Pharmacogenomics of diuretic drugs: data on rare monogenic disorders and on polymorphisms and requirements for further research.
This review summarizes the current status of our knowledge about the role of pharmacogenetic variation in response to diuretics and suggests future research topics for the field. Genes with a role in the pharmacokinetics of most diuretics are renal drug transporters, especially OAT1, OAT3 and OCT2 (genes SLC22A6, SLC22A8 and SLC22A2) whereas variants in carbonic anhydrase (CA), cytochrome P450 enzymes and sulfotransferases are relevant only for specific substances. Genes on the pharmacodynamic side include the primary targets of thiazide, loop, K(+)-sparing and aldosterone antagonistic diuretics: NCC, NKCC2, ENaC and the mineralocorticoid receptor (genes SLC12A3, SLC12A1, SCNN1A, B, G and NR3C2). Rare variants of these proteins cause Gitelman's syndrome, Bartter's syndrome, Liddle's syndrome or pregnancy-induced hypertension. Polymorphisms in these and in associated proteins such as GNB3, alpha-adducin and angiotensin-converting enzyme (ACE) seem to be clinically relevant. In conclusion, first knowledge has evolved that efficacy of diuretic drugs may be determined by genetic polymorphisms in genes determining pharmacokinetics and pharmacodynamics of this drug class. In the future, the selection of a diuretic drug or the dosing schedules may be individually chosen based on pharmacogenetic parameters, however, many questions remain to be answered before this fantasy becomes reality.
Department of Clinical Pharmacology & Department of Vegetative Physiology, Georg August University Göttingen, Robert-Koch-Str. 40, D-37075 Göttingen, Germany. svormfe@gwdg.de
Stefan Viktor
SV
Vormfelde
Gerhard
G
Burckhardt
Alexandra
A
Zirk
Leszek
L
Wojnowski
Jürgen
J
Brockmöller
D000818:Animals; D004232:Diuretics / Q000493:pharmacokinetics / Q000627:therapeutic use*; D006801:Humans; D007674:Kidney Diseases / Q000188:drug therapy / Q000235:genetics* / Q000378:metabolism; D027361:Organic Anion Transporters / Q000737:chemistry / Q000378:metabolism; D010597:Pharmacogenetics / Q000379:methods* / Q000639:trends; D011110:Polymorphism, Genetic / Q000187:drug effects / Q000235:genetics*; D035583:Rare Diseases / Q000188:drug therapy / Q000235:genetics* / Q000378:metabolism
D004232:Diuretics; D027361:Organic Anion Transporters