engleski

Pharmacogenetic variability in drug transport

Transporter proteins play an important role in the absorption, distribution, and elimination of wide variety of drugs in clinical use. They can act as uptake like some solute cariers (SLC) or efflux transporters among which most studied are ATP-binding cassette (ABC). The are currently considered to exert greatest impact on overall drug disposition, pharmacokinetic variability, and drug-drug interactions. The variant allele frequencies of corresponding transporter gene vary widely among different ethnic and racial groups. The increasing number of studies have shown significant associations of genetic variations with pharmacokinetic parameters, therapeutic effects and adverse events. Of particular interest for drug dispositions are ABCB1 (for digoxin, HIV protease inhibitors, some antiepileptics, antidepressants, antipsychotics, immunosuppressants ; ABCC2 (anticancer drugs like methotrexate, cisplatin, irinotecan, antibiotics), ABCG2 (anticancer drugs, fluvastatin, cimetidin). The main uptake carrier systems are organic anion transporters (OATP). OATP1B1 (coded by SLCO1B1 gene) is a polymorphic influx transporter expressed on the sinusoidal membrane of human hepatocytes where it mediates the hepatic uptake of different endogenous compounds and xenobiotics. A common SNP c.521T>C in the SLCO1B1 decreases the transporting activity of OATP1B1, resulting in increased plasma concentrations of drug-substrates like statins. This polymorphism enhances the risk of statin-induced myopathy and even of rhabdomyolysis. Some SLCO1B1 variants can also influence the clearence of methotrexate, and increase the risk of gastrointestinal toxicity. Among other drugs recognized as OATP1B1 substrates are mycophenolic acid, sirolimus, valsartan, enalapril, torsemide, rifampin, cephalosporins, HIV protease inhibitors, methotrexate and irinotecan. Clinically important transporter polymorphysms are incorporated in recommendations for drug development.

drug transporters; genetic polymorphism; drug bioavailability; organic anion transporters; ATP-binding cassette

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