Fluorometric determination of bopindolol and celiprolol in pharmaceutical preparations and biological fluids.

Two sensitive fluorometric methods were developed for the determination of both bopindolol malonate (BOP) and celiprolol HCl (CLP) based on measuring their native fluorescence in methanol and acetonitrile, respectively. For BOP, the fluorescence was measured at 316 nm after excitation at 278 nm. The proposed method was successfully applied to the assay of commercial tablets as well as content uniformity testing. For CLP, the fluorescence was enhanced by the addition of carboxymethylcellulose solution and measured at 455 nm after excitation at 339 nm. The method was successfully applied to the analysis of CLP in tablets and biological fluids. In both methods, interference likely to be introduced from co-formulated, co-administered, or chemically related drugs was studied. The results were statistically compared with those obtained by reference methods and were found to be in good agreement.

Direct determination of celiprolol in human urine using on-line coupled ITP-CZE method with fiber-based DAD.

The present work illustrated possibilities of column-coupling electrophoresis combined with DAD for the direct quantitative determination of trace drug (celiprolol, CEL) in clinical human urine samples. ITP, on-line coupled with CZE, served as an ideal injection technique (high sample load capacity, narrow and sharp drug zone). Moreover, the ITP provided an effective on-line sample pretreatment (preseparation, purification and preconcentration of the drug) producing analyte zone suitable for its direct detection and quantitation in CZE stage. Spectral DAD in comparison with single wavelength ultraviolet detection enhanced value of analytical information (i) verifying purity (i.e., spectral homogeneity) of drug zone (according to differences in spectrum profiles when compared tested and reference drug spectra) and (ii) indicating zones/peaks with spectra similar to the drug spectrum (potential structurally related metabolites). The characterization of trace analyte signals superposed on the baseline noise was more definite thanks to the application of background correction and smoothing procedure to the raw DAD spectra (producing relevant spectral response). The proposed ITP-CZE-DAD method was characterized by favorable performance parameters for CEL in urine matrices {e.g., the lower limit of quantification was 9.7 ng/mL, RSD and relative error of the determinations were lower than 3% (precision) and 1% (accuracy), respectively, analyte peak exhibited spectral homogeneity (reflecting separation selectivity), separation efficiency was 84,500 theoretical plates} and successfully applied in a trial pharmacokinetic study of CEL.

Orange juice substantially reduces the bioavailability of the beta-adrenergic-blocking agent celiprolol.

BACKGROUND: Grapefruit juice was recently found to decrease plasma concentrations of the beta-adrenergic receptor-blocking agent celiprolol. Our objective was to investigate the effect of orange juice on the pharmacokinetics of celiprolol in healthy subjects. METHODS: In a randomized crossover study with 2 phases and a washout of 2 weeks, 10 healthy volunteers ingested either 200 mL normal-strength orange juice or water 3 times a day for 2 days. On the morning of day 3, 1 hour after ingestion of 200 mL orange juice or water, each subject ingested 100 mg celiprolol with either 200 mL orange juice or water. In addition, 200 mL orange juice or water was ingested at 4, 10, 22, and 27 hours after celiprolol intake. The concentrations of celiprolol in plasma and its excretion into urine were measured up to 33 hours after its dosing. Systolic and diastolic blood pressures and heart rate were recorded up to 10 hours. RESULTS: Orange juice reduced the mean peak plasma concentration of celiprolol by 89% (P <.01) and the mean area under the plasma celiprolol concentration-time curve by 83% (P <.01). The time to peak concentration of celiprolol increased from 4 to 6 hours (P <.05), and the half-life was prolonged from 4.6 to 10.8 hours (P =.05) after ingestion of orange juice. Orange juice reduced the urinary excretion of celiprolol by 77% (P <.01). No significant differences were observed in the hemodynamic variables between the phases. CONCLUSIONS: Orange juice substantially reduces the bioavailability of celiprolol, but the mechanism of this interaction remains to be resolved. For example, modulation of intestinal pH and of function of transporters implicated in the absorption of celiprolol may be involved. Because of the great extent of the orange juice-celiprolol interaction and a wide use of orange juice, this interaction is likely to have clinical importance in some patients, although hemodynamic consequences were not seen in young healthy subjects.

Itraconazole increases but grapefruit juice greatly decreases plasma concentrations of celiprolol.

OBJECTIVES: Our objective was to evaluate the effects of itraconazole and grapefruit juice on the pharmacokinetics of the beta-adrenergic receptor-blocking agent celiprolol in healthy volunteers. METHODS: In a randomized 3-phase crossover study, 12 healthy volunteers took itraconazole 200 mg orally or placebo twice a day or 200 mL grapefruit juice 3 times a day for 2 days. On the morning of day 3, 1 hour after ingestion of itraconazole, placebo, or grapefruit juice, each subject ingested 100 mg celiprolol with 200 mL of water (placebo and itraconazole phases) or grapefruit juice. In addition, 200 mL of water or grapefruit juice was ingested 4 and 10 hours after celiprolol intake. The plasma concentrations of celiprolol, itraconazole, and hydroxyitraconazole and the excretion of celiprolol into urine were measured up to 33 hours after dosing. Systolic and diastolic blood pressures and heart rate were recorded with subjects in a sitting position before the administration of celiprolol and 2, 4, 6, and 10 hours later. RESULTS: During the itraconazole phase, the mean area under the plasma concentration-time curve from 0 to 33 hours [AUC(0-33)] of celiprolol was 80% greater (P <.05) than in the placebo phase. During the grapefruit juice phase, the mean AUC(0-33) and peak plasma concentration values of celiprolol were reduced to about 13% (P <.001) and 5% (P <.001) of the respective placebo phase values. The cumulative excretion into urine of celiprolol was increased by 59% by itraconazole (P <.05) and decreased by 85% by grapefruit juice (P <.001). Hemodynamic variables did not differ between the phases. CONCLUSIONS: Itraconazole almost doubles but grapefruit juice greatly reduces plasma concentrations of celiprolol. The itraconazole-celiprolol interaction most likely resulted from increased absorption of celiprolol possibly as a result of P-glycoprotein inhibition in the intestine. The reduced celiprolol concentrations during the grapefruit juice phase were probably caused by physicochemical factors that interfered with celiprolol absorption, although other mechanisms cannot be excluded. The grapefruit juice-celiprolol interaction is probably of clinical relevance.

Experimental design for enantioselective separation of celiprolol by capillary electrophoresis using sulfated beta-cyclodextrin.

A capillary zone electrophoresis method was developed for the enantioseparation of celiprolol enantiomers, using a sulfated beta-cyclodextrin (beta-CD) as a chiral selector. The use of a coated capillary was necessary to achieve stable and reproducible enantioseparations. A central composite design was applied to optimize the method and four parameters were selected for this study: the buffer pH, the buffer concentration, the sulfated beta-CD concentration and the temperature. Resolution between celiprolol enantiomers as well as analysis time and generated current were established as responses. For each response, a model was obtained by a second-degree mathematical expression. From the models, the most favorable conditions were determined by optimizing the resolution between celiprolol enantiomers and by setting the two other responses at threshold values. Response surfaces were also used to assess the robustness of the analytical method around the optimal region. Successful results were obtained with a 52 mM acetate buffer at pH 4.0 in the presence of 3.0 mM sulfated beta-CD at a temperature of 19.5 degrees C. Under these optimized conditions, baseline separation of the celiprolol enantiomers was achieved in less than 10 min. The method showed good validation data in terms of precision, accuracy and linearity, and was found to be suitable in determining celiprolol enantiomers in pharmaceutical preparations and in biological fluids.