Pharmacokinetics Study Of Fluoxetine Hydrochloride Enteric-coated Tablets After A Single Oral Administration In Healthy Chinese Volunteers

BackgroundFluoxetine is metabolized mainly through N-demethylation in the liver and its metabolite norfluoxetine also has pharmacological activity. Fluoxetine hydrochloride enteric-coated tablet is once-weekly fluoxetine and contained 90mg fluoxetine per tablet. There isn't any data of the pharmacokinetic parameters in Chinese after a single oral administration of this new form of fluoxetine. Many studies indicated that the metabolic process of fluoxetine is catalyzed by multiple isoforms of CYP450s in human liver microsomes. Though we still don't know exactly which enzyme is the most important, some domestic studies reported that CYP2C19 plays a chief role in the metabolism of fluoxetine.ObjectiveTo study the pharmacokinetic (PK) parameters of fluoxetine and norfluoxetine after a single oral administration in healthy Chinese volunteers, evaluate the dosage form characteristics of the enteric-coated tablet after the comparison with the common tablet. At the same time, observe the influence of gender and the genotype of CYP2C19 on the metabolic course of fluoxetine.MethodsIn this two period self-cross control study, 16 subjects were divided into two groups randomized. They took the enteric-coated tablet of fluoxetine 90mg in one period and the common tablet 40mg in the other. Each was a single oral dose. The plasma concentrations of fluoxetine and norfluoxetine were determined by high-performance liquid chromatograph (HPLC) with fluorescence detection. Use DAS (ver2.1.1) software to calculate the PK parameters. Through the analysis and comparison of the PK profiles of the two tablets, we can evaluate the dosage form characteristics of the new form. Also we can analyze the influence of gender by the comparison of the two gender group.The genotypes of CYP2C19 were determined by PCR-based sequencing. The PK profiles were observed between the EMs and PMs.ResultsAfter a single oral dose of 90mg enteric-coated fluoxetine, peak plasma levels of FLU occurred at (8.50±2.03) h, and the peak concentration was (68.28±16.83) ng·mL^-1, elimination half-time of FLU was (49.92±14.19) h, area under the plasma concentration-time curve was (4323.45±1026.32) (ng·h)·mL^-1. For NFL, tmax was (80.25±41.27) h, Cmax was (53.25±17.12) ng·mL^-1, t_1/2z was (133.51±96.20) h, AUC_{0～∞} was (16296.73±5628.84) (ng·h)·mL^-1.Compare the pharmacokinetic parameters of the two dosage form, for both FLU and NFL, Mean residence time of the enteric-coated form was significant longer (p<0.01). Furthermore, of the enteric-coated form, tmax were longer and corrected Cmax were lower than the common tablet. The differences were statistically significant (p<0.05).Tmax of FLU and NFL were different between the two gender groups after a single oral dose of enteric-coated fluoxetine (p<0.01).Among 16 subjects, 14 were EMs and only 2 (12.5%) were PMs. ConclusionThe study drug has a PK profile of enteric-coated dosage form. After a single oral dose, its tmax was delayed than common fluoxetine tablet. The pharmacokinetics of fluoxetine was non-linear.The standard deviations of the parameters were larger in female subjects and indicated a more obvious individual variation in female.