RESUMO
BACKGROUND AND OBJECTIVES: Ketoprofen, a potent nonsteroidal anti-inflammatory drug, is clinically administered as a racemic mixture. One of the possible metabolism routes of ketoprofen is the inversion of the R- to S-enantiomer in the gastrointestinal tract. Ketoprofen, as a weak acid drug, might undergo recirculation through pancreatic/intestinal juices. The aim of the work was to investigate if a plasma-gastrointestinal tract recirculation of ketoprofen could explain its R-to-S chiral inversion after the oral administration of two modified-release formulations: a gastro-resistant delayed-release tablet (Reference) and an extended-release-plus-immediate-release bilayer tablet (Test). METHODS: Sixteen healthy Caucasian volunteers (eight women and eight men) participated in a ketoprofen bioequivalence study. Both formulations were administered with and without food. In both cases, standard meals were given throughout the experiment. R- and S-enantiomers were measured separately using a validated HPLC-UV chiral method. Mean concentration-time profiles of ketoprofen enantiomers in plasma were obtained for men and women. Area under the plasma concentration-time curve, maximum ketoprofen plasma concentration, and time-to-peak were also computed for both isomers, both modes of administration, and both sexes. S/R concentration ratio was assessed as an indicator of enantiomer chiral inversion rate. RESULTS: Differences in the pharmacokinetics of S- and R-ketoprofen enantiomers were found after the Test administration. S-Ketoprofen presented a lower plasma exposure compared to R-enantiomer. However, the S/R concentration ratio increased 1 h (in men) and 2 h (in women) after meal intakes. This was related to pancreatic and/or intestinal and/or biliary secretions of the drug, followed by reabsorption and conversion of the R- to the S-isomer. The lower intestinal pH reported for men would lead to a higher oral bioavailability of the Test formulation and a higher reabsorption of both ketoprofen isomers in this sex. Hence, a higher rise of the S/R concentration ratio could be observed in men. No significant differences between isomers exposure were detected in both sexes after the Reference administration. Different lag times were observed after fed and fasting administration of this formulation; however, drug absorption coincided with food ingestion. Then, drug recirculation affected the S/R ratio from the beginning of drug exposure, minimizing the difference between isomers disposition. CONCLUSIONS: R-to-S conversion rate could be mainly associated with several passages of the drug through the intestinal mucosa. The concentration-time profiles of ketoprofen in plasma after the administration of both formulations evidenced R-to-S conversion of recirculating drug following meal intakes.
Assuntos
Anti-Inflamatórios não Esteroides/farmacocinética , Inibidores de Ciclo-Oxigenase/farmacocinética , Composição de Medicamentos , Cetoprofeno/farmacocinética , Administração Oral , Adulto , Anti-Inflamatórios não Esteroides/administração & dosagem , Anti-Inflamatórios não Esteroides/sangue , Anti-Inflamatórios não Esteroides/química , Área Sob a Curva , Disponibilidade Biológica , Biotransformação , Estudos Cross-Over , Inibidores de Ciclo-Oxigenase/administração & dosagem , Inibidores de Ciclo-Oxigenase/sangue , Inibidores de Ciclo-Oxigenase/química , Preparações de Ação Retardada/administração & dosagem , Preparações de Ação Retardada/análise , Preparações de Ação Retardada/química , Preparações de Ação Retardada/farmacocinética , Feminino , Interações Alimento-Droga , Humanos , Absorção Intestinal , Cetoprofeno/administração & dosagem , Cetoprofeno/sangue , Cetoprofeno/química , Masculino , Taxa de Depuração Metabólica , Estrutura Molecular , Caracteres Sexuais , Estereoisomerismo , Comprimidos com Revestimento Entérico , Adulto JovemRESUMO
We report the in vitro release profile and comparative pharmacokinetics and biodistribution of a new peroxisome proliferator-activated receptor-γ agonist and cyclooxygenase inhibitor (Lyso-7) free or associated to poly(D,L-lactic acid) nanocapsules (NC) after intravenous administration in mice. Lyso-7 pertains to the class of insulin-sensitizing agents that shows potential beneficial effects in diabetes therapy. Monodispersed Lyso-7 NC with a mean diameter of 273 nm with high encapsulation efficiency (83%) were obtained. Lyso-7 dissolution rate was reduced (2.6-fold) upon loading in NC. The pharmacokinetic parameters were determined using a non-compartmental approach. In comparison with Lyso-7 in solution, the plasma-AUC increased 14-fold, the mean residence time 2.6-fold and the mean half-life (t1/2) 1.5-fold for Lyso-7-NC; the Lyso-7 plasma clearance, distribution volume and elimination rate were reduced 13, 10 and 1.4 fold, respectively, which indicates higher retention of encapsulated Lyso-7 in the blood compartment. Upon association with NC, organ exposure to Lyso-7 was higher in the heart (3.6-fold), lung (2.8-fold), spleen (2.3-fold), kidney (2-fold) and liver (1.8-fold) compared to Lyso-7 in solution. The analysis of whole data clearly indicates that body exposure to Lyso-7 was enhanced and the general toxicity reduced upon nanoencapsulation, allowing further evaluation of Lyso-7 in nonclinical and clinical studies.
