Estimating the contribution of genes and environment to variation in renal drug clearance.
Renal excretion is the major pathway for elimination of many clinically used drugs and xenobiotics. We estimated the genetic component (rGC) contributing to variation in renal clearance for six compounds (amoxicillin, ampicillin, metformin, terodiline, digoxin and iohexol) using Repeated Drug Application methodology. Data were obtained from published literature. The rGC values of renal clearance of metformin, amoxicillin, and ampicillin, which undergo transporter-mediated secretion, ranged from 0.64-0.94. This finding suggests that variation in the renal clearance of these drugs has a strong genetic component. Additionally, the rGC values of renal clearance of metformin, amoxicillin, and ampicillin were similar to previously reported rGC values for metabolism. By contrast, the rGC values of renal clearance for iohexol, digoxin, and terodiline were low (0.12-0.37). Renal clearance of these compounds occurs mainly through passive processes (e.g. glomerular filtration and passive secretion/reabsorption). The low rGC values of iohexol, digoxin and terodiline suggest that environmental factors may contribute to variation in their renal clearance.
Leabman
Maya K
MK
Department of Biopharmaceutical Sciences, University of California, San Francisco, San Francisco, CA 94143-0446, USA.
Giacomini
Kathleen M
KM
D000658:Amoxicillin / Q000493:pharmacokinetics; D000667:Ampicillin / Q000493:pharmacokinetics; D000900:Anti-Bacterial Agents / Q000493:pharmacokinetics; D002082:Butylamines / Q000493:pharmacokinetics; D002121:Calcium Channel Blockers / Q000493:pharmacokinetics; D002316:Cardiotonic Agents / Q000493:pharmacokinetics; D003287:Contrast Media / Q000493:pharmacokinetics; D004077:Digoxin / Q000493:pharmacokinetics; D004777:Environment; D005796:Genes; D014644:Genetic Variation; D005919:Glomerular Filtration Rate; D006801:Humans; D007004:Hypoglycemic Agents / Q000493:pharmacokinetics; D007472:Iohexol / Q000493:pharmacokinetics; D007668:Kidney / Q000378:metabolism*; D008657:Metabolic Clearance Rate; D008687:Metformin / Q000493:pharmacokinetics
D000900:Anti-Bacterial Agents; D002082:Butylamines; D002121:Calcium Channel Blockers; D002316:Cardiotonic Agents; D003287:Contrast Media; D007004:Hypoglycemic Agents; D007472:Iohexol; C010637:terodiline; D004077:Digoxin; D000667:Ampicillin; D000658:Amoxicillin; D008687:Metformin