Individualizing Pharmacotherapy: Genetic factors and co-prescribed drugs affecting pharmacotherapy

Drug therapies may result in adverse drug reactions or in ineffective therapy. A better prediction which patients will not respond to drug therapy or will develop adverse drug reactions may avoid these events. In this thesis we studied the effect of drug-drug interactions and genetic variation. The exposure to potential life-threatening drug-drug interactions in the elderly general population (≥ 70 years) increased from 1.5 percent in 1992 to 2.9 percent in 2005. About half a percent of all hospital admissions were due to drug-drug interactions. The polymorphism rs622342 in the Organic Cation Transporter 1 and rs2289669 in the Multidrug And Toxin Extrusion 1 were both associated with the glucose lowering effect of metformin. The predictability of the response to metformin increased substantially if also the interaction between both polymorphisms was included. The CYP3A4*1B polymorphisms was associated with adverse drug reactions during simvastatin and atorvastatin therapy. This effect was stronger in women and in patients with the ABCB1 CT or TT genotype. These differences are most likely explained by a lower ABCB1 expression and a higher statin concentration in the hepatocyte. We also studied the association between genetic variation in the CYP2C9 gene and sulphonylurea response, the rs10494366 polymorphisms and sulphonylurea and calcium channel blocker response, genetic variation in the ABCB1 gene and the cholesterol lowering effect of simvastatin, and the association between the rs622342 polymorphism and the response to antiparkinson drugs. The response to drug therapy is better predictable if also the interaction between factors is taken into account.

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