Polymorphisms Affecting Drug Transport

Although cellular uptake of some drugs occurs via passive diffusion, membrane transporters also play a role in the absorption of medicines through the intestines, their excretion into bile and urine and their uptake into sites of action (such as brain, testes and cardiovascular tissue; tumor cells; synaptic cleft; and infectious microorganisms) (Evans and Relling, 1999). Increasing attention is being focused on the possible role of polymorphisms of genes encoding drug transporters, some of which are summarized in Table 43.3.

One example of a transporter with relevance to drug response is p-glycoprotein (Pgp), an ATP-dependent transmembrane efflux pump that serves to extrude numerous drugs and other substances out of cells. Pgp is coded for by the multidrug resistance locus, MDR-1. Hoffmeyer et al. (2000) reported that a specific polymorphism, present in homozygous form in 24% of their Caucasian sample population, correlated with expression levels and function of MDR-1. Homozygous individuals had significantly lower MDR-1 expression and exhibited a four-fold increase in plasma digoxin

Table 43.3. Selected polymorphisms of drug transporters, receptors, targets and disease genes associated with altered drug response.a

Drug transporter, receptor, or target

Variant phenotype


Altered response

Multidrug resistance protein Overexpression in

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