PsychoTropical Research - Dr Ken Gillman, Serotonin Syndrome, Mirtazapine, Dual Action Drugs. Cytochrome P450 enzymes - 2C19.

PsychoTropicalResearch, serotonin and serotonin syndrome research.

Cytochrome P450 enzymes - 2C19

Cytochrome P450 enzymes - 2C19

Inhibitors

  • N-3-benzyl-nirvanol and (-)-N-3-benzyl-phenobarbital (potent selective inhibitors of CYP2C19)
  • fluvoxamine (extremely potent even at sub-therapuetic doses)
  • miconazole K(i), 0.05 microM; sulconazole K(i), 0.008 microM; tioconazole K(i), 0.04 microM) = high affinity
  • sulfaphenazole
  • fluoxetine
  • Omeprazole
  • ticlopidine
  • moclobemide
  • tranylcypromine, isoniazid
  • valproate
  • felbamate
  • topirimate

Substrates

  • S-mephenytoin (marker, used to assess 2C19 activity)
  • phenytoin
  • doxepin
  • propranolol
  • proguanil
  • diclofenac
  • Flunitrazepam diazepam (and 3A4)
  • Citalopram (N-demethylation to N-desmethylcitalopram- partly by CYP2C19 and partly by CYP3A4)
  • sertraline
  • fluoxetine (2C19 plays a major role in N-demethylation at higher conc)
  • moclobemide
  • venlafaxine (mostly 2D6)
  • terodiline
  • Omeprazole and lansoprazole (most proton pump inhibitors are predominantly inactivated by 2C19)

Inducers

  • colchicine
  • rifampicin
  • dexamethasone

Genetic polymorphism

CYP2C19 PMs ~ 3-5% of Caucasians and African-Americans and between 12% and 100% in different Asian groups.

Clinical consequences

One of the factors associated with success or failure of cure of H pylori infection by the proton pump inhibitor-based triple therapy appeared to be CYP2C19 genotype status.

CYP2C19 genotype status influences gastric acid suppression by lansoprazole, but not by rabeprazole.

The polymorphic CYP2C19 appears to be a major enzyme involved in the N-demethylation of sertraline, extensive vs poor metabolisers had marked differences in sertraline levels.

CYP2C19 and CYP3A are inhibited potently by isoniazid in a concentration-dependent manner.

CYP2C19 is an important enzyme in the elimination of moclobemide and it is inhibited by Omeprazole in extensive metabolisers, but not in poor metabolisers.

Trimipramine CYP2D6 involved in the 2-hydroxylation of (L)-TRI; CYP2C19 involved in the demethylation pathway. CYP3A4/5 appears to be involved in the metabolism of (L)-TRI to a presently undetermined metabolite.

Possession of the CYP2C19*2 allele appears to contribute to adverse cardiac reactions to terodiline.

Fluoxetine 20 mg/day for 6 weeks 40 mg/day for an additional 6 weeks:-- The half-life for fluoxetine was 5.0 days and norfluoxetine 20 days. Fluoxetine substantially inhibited the metabolism of the CYP2C19 substrate (S)-mephenytoin (increased mephenytoin ratio X 4).

Flunitrazepam:-- the relative contributions of CYP2C19 and CYP3A4 to the formation of desmethyl-flunitrazepam in vivo have been estimated as 63 and 37%, respectively. CYP2C19 catalyses flunitrazepam demethylation, CYP3A4 catalyses the formation of 3-hydroxy-flunitrazepam.

Ticlopidine appears to be a broad-spectrum inhibitor of the CYP isoforms, but clinically significant adverse drug interactions are most likely with drugs that are substrates of CYP2C19 or CYP2D6.

In one paper inhibition of moclobemide was significant in extensive metabolisers after just one dose of omeprazole. After one week on omeprazole the pharmacokinetics in extensive metabolisers changed to values similar to those of poor metabolisers (moclobemide is known to be metabolized by CYP2C19 and is reported to be an inhibitor of CYP2C19, CYP2D6, and CYP1A2)

There are four members of the subfamily, CYP2C8, CYP2C9, CYP2C19, and CYP2C18. Of these CYP2C8, CYP2C9, and CYP2C19 are of clinical importance, all seem to be genetically polymorphic.

A dose of only 20 mg (yes, twenty) of fluvoxamine significantly inhibits omeprazole (CYP2C19) metabolism.

Citalopram is N-demethylated to N-desmethylcitalopram partially by CYP2C19 and partially by CYP3A4 and N-desmethylcitalopram is further N-demethylated by CYP2D6 and the inactive metabolite di-desmethylcitalopram.

Isoniazid (INH)-- Inhibition of one or both CYP2C19 and CYP3A isoforms is the likely mechanism by which INH slows the elimination of coadministered drugs, including phenytoin, carbamazepine, diazepam, triazolam, and primidone. Slow acetylators of INH may be at greater risk for adverse drug interactions, as the degree of inhibition was concentration dependent.