Clinical impact of polymorphisms of transport proteins and enzymes involved in the metabolism of immunosuppressive drugs.
Individualization of immunosuppressive therapy after solid organ transplantation is a goal that has been pursued for a long time. Nevertheless, in clinical practice, we are still stratifying patients in subgroups in which risk is assessed using demographic information and population analysis. Then, a combination of immunosuppressive drugs is chosen and doses are individualized to compensate for intra- and interindividual variabilities in drug pharmacokinetics, to obtain similar plasma/blood concentrations that are believed to be therapeutic, again based on data derived from population analysis. One step further in this strategy is to recognize, before initiation of immunotherapy, those patients at higher risk to be either under- or overexposed to currently used immunosuppressive drugs. Several studies have been undertaken to correlate single nucleotide polymorphisms in genes encoding transport proteins and metabolizing enzymes involved in the disposition of immunosuppressive drugs. Overall, the results from these studies have been mixed. The causes of these sometimes conflicting results include methodologic, genetic, or nongenetic factors. The degree of linkage disequilibrium, the measure of nonrandom associations between polymorphisms at different loci, not necessarily on the same chromosome, is perhaps the main genetic factor. The influence of the environment, physiology (such as kidney and liver functions), disease state, use of multidrug regimens, and inherent drug-to-drug interactions are present nongenetic factors. Moreover, it is also important to increase our knowledge of the genetic factors involved in the variabilities observed in drug responses of pharmacodynamics. True individualized therapy, with the ability to improve health outcomes of each transplant recipient, will depend on our knowledge of the genetic factors involved in immunological response and drug pharmacokinetics and pharmacodynamics.
Rosso Felipe
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Hospital do Rim e Hipertensão Nephrology Division, Universidade Federal de São Paulo, São Paulo, Brazil.
de Sandes
T Veras
TV
Sampaio
E L Mandia
EL
Park
S I
SI
Silva
H Tedesco
HT
Medina Pestana
J O
JO
D018435:ATP Binding Cassette Transporter, Subfamily B; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000235:genetics / Q000378:metabolism; D000305:Adrenal Cortex Hormones / Q000378:metabolism / Q000627:therapeutic use; D001692:Biological Transport; D002352:Carrier Proteins / Q000235:genetics*; D016572:Cyclosporine / Q000378:metabolism / Q000627:therapeutic use; D051544:Cytochrome P-450 CYP3A / Q000235:genetics; D006801:Humans; D007166:Immunosuppressive Agents / Q000378:metabolism* / Q000627:therapeutic use*; D009173:Mycophenolic Acid / Q000378:metabolism / Q000627:therapeutic use; D011110:Polymorphism, Genetic; D020641:Polymorphism, Single Nucleotide; D020123:Sirolimus / Q000378:metabolism / Q000627:therapeutic use
C513055:ABCB1 protein, human; D018435:ATP Binding Cassette Transporter, Subfamily B; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000305:Adrenal Cortex Hormones; D002352:Carrier Proteins; D007166:Immunosuppressive Agents; D016572:Cyclosporine; C510164:CYP3A5 protein, human; D051544:Cytochrome P-450 CYP3A; C510163:CYP3A4 protein, human; D009173:Mycophenolic Acid; D020123:Sirolimus