Ronidazole Pharmacokinetics in Cats After IV Administration and Oral Administration of an Immediate Release Capsule and a Colon-Targeted Delayed Release Tablet
Tritrichomonas foetus, a parasite of feline colonic mucosa, causes unrelenting diarrhea for which ronidazole (RDZ) has been identified as the only effective treatment. RDZ kills T. foetus in vitro (RDZ > 0.1µg/ml) and has eliminated T. foetus in cats (30-50 mg/kg PO q12h for 14 days). RDZ produces neurotoxicity in some cats and disposition of the drug in felines is unknown. The objective of this study was to characterize the pharmacokinetics of RDZ in cats after intravenous (IV) and oral administration and to assess a novel formulation for colon-targeted delivery of RDZ.
RDZ was compounded into immediate-release capsules (95 mg), with immediate-release confirmed by in vitro dissolution studies. An IV solution was prepared by dissolving RDZ in 5% dextrose in water (3.2mg/ml). RDZ was administered orally (mean dose 28.2 mg/kg) and IV (~9.2mg/kg) to 6 healthy adult cats in a crossover design with at least one-week washout between crossovers. Plasma was collected from catheters over 48 hours and analyzed for RDZ using high pressure liquid chromatography. RDZ was well-tolerated by the cats after each administration.
Following IV administration of RDZ, the terminal half-life (t1/2) was 9.72±0.38 hrs and initial concentration (C0) was 14.94± 2.77 µg/ml. Volume of distribution at steady state was 0.66± 0.06 L/kg and the systemic clearance was 0.80±0.07 mL/kg/min. Following oral administration, RDZ was rapidly and completely absorbed with detection in plasma of all 6 cats by 10 min after dosing and systemic availability of 99.3±17.2%. The maximum plasma concentration (Cmax) of RDZ was 36.20±2.63 µg/mL, time to maximum plasma concentration (Tmax) was 1.39±1.29 hr, and terminal t1/2 was 10.44±0.83hr. After recognizing that RDZ was rapidly absorbed from immediate-release capsules we formulated delayed release RDZ by coating tablets with guar gum. Bacterial digestion of guar gum and subsequent drug release are theoretically restricted to the colon where T. foetus resides. In vitro dissolution studies confirmed that RDZ was not released from guar gum coated tablets at either gastric or intestinal pH. These tablets were administered to four cats orally (~32.9mg/kg) and absorption studies repeated. The delayed release formulation extended the TMAX to 16 hrs and produced a Cmax of 28.90±9.77 µg/ml. Drug absorption was complete (bioavailability 117.0 ± 31.8%) and corresponded to time of projected arrival of RDZ in the colon.
In conclusion, RDZ is rapidly and completely absorbed from immediate-release capsules in the proximal GI tract and persists in plasma for over 48 hrs. These attributes may predispose cats to neurotoxicity with twice-daily administration. By targeting release of RDZ to the colon, the site of T.foetus infection, delayed release tablets may provide improved efficacy at lower doses or less frequent intervals that reduce risk of systemic toxicity.