Inhibitory effects of indoxyl sulfate and creatinine on the renal transport of meropenem and biapenem in rats

• Published in: Drug metabolism and pharmacokinetics 2021-10, Vol.40, p.100406, Article 100406
• Main Authors: Ichimura, Yuichi, Kudoh, Natsumi, Murabe, Takashi, Akao, Takumi, Watanuki, Sho, Suzuki, Takanao, Saito, Toshihide, Oda, Masako, Saitoh, Hiroshi
• Format: Article
• Language: English
• Subjects: Animals; Carbapenem antibiotics; Creatinine; Humans; Indican; Interaction; Kidney; Meropenem; Organic anion transporter; Organic Anion Transporters, Sodium-Independent; Rat renal cortical slices; Rats; Thienamycins; Uremic Toxins
• ISSN: 1347-4367; 1880-0920
• DOI: 10.1016/j.dmpk.2021.100406

Carbapenem antibiotics are excreted preferentially in the urine after intravenous administration, with organic anion transporters (OATs) known to be involved in the renal tubular secretion of carbapenem antibiotics. Various uremic toxins (UTs) accumulate in the blood of patients with end-stage renal failure, and some UTs such as indoxyl sulfate (IS) and creatinine (Cr) are excreted in the urine via OATs. However, information about the possible interactions between these UTs and carbapenems in the renal secretion remains limited. In this study, we investigated the effects of IS and Cr on the renal transport of anionic meropenem and zwitterionic biapenem by using rat renal cortical slices. The uptake of meropenem and biapenem in the renal cortical slices was significantly decreased in the presence of 0.1 mM IS or 1 mM Cr. When biapenem and Cr were co-administered to rats intravenously, biapenem clearance from the plasma was clearly retarded, reflecting the current in vitro results. However, IS and Cr exerted no inhibitory effect on the uptake of metformin, a substrate of renal organic cation transporter (OCT) 2, in the renal cortical slices. Thus, our findings indicate that IS and Cr interfere with the renal secretion of carbapenem antibiotics by preferentially inhibiting OATs.