Influence of ABC transporters on the excretion of ciprofloxacin assessed with PET imaging in mice

Abstract

Ciprofloxacin is a commonly prescribed fluoroquinolone antibiotic which is cleared by active tubular secretion and intestinal excretion. Ciprofloxacin is a known substrate of the ATP-binding cassette (ABC) transporters breast cancer resistance protein (BCRP) and multidrug resistance-associated protein 4 (MRP4). In this work, we used positron emission tomography (PET) imaging to investigate the influence of BCRP, MRP4, MRP2 and P-glycoprotein (P-gp) on the excretion of [¹⁸F]ciprofloxacin in mice. Dynamic 90-min PET scans were performed after intravenous injection of [¹⁸F]ciprofloxacin in wild-type mice without and with pre-treatment with the broad-spectrum MRP inhibitor MK571. Moreover, [¹⁸F]ciprofloxacin PET scans were performed in Abcc4^(-/-), Abcc2^(-/-), Abcc4^(-/-)Abcg2^(-/-) and Abcb1a/b^(-/-)Abcg2^(-/-) mice. In addition to non-compartmental pharmacokinetic (PK) analysis, a novel three-compartment PK model was developed for a detailed assessment of the renal disposition of [¹⁸F]ciprofloxacin. In MK571 pre-treated mice, a significant increase in the blood exposure to [¹⁸F]ciprofloxacin was observed along with a significant reduction in the renal and intestinal clearances. PK modelling revealed a significant reduction in renal radioactivity uptake (CL₁) and in the rate constants for transfer of radioactivity from the corticomedullary renal region into blood (k₂) and urine (k₃), respectively, after MK571 administration. No changes in the renal clearance or in the estimated kidney PK model parameters were observed in any of the studied knockout models, while a significant reduction in the intestinal clearance was observed in Abcc2^(-/-) and Abcc4^(-/-)Abcg2^(-/-) mice. Our data failed to reveal a role of any of the studied ABC transporters in the tubular secretion of ciprofloxacin. This may indicate that ciprofloxacin is handled in the kidneys by more than one transporter family, most likely with a great degree of mutual functional redundancy. Our study highlights the potential of PET imaging for an assessment of transporter-mediated renal excretion of radiolabelled drugs.

Keywords: Breast cancer resistance protein (BCRP); Multidrug resistance-associated protein 4 (MRP4); Pharmacokinetic modelling; Positron emission tomography; Tubular secretion; [(18)F]Ciprofloxacin.