Prediction of fluoroquinolone-induced elevation in serum creatinine levels: a case of drug-endogenous substance interaction involving the inhibition of renal secretion

Clin Pharmacol Ther. 2011 Jan;89(1):81-8. doi: 10.1038/clpt.2010.232. Epub 2010 Dec 1.

Abstract

The aim of this study was to examine the mechanism underlying the elevation in serum creatinine levels caused by a novel des-fluoro(6)-quinolone antibacterial agent, DX-619, in healthy subjects. hOCT2 showed a prominent uptake of creatinine (K(m) = 56.4 mmol/l) among renal organic ion transporters. DX-619 is a potent inhibitor of hOCT2 (K(i) = 0.94 micromol/l), hMATE1 (0.82 µmol/l), and hMATE2-K (0.10 micromol/l). The pharmacokinetic model involving the inhibition of hOCT2 (model 1), hOCT2, and MATE1 or MATE2-K (model 2) could predict the elevation in serum creatinine levels in individual subjects receiving DX-619. This assumes that a significant contribution of tubular secretion (59, 38, and 31%) and reabsorption ranged from 3-50, 4-30, and 5-21% in model 1, -2a (hOCT2/hMATE1), and -2b (hOCT2/hMATE2-K), respectively, for creatinine. In conclusion, DX-619, at its therapeutic dose, is able to inhibit hOCT2, hMATE1, and hMATE2-K, leading to a significant inhibition of tubular secretion of creatinine and consequently to elevation of serum creatinine levels.

Publication types

  • Randomized Controlled Trial

MeSH terms

  • Adult
  • Anti-Bacterial Agents / blood
  • Anti-Bacterial Agents / pharmacokinetics
  • Anti-Bacterial Agents / pharmacology*
  • Cell Line
  • Creatinine / blood*
  • Creatinine / metabolism
  • Creatinine / urine
  • Double-Blind Method
  • Female
  • Fluoroquinolones / blood
  • Fluoroquinolones / pharmacokinetics
  • Fluoroquinolones / pharmacology*
  • HEK293 Cells
  • Humans
  • Kidney Tubules, Proximal / drug effects*
  • Kidney Tubules, Proximal / metabolism
  • Kinetics
  • Male
  • Membrane Transport Modulators / blood
  • Membrane Transport Modulators / pharmacokinetics
  • Membrane Transport Modulators / pharmacology*
  • Middle Aged
  • Models, Biological
  • Organic Anion Transporters, Sodium-Independent / antagonists & inhibitors
  • Organic Anion Transporters, Sodium-Independent / genetics
  • Organic Anion Transporters, Sodium-Independent / metabolism
  • Organic Cation Transport Proteins / antagonists & inhibitors
  • Organic Cation Transport Proteins / genetics
  • Organic Cation Transport Proteins / metabolism
  • Organic Cation Transporter 2
  • Pyrrolidines / blood
  • Pyrrolidines / pharmacokinetics
  • Pyrrolidines / pharmacology*
  • Quinolones / blood
  • Quinolones / pharmacokinetics
  • Quinolones / pharmacology*
  • Young Adult

Substances

  • Anti-Bacterial Agents
  • DX 619
  • Fluoroquinolones
  • MATE1 protein, human
  • MATE2-K protein, human
  • Membrane Transport Modulators
  • Organic Anion Transporters, Sodium-Independent
  • Organic Cation Transport Proteins
  • Organic Cation Transporter 2
  • Pyrrolidines
  • Quinolones
  • SLC22A2 protein, human
  • SLC22A7 protein, human
  • Creatinine