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Testing places individuals in one of three categories:
- Normal metabolizers (NM) represent the norm for metabolic capacity. In general normal metabolizers can be administered drugs which are substrates of the CYP2C19 enzyme following standard dosing practices. Genotypes consistent with the normal metabolizer phenotype include two active CYP2C19 alleles.
- Intermediate metabolizers (IM) may require lower than average drug dose for optimal therapeutic response to medications with the exception of prodrugs. For the majority of drugs consider decreased dosage. For prodrugs, like Plavix, that require activation by CYP2C19, an alternative treatment or increased dose should be considered. Genotypes consistent with the intermediate metabolizer phenotype are those with one active and one inactive CYP2C19 allele.
- Poor metabolizers (PM) are at increased risk of drug-induced side effects due to diminished drug elimination or for prodrugs, like Plavix, lack of therapeutic effect resulting from failure to generate the active form of the drug. Alternative treatment should be considered. Genotypes consistent with the poor metabolizer phenotype are those with no active CYP2C19 alleles.
Co-administration of other drugs
Genotype results should be interpreted in context of the individual clinical situation. In all cases monitor for co-administration of CYP2C19 inhibitors which may convert patients to poor metabolizer status. Potential adverse outcomes included overdose toxicity or treatment failure particularly for prodrugs. For more information see GeneMedRx drug-drug and drug-gene interaction software and Cytochrome P450 Metabolism Inhibitor/Inducer Tables. Access GeneMedRx via the patient access code provided at www.GeneMedRx.com/DNAlogin.
A complicating factor in correlating CYP2C19 genotype with phenotype is that most drugs may reduce CYP2C19 catalytic activity but prodrugs increase CYP2C19 activity. It is important to interpret the results of testing in the context of other co administered drugs.
CYP2C19 activity also is dependent upon hepatic and renal function status, as well as age. Patients also may develop toxicity if hepatic or renal function is decreased. Consider the results of testing and dose adjustments in the context of renal and hepatic function and age.
Prodrugs, such as Plavix, require activation by CYP2C19:
- Normal Metabolizer (NM) (homozygous normal) No change.
- Intermediate Metabolizer (IM) (heterozygous one functional allele, one deficient allele). An alternative treatment or increased dose should be considered. For Plavix: Consider doubling maintenance dose, e.g. 1200 mg loading and 150 mg maintenance; monitor for decrease in platelet function. Maintenance dosage of up to 300mg/day might be required to achieve adequate platelet inhibition.
- Poor Metabolizer (PM) (homozygous non-functional alleles) Consider alternative therapy.
- Intermediate Metabolizers (IM)
Start IM’s at lowest efficacious dose, avoid multiple drug therapy that inhibits or is processed through the same pathway.
- Poor Metabolizers (PM)
Reduce dose to 20-60% of standard dosage.
Therapeutic drug monitoring in PM and IM subjects is highly recommended. Again standard measures of efficacy For specific dosages see charts and tables are adapted from Julia Kirchheiner, et al Molecular Psychiatry Feature Review, 9 442-473 (2004), "Pharmacokinetics of antidepressants and antipsychotics: the contribution of allelic variations to the phenotype of drug response," a meta analysis of published research from 1970-2003 on the relevance of pharmacokinetic effects of CYP2D6 and CYP2C19 on 36 antidepressants and 38 antipsychotics.
Drug Metabolism Guide
Substrates Metabolized through Cytochrome P-450 2C19
Substrates refers to drugs that are either activated or deactivated by the pathway.
|Note=italics indicated minor pathway
Inhibitors of Cytochrome P-450 2C19
Inhibitors refer to drugs that reduce the ability of the pathway to process drugs. Co-administration will decrease the rate of metabolism of drugs through the metabolic pathway listed, increasing the possibility of toxicity.
Inducers of Cytochrome P-450 2C19
Inducers refers to drugs that increase the activity of a pathway. Co-administration increases the rate of excretion for drugs metabolized through the pathway indicated, reducing the drug's effectiveness.
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