

The subjects who may experience drastic changes in blood levels are those who were previously fast (extensive-- 'EM') metabolisers; their levels may go from low to high when they are converted from fast to slow by fluoxetine or paroxetine. This change can be great enough to be dangerous.

Fluoxetine is particularly problematic being a potent 2D6 inhibitor and also a inhibitor of 3A4 and 2C19. These effects can persist for many weeks after cessation because of its long elimination half life.

Sertraline has a small effect that is not usually significant; high doses may raise levels of co-administered TCAs by around 30%.

Beta-blocker eye drops get into the systemic circulation more than is appreciated. In PMs- (poor (slow) metabolisers) this has a more marked effect. Symptoms caused by systemic effects have included decreased heart rate, depression, confusion, headache, fatigue and hallucinations.

Codeine phosphate (which is a pro drug, ie not itself pharmacologically active) is metabolised by 2D6, hence PMs will be substantially immune to its clinical effect because they will metabolise it to its active metabolite much more slowly and therefore have much lower blood levels. Also patients on fluoxetine and paroxetine may fail to respond to codeine because their 2D6 is blocked, producing the same end result.