Assuntos
Inibidores de Ciclo-Oxigenase/administração & dosagem , Inibidores de Ciclo-Oxigenase/farmacocinética , Indóis/administração & dosagem , Indóis/farmacocinética , Nanocápsulas/administração & dosagem , PPAR gama/agonistas , Tiazolidinedionas/administração & dosagem , Tiazolidinedionas/farmacocinética , Animais , Inibidores de Ciclo-Oxigenase/sangue , Inibidores de Ciclo-Oxigenase/química , Eritrócitos/efeitos dos fármacos , Feminino , Hemólise/efeitos dos fármacos , Indóis/sangue , Indóis/química , Rim/metabolismo , Fígado/metabolismo , Pulmão/metabolismo , Camundongos , Miocárdio/metabolismo , Nanocápsulas/química , Nanocápsulas/ultraestrutura , Tamanho da Partícula , Baço/metabolismo , Propriedades de Superfície , Tiazolidinedionas/sangue , Tiazolidinedionas/química , Distribuição TecidualRESUMO
OBJECTIVE: In this study, the bioavailability of 2 meloxicam 15 mg tablet formulations was compared. A single dose of each formulation was administered to 24 healthy volunteers (12 males and 12 females). MATERIAL AND METHODS: The study was conducted using an open, randomized and crossover design with a 2-week washout interval. The plasma samples were obtained over a 96-hour interval and meloxicam concentrations were analyzed by high-performance liquid chromatography (an agilent) coupled to an API 2000 turboionspray tandem mass spectrometry (LC-MS-MS). An electrospray ionization (ESI) source operating in the positive ion mode, using a cross flow counter electrode and set for the multiple reaction monitoring (MRM) was employed. The plasma protein precipitate was reconstituted with acetonitrile/water + 10 mM acetic acid (20/80, v/v) and injected in a Prevail C8 5 microm (150 mm x 4.6 mm i.d.) analytical column with reverse-phase liquid chromatography. The retention time observed for meloxicam and tenoxicam (internal standard) was 1.8 and 1.4 minutes, respectively. The mean recovery of meloxicam was 95.9% and the limit ofquantification was 0.02 microg/ml. RESULTS: The geometric mean of meloxicam/movatec 15 mg individual % ratio was 101.3% for AUC(last), 99.9% for AUC(0-infinity) and 107.7% for C(max). The 90% confidence intervals were 97.3 - 105.4%, 96.0 - 104.0% and 98.8 - 117.4%, respectively. CONCLUSION: Since the 90% CI for both AUC(Iast), AUC(0-infinity) and C(max), ratios were all inside the 80 - 125% interval proposed by the US Food and Drug Administration Agency and accepted by Brazilian ANVISA (Sanitary Surveillance Agency), it was concluded that the meloxicam formulation produced by Merck S.A. lndústrias Químicas is bioequivalent to the movatec formulation regarding both the rate and extent of absorption. This assay method was faster, more simple, specific, precise and accurate in determining the bioequivalence of meloxicam than any method previously described.
Assuntos
Cromatografia Líquida de Alta Pressão/métodos , Inibidores de Ciclo-Oxigenase/farmacocinética , Espectrometria de Massas em Tandem/métodos , Tiazinas/farmacocinética , Tiazóis/farmacocinética , Adulto , Área Sob a Curva , Brasil , Estudos Cross-Over , Inibidores de Ciclo-Oxigenase/sangue , Feminino , Meia-Vida , Humanos , Masculino , Meloxicam , Valores de Referência , Reprodutibilidade dos Testes , Espectrometria de Massas por Ionização por Electrospray/métodos , Equivalência Terapêutica , Tiazinas/sangue , Tiazóis/sangueRESUMO
BACKGROUND: The purpose of the present study was to evaluate the effect of a potent selective cyclooxygenase-2 (COX-2) inhibitor, etoricoxib, on the prevention of alveolar bone loss in experimental periodontitis induced in rats. METHODS: Ninety Wistar rats were separated into three experimental groups. Cotton ligatures were placed at the gingival margin level of lower right first molars. The rats were randomly assigned to one of the following groups: control received a daily oral dose of 1 ml/kg of saline solution; Eto1 received 6 mg/kg of etoricoxib; Eto2 received 12 mg/kg of etoricoxib. Serum levels of etoricoxib and white blood cells were determined. Standardized digital radiographs were taken after death at 3, 5, 10, 18 and 30 days to measure the amount of bone loss at the mesial root surface of the first molar tooth in each rat. RESULTS: One-way analysis of variance (anova) indicated that groups treated with both doses of etoricoxib had significantly (p < 0.05) less alveolar bone loss when compared to controls. Furthermore, etoricoxib treatment significantly inhibited the leukocytosis observed 3 days after the induction of periodontitis. CONCLUSION: These data provide evidence that systemic therapy with etoricoxib can retard alveolar bone loss in a ligature-induced periodontitis model in rats.
