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- Title
Prediction of Fluoroquinolone-Induced Elevation in Serum Creatinine Levels: A Case of Drug-Endogenous Substance Interaction Involving the Inhibition of Renal Secretion.
- Authors
Imamura, Y.; Murayama, N.; Okudaira, N.; Kurihara, A.; Okazaki, O.; Izumi, T.; Inoue, K.; Yuasa, H.; Kusuhara, H.; Sugiyama, Y.
- 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 (Km = 56.4 mmol/l) among renal organic ion transporters. DX-619 is a potent inhibitor of hOCT2 (Ki = 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.
- Subjects
FLUOROQUINOLONES; DRUG interactions; SECRETION; QUINOLONE antibacterial agents; CREATININE
- Publication
Clinical Pharmacology & Therapeutics, 2011, Vol 89, Issue 1, p81
- ISSN
0009-9236
- Publication type
Article
- DOI
10.1038/clpt.2010.232