PsychoTropical Research - Dr Ken Gillman, Serotonin Syndrome, Mirtazapine, Dual Action Drugs.Cytochrome P450 enzymes - 3A4.

PsychoTropicalResearch, serotonin and serotonin syndrome research.

Cytochrome P450 enzymes - 3A4

Cytochrome P450 enzymes - 3A4

The newer antidepressants that are clinically significant inhibitors of CYP450 3A4 are:--

  • Inhibitors
  • fluoxetine (mostly its metabolite, nor-fluoxetine)
  • fluvoxamine (much more potent for 1A2 and 2C19 and 2C9)
  • nefazodone.

There is an apparent structural homology for some CYP3A4 inhibitors and the P-Gp pump and many CYP3A4 inhibitors are inhibitors of P-Gp:- erythromycin, calcium channel blockers, cephalosporins

Drugs (other than antidepressants) known to inhibit 3A4 to a clinically significant extent:--

  • isoniazid
  • macrolide antibiotics (especially clarithromycin and erythromycin and, most potent, troleandomycin)
  • clotrimazole K(i), 0.02 microM; miconazole K(i), 0.03 microM; tioconazole K(i), 0.02 microM) = high affinity; ketoconazole, itraconazole
  • All calcium channel blockers (bar nifedipine) inhibit CYP3A activities: nicardipine (1 microM), verapamil (2 microM), and diltiazem (5 microM) amlodipine (5 microM) and felodipine (13 microM) mibefradil
  • gestodone
  • valproate
  • cyclosporin
  • cimetidine
  • ritnavir, indinavir, nelifinavir
  • furocoumarins in:-- grapefruit juice and seville orange juice (a newly identified furocoumarin, bergapten, was detected only in Seville orange juice)
  • furanocoumarins in umbelliferous plants such as carrot, parsley, celery, dill (similar potency as ketoconazole)
  • polyphenolic compounds in red wine, including trans-resveratrol [sold as a 'nutraceutical' product]. Red wine concentrate has been shown to inhibit 3A4.
  • flavonolignans in 'Milk thistle' [the extract is a commonly used herbal remedy]
  • Dillapiol, hypericin.

Substrates

CYP3A4 is the main enzyme inactivating the following common drugs:--

  • most of the benzodiazepines (-azepams) including diazepam, flunitrazepam, alprazolam midazolam, triazolam) and zopiclone and buspirone (but not oxazepam, temazepam or lorazepam)
  • carbamazepine, primidone
  • cisapride
  • fentanyl, alfentanil, methadone
  • nimodipine, felodipine, amiodipine
  • terfenidine, astemizole
  • some of the old antihistamines, tricyclic antidepressants and both old and new neuroleptics*. eg Quetiapine, azelastine
  • mirtazapine (CYP3A, CYP1A2 and CYP2D6 contribute about equally)
  • cisapride
  • Various statins
  • repaglinide
  • propafenone
  • sildenafil
  • tacrolimus
  • ergotamine***.

Inducers

  • carbamazepine, phenytoin, phenobarbital, felbamate
  • colchicine
  • rifampicin

Genetic polymorphism

Likely. CYP3A4 exhibits a 20-fold interindividual activity variation. This may be partly explained by genetic polymorphism. The mechanisms are poorly understood, but may include gene induction, protein inhibition and genetic polymorphisms.

Single nucleotide polymorphisms:-28 SNPs identified, five which produce coding changes M445T (CYP3A4*3), R162Q (CYP3A4*15), F189S (CYP3A4*17), L293P (CYP3A4*18), and P467S (CYP3A4*19).

Clinical consequences

* most of these drugs, including amitriptyline, chlorpromazine, clozapine and olanzapine are metabolised by multiple CYP enzymes including P450 1A2 and 2C9 and 3A4.

(Nefazodone -inhibitor of CYP3A4, had minimal effects on clozapine metabolism)

***Unexpectedly high levels resulting from these interactions may be associated with, for example: potentially dangerous cardiac arrhythmias, and for ergotamine-- ergotism. I am aware of a recent case where a patient lost a leg as a result of ergotism secondary to an interaction between ergotamine and erythromycin.

When nefazodone treatment follows fluoxetine all sorts of interesting things may happen which might result in significant clinical problems. Such a chain of events illustrates the complexities involved. eg. Fluoxetine (and more potently its metabolite, nor-fluoxetine) is an inhibitor of cytochrome P450 3A4. Cytochrome P450 3A4 metabolises nefazodone into the metabolite m-CPP. This is anxio-genic through it's agonist activity at 5-HT2C receptors. m-CPP is then further metabolised (ie inactivated) by cytochrome P450 2D6.

Fluoxetine is also an potent inhibitor of cytochrome P450 2D6 Fluoxetine can have a very long elimination half-life of up to 7-14 days in some people; so even eight or so weeks after ceasing it sufficient may remain to set in motion the above chain of events; as well as many other potential interactions.

This might result in the accumulation of m-CPP and an exaggeration of the patients anxiety symptoms. One would predict that anyone genetically deficient in cytochrome P450 2D6 (that is 8% of the caucasian population) who takes nefazodone will experience increased levels of m-CPP and thus possibly be liable to increased anxiety symptoms. That is because m-CPP is dependent on cytochrome P450 2D6 for its breakdown so it will accumulate if cytochrome P450 2D6 is genetically deficient or blocked by another drug (such as fluoxetine or paroxetine).

Rhabdomyolysis has been associated with the coadministration of some 3-hydroxy-3-methylglutaryl-coenzyme A reductase inhibitors ('statins') and CYP3A4 inhibitors.

Note; the 3-OH benzodiazepines (oxazepam, lorazepam, temazepam) can be conjugated directly and are not affected by 3A4. Most other benzodiazepines are elevated by 3A4 blockade.

One glass of grapefruit juice can produce an increase in cisapride as can red wine (to a lesser but potentially significant extent). Symptomatic hypotension can occur when CYP3A4 inhibitors are given with some dihydropyridine calcium antagonists, as well with sildenafil.

A recent paper looked at 21 herbal extracts for 3A4 inhibitory capability:--

75% of the commercial products showed significant inhibition of CYP3A4 metabolite formation. Among the commercial extracts, Hydrastis canadensis (goldenseal), Hypericum perforatum (St. John's wort), and Uncaria tomentosa (cat's claw) were potent, followed by Echinacea angustifolia roots, Trifolium pratense (wild cherry), Matricaria chamomilla (chamomile), and Glycyrrhiza glabra (licorice). Dillapiol, hypericin, and naringenin had the lowest IC50 values among the pure plant compounds at < 0.5 mM; dillapiol was the most potent inhibitor at 23.3 times the concentration of ketoconazole.

One recent paper showed that even low doses of the 3A4 clarithromycin increase the plasma concentrations and effects of repaglinide and may increase the risk of hypoglycemia.