Merck
  • Home
  • Search Results
  • Renal handling of amphotericin B and amphotericin B-deoxycholate and potential renal drug-drug interactions with selected antivirals.

Renal handling of amphotericin B and amphotericin B-deoxycholate and potential renal drug-drug interactions with selected antivirals.

Antimicrobial agents and chemotherapy (2014-06-25)
František Trejtnar, Jana Mandíková, Jana Kočíncová, Marie Volková
ABSTRACT

Amphotericin B (AmB) is excreted via the renal excretion route. This excretion process may result in nephrotoxicity. However, relevant information on the precise renal excretion mechanisms is not available. The aim of the study was to analyze the possible interaction of AmB or its prodrug AmB deoxycholate (AmB-DOC) with the typical renal organic anion transporters (OATs) and organic cation transporters (OCTs), using cellular and organ models. The relevant transport systems were then investigated in terms of the drug-drug interactions of AmB-DOC with antivirals that might potentially be used concomitantly. To analyze the renal excretion mechanisms of [(3)H]AmB, perfused rat kidney was employed. HeLa and MDCK II cells transiently transfected with human OAT1 (hOAT1) or hOCT2 were used as the cellular models. A significant tubular secretion of AmB was demonstrated in the perfused rat kidney. The cellular studies performed confirmed the active transport of AmB into cells. AmB did not interact with hOAT1 but strongly inhibited hOCT2. In contrast, AmB-DOC inhibited both hOAT1 and hOCT2. However, [(3)H]AmB cellular uptake by hOAT1 and hOCT2 was not found. AmB-DOC interacted significantly with adefovir, tenofovir, and cidofovir in hOAT1-transfected cells at supratherapeutic concentrations. In conclusion, the significant potency of AmB and AmB-DOC for inhibiting the transporters was demonstrated in this study. The secretion of AmB in the renal tubules is likely not related to the transporters here, since the drug was not proven to be a substrate for them. Drug-drug interactions of AmB and the antivirals used in this study on the investigated transporters are not probable.

MATERIALS
Product Number
Brand
Product Description

Supelco
Benzoic acid, Pharmaceutical Secondary Standard; Certified Reference Material
Supelco
Melting point standard 121-123°C, analytical standard
Sigma-Aldrich
Benzoic acid, meets analytical specification of Ph. Eur., BP, USP, FCC, E210, 99.5-100.5% (alkalimetric)
Sigma-Aldrich
Benzoic acid, purified by sublimation, ≥99%
Sigma-Aldrich
Benzoic acid, natural, ≥99.5%, FCC, FG
Sigma-Aldrich
Benzoic acid, ≥99.5%, FCC, FG
Sigma-Aldrich
Benzoic acid, ReagentPlus®, 99%
Supelco
Benzoic acid, certified reference material for titrimetry, certified by BAM, ≥99.5%
Sigma-Aldrich
Benzoic acid, puriss. p.a., ACS reagent, reag. Ph. Eur., ≥99.9% (alkalimetric)
Sigma-Aldrich
Benzoic acid, ACS reagent, ≥99.5%
Sigma-Aldrich
Probenecid
Sigma-Aldrich
Benzoic acid, SAJ first grade, ≥99.5%
Sigma-Aldrich
Benzoic acid, SAJ special grade, ≥99.5%
Supelco
Benzoic acid, Standard for quantitative NMR, TraceCERT®
USP
Probenecid, United States Pharmacopeia (USP) Reference Standard
Probenecid, European Pharmacopoeia (EP) Reference Standard
USP
Benzoic acid, United States Pharmacopeia (USP) Reference Standard
Benzoic acid, European Pharmacopoeia (EP) Reference Standard
Supelco
SS Benzoic Acid, 2000 μg/mL in dichloromethane, analytical standard
Amphotericin B, European Pharmacopoeia (EP) Reference Standard
Supelco
Mettler-Toledo Calibration substance ME 18555, Benzoic acid, analytical standard, for the calibration of the thermosystem 900, traceable to primary standards (LGC)
Sigma-Aldrich
Adefovir, ≥98% (HPLC)
Sigma-Aldrich
Cidofovir hydrate, ≥98% (HPLC)