Pharmacokinetics of Clarithromycin Citrate Salt after Oral Administration to Beagle Dogs and Food Effects on Its Absorption

Abstract

To investigate the pharmacokinetics of clarithromycin citrate salt and the effect of food on the absorption of free base and citrate salt, clarithromycin citrate was prepared and the in vitro intrinsic dissolution profiles of the free base and the salt were examined at pH 5.0 and pH 6.8. The pharmacokinetic profiles of clarithromycin following a single oral administration as the free base and its citrate salt (equivalent to 75 mg clarithromycin) were evaluated in eight beagle dogs. The plasma concentrations of clarithromycin were determined by reversed-phase liquid chromatography coupled to tandem mass with positive ion electrospray ionization using the multiple reaction monitoring method. The dissolution rates of clarithromycin and its citrate salt were similar at pH 5.0; however, at pH 6.8 citrate salt significantly enhanced the dissolution rate of clarithromycin. Clarithromycin's relative bioavailability value as expressed by the ratio of total mean area under the curve for clarithromycin citrate to that of clarithromycin was 104.2% and 110.1% under fast and fed conditions, respectively. The clarithromycin plasma area under the curve ratio was 33.4% and 25.7%, respectively, following oral clarithromycin or clarithromycin citrate salt drug co-administration with breakfast compared to fast-state controls (P < 0.05). There was no difference in pharmacokinetic parameters between clarithromycin and clarithromycin citrate salt under fast and fed conditions, but under the fed condition, T_max was delayed and the C_max of clarithromycin citrate salt and clarithromycin was decreased relative to the fasted condition, indicating that the consumption of this meal substantially reduced the drug's bioavailability.