Positron Emission Tomography-Based Pharmacokinetic Analysis To Assess Renal Transporter-Mediated Drug-Drug Interactions of Antimicrobial Drugs

Abstract

Transporter-mediated drug-drug interactions (DDIs) are of concern in antimicrobial drug development, as they can have serious safety consequences. We used positron emission tomography (PET) imaging-based pharmacokinetic (PK) analysis to assess the effect of different drugs, which may cause transporter-mediated DDIs, on the tissue distribution and excretion of [¹⁸F]ciprofloxacin as a radiolabeled model antimicrobial drug. Mice underwent PET scans after intravenous injection of [¹⁸F]ciprofloxacin, without and with pretreatment with either probenecid (150 mg/kg), cimetidine (50 mg/kg), or pyrimethamine (5 mg/kg). A 3-compartment kidney PK model was used to assess the involvement of renal transporters in the examined DDIs. Pretreatment with probenecid and cimetidine significantly decreased the renal clearance (CL_renal) of [¹⁸F]ciprofloxacin. The effect of cimetidine (-86%) was greater than that of probenecid (-63%), which contrasted with previously published clinical data. The kidney PK model revealed that the decrease in CL_renal was caused by inhibition of basal uptake transporters and apical efflux transporters in kidney proximal tubule cells. Changes in the urinary excretion of [¹⁸F]ciprofloxacin after pretreatment with probenecid and cimetidine resulted in increased blood and organ exposure to [¹⁸F]ciprofloxacin. Our results suggest that multiple membrane transporters mediate the tubular secretion of ciprofloxacin, with possible species differences between mice and humans. Concomitant medication inhibiting renal transporters may precipitate DDIs, leading to decreased urinary excretion and increased blood and organ exposure to ciprofloxacin, potentially exacerbating adverse effects. Our study highlights the strength of PET imaging-based PK analysis to assess transporter-mediated DDIs at a whole-body level.

Keywords: antimicrobial drug disposition; drug-drug interaction; membrane transporters; positron emission tomography; renal clearance.

FIG 1

Representative coronal PET summation images (0 to 40 min) of one untreated mouse (baseline) and one mouse pretreated with either probenecid (150 mg/kg), cimetidine (50 mg/kg), or pyrimethamine (5 mg/kg). Radioactivity concentration is expressed as percentage of injected dose per milliliter (%ID/mL). Anatomical regions are labeled with arrows (L, liver; LK, left kidney; RK, right kidney; UB, urinary bladder).

FIG 2

Mean concentration-time curves (%ID/mL ± SD) of [¹⁸F]ciprofloxacin in blood (image-derived blood curve from the left ventricle of the heart) (A), brain (B), and right lung (C) of ciprofloxacin mice without (baseline) and with pretreatment with either probenecid (150 mg/kg), cimetidine (50 mg/kg), or pyrimethamine (5 mg/kg).

FIG 3

Mean concentration-time curves (%ID/mL or %ID ± SD) of [¹⁸F]ciprofloxacin in excretory organs of mice without (baseline) and with pretreatment with either probenecid (150 mg/kg), cimetidine (50 mg/kg), or pyrimethamine (5 mg/kg). (A) Left kidney (corticomedullary region); (B) liver; (C) urinary bladder (assumed to represent excreted urine); (D) intestine.

FIG 4

Pharmacokinetic parameters (mean ± SD) obtained with noncompartmental pharmacokinetic analysis in untreated mice (baseline) and mice pretreated with either probenecid (150 mg/kg), cimetidine (50 mg/kg), or pyrimethamine (5 mg/kg). One animal of the cimetidine-treated group received a 100 mg/kg dose of cimetidine (open triangle). (A) CL_T is the total blood clearance. (B) CL_renal is the renal clearance with respect to the blood concentration. (C) CL_intestinal is the intestinal clearance with respect to the blood concentration. Kruskal-Wallis test followed by a Dunn’s multiple-comparison test against the baseline group; *, P ≤ 0.05; **, P ≤ 0.01.

FIG 5

Pharmacokinetic parameters (mean ± SD) obtained with the 3-compartment kidney pharmacokinetic model in untreated mice (baseline) and mice pretreated with either probenecid (150 mg/kg), cimetidine (50 mg/kg), or pyrimethamine (5 mg/kg). One animal of the cimetidine-treated group received a 100 mg/kg dose of cimetidine (open triangle). (A) CL₁ represents both the renal uptake clearance and the glomerular filtration rate of [¹⁸F]ciprofloxacin. (B) k₂ is the rate constant describing the transfer of [¹⁸F]ciprofloxacin from the kidney into the sink compartment (blood). (C) k₃ is the rate constant describing the transfer of [¹⁸F]ciprofloxacin from the kidney into the excreted urine. Kruskal-Wallis test followed by a Dunn’s multiple-comparison test against the baseline group; *, P ≤ 0.05; **, P ≤ 0.01.