Prediction of Fluoroquinolone-Induced Elevation in Serum Creatinine Levels: A Case of Drug–Endogenous Substance Interaction Involving the Inhibition of Renal Secretion

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.

Utility of Bilirubins and Bile Acids as Endogenous Biomarkers for the Inhibition of Hepatic Transporters

“…Recently, many researchers have focused on the mechanism of drug-induced hyperbilirubinemia (Zucker et al, 2001;Campbell et al, 2004;Chang et al, 2013;Wlcek et al, 2013;Chiou et al, 2014); however, the exact mechanism of drug-induced hyperbilirubinemia in humans and the relationship between the biomarkers and DDI from a quantitative perspective have not been elucidated. In other cases, previous studies have shown that when the renal transporters were inhibited by drugs, the plasma concentrations of creatinine, N-methylnicotinamide, and 6b-hydroxycortisol increased with the inhibition of OCT2 and/or MATEs, MATEs, and OAT3 by drugs, respectively (Imamura et al, 2011(Imamura et al, , 2014Ito et al, 2012). The utility of an endogenous substrate as a biomarker for transporter inhibition has been a topic of great interest.…”

Handling of Drugs, Metabolites, and Uremic Toxins by Kidney Proximal Tubule Drug Transporters

“…This focus on drug transporters promises to eventually improve understanding of pharmacokinetics in normal and diseased states (5). The endogenous metabolite, creatinine, is a well described substrate for OCT2 and apical MATEs; competitive inhibition of these carriers can cause increases in serum creatinine by blocking its excretion (Figure 2A) (29)(30)(31). Drugs such as cimetidine and trimethoprim are examples.…”

Assessment of Vandetanib as an Inhibitor of Various Human Renal Transporters: Inhibition of Multidrug and Toxin Extrusion as a Possible Mechanism Leading to Decreased Cisplatin and Creatinine Clearance

“…Similar to cisplatin, creatinine serves as an OCT2, MATE1, and MATE2K substrate (Urakami et al, 2004;Tanihara et al, 2007;Imamura et al, 2011;Ciarimboli et al, 2012); therefore, the possibility that vandetanib impacts creatinine clearance by inhibiting one or more of these transporters was also considered. Inhibition of transporters by vandetanib may influence the renal elimination and systemic exposure of certain transporter substrates, leading to drug-drug interactions (DDIs) and increased toxicity.…”