Prediction of Fluoroquinolone-Induced Elevation in Serum Creatinine Levels: A Case of Drug–Endogenous Substance Interaction Involving the Inhibition of Renal Secretion
| Autor: | Takashi Izumi, Nobuyuki Murayama, Katsuhisa Inoue, Yuichiro Imamura, Hiroyuki Kusuhara, Yuichi Sugiyama, Hiroaki Yuasa, Atsushi Kurihara, Noriko Okudaira, Osamu Okazaki |
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| Rok vydání: | 2010 |
| Předmět: |
Adult
Male medicine.medical_specialty Pyrrolidines Organic Cation Transport Proteins Organic anion transporter 1 Renal function Organic Anion Transporters Sodium-Independent Quinolones Models Biological Cell Line Kidney Tubules Proximal Young Adult chemistry.chemical_compound Double-Blind Method Pharmacokinetics Membrane Transport Modulators Internal medicine medicine Humans Pharmacology (medical) Antibacterial agent Pharmacology Kidney Creatinine biology Reabsorption Organic Cation Transporter 2 Middle Aged Anti-Bacterial Agents Kinetics HEK293 Cells Endocrinology medicine.anatomical_structure chemistry Renal physiology biology.protein Female Fluoroquinolones |
| Zdroj: | Clinical Pharmacology & Therapeutics. 89:81-88 |
| ISSN: | 1532-6535 0009-9236 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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