Role of CYP pharmacogenetics and drug-drug interactions in the efficacy and safety of atypical and other antipsychotic agents

Abstract

Cytochrome P450 (CYP) drug oxidases play a pivotal role in the elimination of antipsychotic agents, and therefore influence the toxicity and efficacy of these drugs. Factors that affect CYP function and expression have a major impact on treatment outcomes with antipsychotic agents. In particular, aspects of CYP pharmacogenetics, and the processes of CYP induction and inhibition all influence invivo rates of drug elimination. Certain CYPs that mediate the oxidation of antipsychotic drugs exhibit genetic variants that may influence in-vivo activity. Thus, single nucleotide polymorphisms (SNPs) in CYP genes have been shown to encode enzymes that have decreased drug oxidation capacity. Additionally, psychopharmacotherapy has the potential for drug-drug inhibitory interactions involving CYPs, as well as drug-mediated CYP induction. Literature evidence supports a role for CYP1A2 in the clearance of the atypical antipsychotics clozapine and olanzapine; CYP1A2 is inducible by certain drugs and environmental chemicals. Recent studies have suggested that specific CYP1A2 variants possessing individual SNPs, and possibly also SNP combinations (haplotypes), in the 5 0 -regulatory regions may respond differently to inducing chemicals. CYP2D6 is an important catalyst of the oxidation of chlorpromazine, thioridazine, risperidone and haloperidol. Certain CYP2D6 allelic variants that encode enzymes with decreased drug oxidation capacity are more common in particular ethnic groups, which may lead to adverse effects with standard doses of psychoactive drugs. Thus, genotyping may be useful for dose optimization with certain psychoactive drugs that are substrates for CYP2D6. However, genotyping for inducible CYPs is unlikely to be sufficient to direct therapy with all antipsychotic agents. In-vivo CYP phenotyping with cocktails of drug substrates may assist at the commencement of therapy, but this approach could be complicated by pharmacokinetic interactions if applied when an antipsychotic drug regimen is ongoing.

Cytochrome P450 inhibition potential of new psychoactive substances of the tryptamine class

“…Prodrugs such as tramadol, tilidine, or risperidone, mainly metabolized by one or two isoenzyme, could lose their potency, if bioactivation was blocked (Mannheimer et al, 2008;Stamer et al, 2007;Wustrow et al, 2012). Neuroleptics such as clozapine or haloperidol could accumulate in plasma and lead to toxic concentrations (Murray, 2006). The inhibition of CYP2D6 and CYP3A4 could be important because many endogenous compounds and xenobiotics were metabolized by these two isoenzymes (http://medicine.iupui.edu/clinpharm/ddis/clinical-table/).…”

Pharmacogenetics and olanzapine treatment: CYP1A2*1F and serotonergic polymorphisms influence therapeutic outcome

“…Moreover, the CYP1A2 substrate caffeine might have an influence-there have been several reports that ingestion or removal of caffeine containing beverages influenced concentrations of the CYP1A2 substrate clozapine. 40 Our patients, however, had been hospitalized and were on a standard diet which did not contain major amounts of these foods. An unusual exposure to and influence of alimentary inducers is, therefore, unlikely.…”

A common variant in DRD3 gene is associated with risperidone-induced extrapyramidal symptoms

“…18 These strategies are commonplace in psychopharmacology and have been used in several pharmacogenetic studies. 19,20 This pharmacogenetic study revealed an association of risperidone-induced EPS with rs167771, a common genetic variant in the third intron of the DRD3 gene. The D3 receptor was cloned and characterized as a D2-like receptor in 1990.…”