RESUMO
OBJECTIVE: To evaluate the plasma and aqueous humor disposition of prednisolone after oral administration in cats. METHODS: Six cats were administered with a single oral dose of prednisolone (10 mg). Blood and aqueous humor samples were serially collected after drug administration. Prednisolone concentrations in plasma and aqueous humor were measured at 0.25, 0.5, 1.0, 1.5, 2.0, 3.0, 4.0, and 5.0 h after administration by a high-performance liquid chromatographic analytical method developed and validated for this purpose. RESULTS: Mean ± standard error (SE) of maximum plasma prednisolone concentration (300.8 ± 67.3 ng/mL) was reached at 1 h after administration. Prednisolone was distributed to the aqueous humor reaching a mean peak concentration of 100.9 ± 25.5 ng/mL at 1.25 h after administration. The mean ± SE systemic and aqueous humor exposure (AUC) was 553.3 ± 120.0 ng h/mL and 378.8 ± 64.9 ng h/mL, respectively. A high AUC(aqueous humor)/AUC(plasma) ratio was observed (0.68 ± 0.13). The mean half-life time of elimination in plasma and aqueous humor was 0.87 ± 0.16 h and 2.25 ± 0.44 h, respectively. CLINICAL SIGNIFICANCE: The observed high ratio between aqueous humor and plasma prednisolone concentrations indicates that extensive penetration of prednisolone to the anterior segment of the eye may occur. This is the first step that contributes to the optimization of the pharmacological therapeutics for the clinical treatment of uveitis.
Assuntos
Humor Aquoso/efeitos dos fármacos , Prednisolona/sangue , Prednisolona/farmacologia , Administração Oral , Animais , Gatos , Cromatografia Líquida de Alta Pressão , Masculino , Prednisolona/administração & dosagem , Prednisolona/farmacocinética , Reprodutibilidade dos Testes , Fatores de Tempo , Distribuição Tecidual/efeitos dos fármacosRESUMO
A high-performance liquid chromatographic technique for the simultaneous determination of prednisolone and prednisone in human plasma, whole blood, urine, and bound-to-plasma proteins, using betamethasone as internal standard, is presented. Liquid-liquid extraction is used for whole blood samples, and solid phase extraction is used for plasma, urine, and proteins bound to plasma. The accuracy, precision, specificity, linearity, and repeatability meet the requirements of current recommendations in bioanalytical method validation. The method is suitable for high altitude pharmacokinetic studies, in which the quantitation of drugs in those fluids is required. The results from healthy volunteers are presented.
Assuntos
Cromatografia Líquida de Alta Pressão/métodos , Prednisolona/sangue , Prednisona/sangue , Proteínas Sanguíneas/metabolismo , Humanos , Prednisolona/urina , Prednisona/urina , Reprodutibilidade dos Testes , Sensibilidade e EspecificidadeRESUMO
To develop limited-sampling strategy (LSS) models for estimating prednisolone's area under plasma concentration versus time curve (AUC(0-infinity)), its maximum concentration in plasma (C(max)), and total clearance (CL/F). Healthy subjects (n = 24), enrolled in a bioequivalence study, received 20 mg PO of the prodrug prednisone as reference and test tablets, and plasma prednisolone concentrations (n = 576) were measured by a validated HPLC assay. A linear regression analysis of AUC(0-infinity), C(max), CL/F, and log(CL/F) against the plasma prednisolone concentrations for the reference formulation was carried out to develop LSS models to estimate these parameters. The LSS models were validated on the test formulation data sets and on simulated sets generated by the software ADAPT II. LSS models based on a single [1.5 hours for C(max) and 7 hours for AUC(0-infinity), CL/F, and log(CL/F)] plasma sample, accurately estimated (R2 = 0.84-0.97, mean bias < 1%; mean precision < 10%) these pharmacokinetic parameters. Validation tests indicated that the most informative single-point LSS models developed for the reference formulation provide precise estimates (R(2) > 0.83; mean bias < 3%; mean precision < 10%) of the corresponding pharmacokinetic parameters for the test formulation. LSS models based on the two most informative sampling points (1.5 and 7 hours) were required for accurate estimates (R(2) > 0.87; mean bias < 6%; mean precision < 8%) of prednisolone's C(max), AUC(0-infinity), CL/F, and log(CL/F) for the simulated data sets. Finally, bioequivalence assessment of the prednisone formulations, based on LSS-derived AUC(0-infinity) and C(max) values provided results identical to those obtained using the original values for these parameters. One- and 2-point LSS models provided accurate estimates of prednisolone's C(max), AUC(0-infinity), and CL/F, following single oral doses of prednisone, and allowed correct assessment of bioequivalence between two prednisone formulations.
Assuntos
Glucocorticoides/farmacocinética , Prednisolona/farmacocinética , Adolescente , Adulto , Área Sob a Curva , Cromatografia Líquida de Alta Pressão , Estudos Cross-Over , Glucocorticoides/sangue , Meia-Vida , Humanos , Masculino , Taxa de Depuração Metabólica , Modelos Biológicos , Prednisolona/sangue , Reprodutibilidade dos Testes , Projetos de Pesquisa , Tamanho da Amostra , Equivalência TerapêuticaRESUMO
Six lactating women receiving long-term treatment with prednisolone in doses from 10 to 80 mg/day were studied. Serum and milk samples were assayed for prednisolone and endogenous cortisol by a specific high-performance liquid chromatographic method. The milk and serum concentrations vs time curves for prednisolone were virtually parallel, and the milk concentrations were 5% to 25% of those in serum. The milk/serum concentration ratio increased with increasing serum concentration. At a daily dose of 80 mg prednisolone, the infant would ingest less than 0.1% of that dose; this corresponds to less than 10% of the infant's endogenous cortisol production. Because there is an equilibrium between the concentration of prednisolone in milk and serum, the exposure of the infant is minimized if breast-feeding is avoided during the first 4 hours after the dose. We conclude that from a quantitative point of view the exposure of the infant is minimal, and breast-feeding may be permitted at maternal prednisolone doses of at least 20 mg once or twice daily. At higher doses, exposure may be minimized if nursing is performed greater than 4 hours after the dose.
Assuntos
Leite Humano/metabolismo , Prednisolona/metabolismo , Feminino , Humanos , Cinética , Prednisolona/sangue , Fatores de TempoRESUMO
Plasma prednisolone levels have been measured hourly in children receiving a single dose of oral prednisone. Peak prednisolone levels occurred one to two hours after ingestion; half-life studies gave a mean value of 132 minutes in most children. Some children had marked variability in absorption and metabolism of prednisone. Somatomedin activity and cell-mediated immunity were inhibited by plasma prednisolone values which were achieved by single doses of prednisone of 0.5 mg/kg or higher. Monitoring prednisolone levels may be of value in identifying those children who accumulate excessively high levels on moderate dosage regimens.