Prediction of fluoroquinolone-induced elevation in serum creatinine levels: a case of drug-endogenous substance interaction involving the inhibition of renal secretion.
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.
Drug Metabolism and Pharmacokinetics Research Laboratories, R&D Division, Daiichi Sankyo Co., Ltd., Tokyo, Japan.
Y
Y
Imamura
N
N
Murayama
N
N
Okudaira
A
A
Kurihara
O
O
Okazaki
T
T
Izumi
K
K
Inoue
H
H
Yuasa
H
H
Kusuhara
Y
Y
Sugiyama
D000328:Adult; D000900:Anti-Bacterial Agents / Q000097:blood / Q000493:pharmacokinetics / Q000494:pharmacology*; D002460:Cell Line; D003404:Creatinine / Q000097:blood* / Q000378:metabolism / Q000652:urine; D004311:Double-Blind Method; D005260:Female; D024841:Fluoroquinolones / Q000097:blood / Q000493:pharmacokinetics / Q000494:pharmacology*; D057809:HEK293 Cells; D006801:Humans; D007687:Kidney Tubules, Proximal / Q000187:drug effects* / Q000378:metabolism; D007700:Kinetics; D008297:Male; D049990:Membrane Transport Modulators / Q000097:blood / Q000493:pharmacokinetics / Q000494:pharmacology*; D008875:Middle Aged; D008954:Models, Biological; D029362:Organic Anion Transporters, Sodium-Independent / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D027701:Organic Cation Transport Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D000075102:Organic Cation Transporter 2; D011759:Pyrrolidines / Q000097:blood / Q000493:pharmacokinetics / Q000494:pharmacology*; D015363:Quinolones / Q000097:blood / Q000493:pharmacokinetics / Q000494:pharmacology*; D055815:Young Adult
D000900:Anti-Bacterial Agents; C505440:DX 619; D024841:Fluoroquinolones; D049990:Membrane Transport Modulators; D029362:Organic Anion Transporters, Sodium-Independent; D027701:Organic Cation Transport Proteins; D000075102:Organic Cation Transporter 2; D011759:Pyrrolidines; D015363:Quinolones; C491013:SLC22A2 protein, human; C490280:SLC22A7 protein, human; C521869:SLC47A1 protein, human; C521870:SLC47A2 protein, human; D003404:Creatinine