Pharmacogenetics

Individual variations in response to pharmaceuticals are frequently encountered phenomena in clinical practise. Patients and physicians regularly face therapeutic problems such as poor drug effects and therapy failure as well as exacerbated or adverse drug reactions. The causes underlying these inconsistencies in individual drug responses are yet not fully elucidated. Beside environmental factors (e.g. nutrition, co-administered drugs), genetic variations appear to make a major contribution to the variability of pharmacokinetic and pharmacodynamic drug properties. Polymorphisms in genes encoding receptors, transporters or metabolizing enzymes seem to remarkably affect the individual therapy outcome.

CYP2D6

How genetic variations can impact the clinical response to a drug is most excellent exemplified by the highly polymorphic drug metabolizing enzyme Cytochrome P450 2D6 (CYP2D6). This member of the cytochrome-superfamily metabolizes more than 20% of all currently prescribed drugs. Genetic polymorphisms in this gene significantly influence a person’s ability to mediate CYP2D6-dependent hydroxylation. Depending on the allelic state, individuals can be categorized in poor, extensive or ultrarapid metabolizers. We are interested in determining the influence of the CYP2D6 genotype on plasma levels of pharmaceutical compounds and their metabolites.

Opioid Pharmacogenetics

A narrow therapeutic range and a large inter-person variability in response can be observed regarding opioid pharmaceuticals. The minimal effective analgesic concentration of opioids required for adequate analgesia can vary considerably among patients, even in relatively homogeneous patient cohorts. Similar variations can be observed regarding the dosages of opioids prescribed in the context of drug replacement therapy, the major and most cost-effective form of medical therapy for heroin dependence. Increasing evidence suggests that genetic polymorphisms considerably affect the individual demand for opioids. Accordingly, we are exploring the contribution of genetic polymorphisms to the pharmacokinetics and to the pharmacodynamics of opioid. In particular, we are interested in identifying genetic variations that significantly affect opiod requirements and/or tolerance in the context of addiction and replacement therapy. An improved understanding of opiod pharmacogenetics will bring about valueable implications for patients in maintenance treatment as well as for patients receiving opioid therapy for the management of chronic pain.

Grant

Jubiläumsfond der Österreichischen Nationalbank: Opioid Pharmacogenetics – Contribution of genetic polymorphisms to individual-specific bupronorphine requirements in context of opioid replacement therapy, Projekt 13253, 2009-2010.

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