111Polymorphism of Drug Transporters
Transporters are involved in the transport of proteins, peptides, amino acids, ions
and certain drugs. Transport proteins have an important role in regulating the
absorption, distribution, and excretion of many medications. Membrane transport-
ers are encoded by numerous genes. Disorders associated with defects in solute
transporters, such as severe diarrhea in glucose/galactose malabsorption and pri-
mary bile acid malabsorption may be associated with pronounced general changes
in drug absorption. Several investigations are aimed at clarifying the role of trans-
porters in drug absorption, disposition, and targeting.
ABC (ATP-binding Cassette) transporter super family is widely distributed in all
living organisms examined to date. It consists of eight subfamilies encoded by genes
on different chromosomes. One of these is P-glycoprotein, also called multidrug
resistance protein (MDR-1), which serves as a transporter that extrudes numerous
drugs out of cells. A variant form of MDR-1 has been associated with low MDR-1
expression and altered drug distribution, resulting in enhanced digoxin plasma lev-
els and suggesting broad implications for drug disposition. An overview of poly-
morphisms of ABC drug transporters as well as their phenotypical consequences
and pharmacological implications has been presented elsewhere.
Another important gene family is the biogenic amine transporters, which regu-
late neurotransmitter levels in synaptic transmission, with a number of documented
variants that may affect function. These transporters are the direct target receptors
for numerous drugs, including antidepressants and cocaine. Allelic variations, in
particular of the serotonin transporter, are associated with the modulation of com-
plex behavior and may play a signifi cant role in therapy with specifi c serotonin
transporter inhibitors.
Genetic Variation in Drug Targets
Drug targets (e.g. receptors) can have a profound effect on drug effi cacy, with over
25 examples already identifi ed. Variation in neurotransmitter receptors can also be
the cause of treatment failure. The β2-adrenoreceptor (coded by the ADRB2 gene)
illustrates another link between genetic polymorphisms in drug targets and clinical
responses. Genetic polymorphism of the β2-adrenoreceptor can alter the process of
signal transduction by these receptors. Polymorphisms in drug target genes that can
infl uence drug response are listed in Table 4.5.
Polymorphisms of Kinase Genes
Kinases are central players in cell biology and disease. Protein kinases are coded by
more than 2,000 genes and thus constitute the largest single enzyme family in the
human genome. Kinases are important drug targets. Agencourt Bioscience
Role of Pharmacogenetics in Pharmaceutical Industry