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Prediction of Fluoroquinolone‐Induced Elevation in Serum Creatinine Levels: A Case of Drug–Endogenous Substance Interaction Involving the Inhibition of Renal Secretion
Author(s) -
Imamura Y,
Murayama N,
Okudaira N,
Kurihara A,
Okazaki O,
Izumi T,
Inoue K,
Yuasa H,
Kusuhara H,
Sugiyama Y
Publication year - 2011
Publication title -
clinical pharmacology and therapeutics
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.941
H-Index - 188
eISSN - 1532-6535
pISSN - 0009-9236
DOI - 10.1038/clpt.2010.232
Subject(s) - creatinine , reabsorption , drug , renal function , pharmacokinetics , pharmacology , endocrinology , chemistry , renal physiology , secretion , medicine , kidney
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 µmol/l), hMATE1 (0.82 µmol/l), and hMATE2‐K (0.10 µmol/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. Clinical Pharmacology & Therapeutics (2011) 89 1, 81–88. doi: 10.1038/clpt.2010.232