Assuntos
Perda do Osso Alveolar/prevenção & controle , Inibidores de Ciclo-Oxigenase/sangue , Periodontite/tratamento farmacológico , Piridinas/sangue , Sulfonas/sangue , Animais , Avaliação Pré-Clínica de Medicamentos , Etoricoxib , Leucocitose/tratamento farmacológico , Linfócitos/efeitos dos fármacos , Masculino , Doenças Mandibulares/prevenção & controle , Distribuição Aleatória , Ratos , Ratos WistarRESUMO
The pharmacokinetics of a meloxicam suspension were studied in 18 children with juvenile rheumatoid arthritis. Children received a single 0.25-mg/kg dose up to a maximum of 15 mg. Pharmacokinetic parameters after the first dose were calculated by noncompartmental methods. Geometric mean (percent coefficient of variation for geometric mean [gCV]) C(max), AUC(0- infinity ), apparent clearance, apparent volume of distribution, and elimination half-life values were 1.24 microg/mL (47% gCV), 25.6 microg x h/mL (81% gCV), 0.17 mL/min/kg (83% gCV), 0.19 L/kg (63% gCV), and 13.4 hours (54% gCV) in the younger group and 1.89 microg/mL (25% gCV), 35.8 microg x h/mL (21% gCV), 0.12 mL/min/kg (23% gCV), 0.13 L/kg (22% gCV), and 12.7 hours (21% gCV) for the older group, respectively. Area under the curve, volume of distribution, and clearance tended to be higher in the younger group, whereas elimination half-lives were similar. A post hoc comparison to pharmacokinetic data in adults revealed no relevant differences. Thus, a common body weight-normalized dose is considered appropriate for children older than 2 years.
Assuntos
Anti-Inflamatórios não Esteroides/farmacocinética , Artrite Juvenil/tratamento farmacológico , Inibidores de Ciclo-Oxigenase/farmacocinética , Tiazinas/farmacocinética , Tiazóis/farmacocinética , Administração Oral , Adolescente , Fatores Etários , Anti-Inflamatórios não Esteroides/sangue , Anti-Inflamatórios não Esteroides/uso terapêutico , Área Sob a Curva , Criança , Pré-Escolar , Inibidores de Ciclo-Oxigenase/sangue , Inibidores de Ciclo-Oxigenase/uso terapêutico , Feminino , Alemanha , Meia-Vida , Humanos , Masculino , Meloxicam , México , Tiazinas/sangue , Tiazinas/uso terapêutico , Tiazóis/sangue , Tiazóis/uso terapêuticoRESUMO
This study was aimed to investigate the influence of diabetes or arthritis on the enantioselective metabolism and kinetic disposition of fenoprofen in rats with streptozotocin-induced diabetes or Mycobacteriumtuberculosis adjuvant-induced arthritis. Animals received i.v. 10 mg/kg racemic fenoprofen and blood samples were collected up to 24 h thereafter, with 5 animals studied at each time point. Plasma concentrations of the fenoprofen enantiomers were determined by HPLC. Diabetic and arthritic animals showed significant differences when compared with respective controls for the following pharmacokinetic variables of the (+)-(S)-fenoprofen eutomer: area under the plasma concentration time curve, total clearance and volume of distribution. The results indicate that experimental diabetes and adjuvant-induced arthritis influence the fenoprofen enantioselective metabolism.
Assuntos
Anti-Inflamatórios não Esteroides/química , Anti-Inflamatórios não Esteroides/farmacocinética , Artrite Experimental/metabolismo , Diabetes Mellitus Experimental/metabolismo , Fenoprofeno/química , Fenoprofeno/farmacocinética , Animais , Anti-Inflamatórios não Esteroides/sangue , Área Sob a Curva , Cromatografia Líquida de Alta Pressão , