Overview of the pharmacogenetics of HIV therapy.
The administration of standard doses of most antiretroviral drugs results in significant variations in plasma drug concentrations among different individuals, influencing antiviral activity as well as incidence of drug-related toxicities. The reasons for this large inter-individual variability in drug levels are multifactorial, and involve differences in metabolism related to gender, concomitant medications, drug compliance, underlying diseases and genetic factors. Pharmacogenetics is the discipline that analyses the genetic basis for the inter-individual variation in the body disposition of drugs. One of its main goals is to give grounds to individualized treatment. The majority of pharmacogenetic traits so far have involved drug metabolism. This is the case for the inherited variation in the pharmacokinetics and pharmacodynamics of drugs such as hydralazine or isoniazid, which is due to polymorphisms in the N-acetyltransferase-2 (NAT2) gene, which allows splitting the population into three categories: slow, intermediate, and fast metabolizers. Pharmacogenetic studies conducted so far with antiretroviral drugs have focussed on metabolizer enzymes at the liver and on transporter proteins on cell membranes. Herein, we review the most relevant metabolizer enzymes and protein transporters, along with the genetic polymorphisms, which seem to influence the pharmacokinetics of antiretroviral drugs, ultimately determining its efficacy and toxicity.
Rodríguez-Nóvoa
S
S
Pharmacokinetic Unit, Hospital Carlos III, Madrid, Spain.
Barreiro
P
P
Jiménez-Nácher
I
I
Soriano
V
V
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000235:genetics / Q000378:metabolism; D044966:Anti-Retroviral Agents / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D001189:Aryl Hydrocarbon Hydroxylases / Q000235:genetics / Q000378:metabolism; D065702:Cytochrome P-450 CYP2B6; D051544:Cytochrome P-450 CYP3A; D003577:Cytochrome P-450 Enzyme System / Q000235:genetics / Q000378:metabolism; D014453:Glucuronosyltransferase / Q000235:genetics / Q000378:metabolism; D015658:HIV Infections / Q000188:drug therapy* / Q000201:enzymology / Q000235:genetics*; D017320:HIV Protease Inhibitors / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use; D006801:Humans; D010089:Oxidoreductases, N-Demethylating / Q000235:genetics / Q000378:metabolism; D010597:Pharmacogenetics; D011110:Polymorphism, Genetic; D018894:Reverse Transcriptase Inhibitors / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use; D000099148:UGT1A1 Enzyme
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D044966:Anti-Retroviral Agents; D001189:Aryl Hydrocarbon Hydroxylases; D065702:Cytochrome P-450 CYP2B6; D051544:Cytochrome P-450 CYP3A; D003577:Cytochrome P-450 Enzyme System; D014453:Glucuronosyltransferase; D017320:HIV Protease Inhibitors; D010089:Oxidoreductases, N-Demethylating; D018894:Reverse Transcriptase Inhibitors; D000099148:UGT1A1 Enzyme; C585599:CYP2B6 protein, human; C510163:CYP3A4 protein, human