November 2006
Pharmacogenomic research strives to understand the influence of human genetics on interindividual variability in response to medications. This field holds great promise to improve treatment outcomes for HIV infection and its complications. As we increase our ability to precisely define relationships between genetic polymorphisms and antiretroviral treatment response, so will the likelihood that human genetic testing will be used in clinical practice to inform antiretroviral prescribing. In addition to advancing the paradigm of "personalized medicine" through genetic testing, knowledge of genotype-phenotype associations may also help large HIV-infected populations by informing guidelines for antiretroviral therapy in resource-limited settings. For example, suppose it is discovered that human genetic variant X predicts suboptimal response to drug Y (decreased efficacy and/or increased toxicity), and genetic variant X is disproportionately represented in persons of the predominant geographic ancestry of country Z. Such information could help inform approaches to country-wide roll-out of drug Y in country Z, especially if previous experience is limited for drug Y in country Z.
February 2007
The relatively “new” isoenzyme CYP2B6 is characterized by wide interindividual variability in hepatic expression and activity. Recent pharmacogenetic studies suggest that CYP2B6 is highly polymorphic and that genetic variants are of great importance for efavirenz pharmacokinetics.
October 2007
Because of its abundance in the intestine and liver, CYP3A, a term that in adults reflects the collective activity of CYP3A4, CYP3A5, and CYP3A7, plays a central role in the metabolism of a wide variety of therapeutic compounds and is responsible for the metabolism of more than 50 % of drugs in the market. There is a large overlap in the specificity of these isozymes towards their substrates. This is clinically important because it potentially reduces the influence of genetic heterogeneity of CYP3A genes on the pharmacokinetics of CYP3A dependent drugs. This assumption is supported by the broad unimodal curve, with no evidence of the existence of poor or ultra rapid metabolizers, when phenotyping subjects without comedications and/or diet affecting CYP3A activity with classical CYP3A substrates such as the benzodiazepine midazolam, the anti-hypertensive nifedipine or the antibiotic erythromycin. This assumption is also reflected by the modest interindividual variability (usually 3 - 4 fold) of the metabolic clearance of CYP3A phenotyping probes. However, rare cases of CYP3A poor metabolizers, with the simultaneous occurrence of mutations in different isoforms, leading to very low or null CYP3A activity, have been described.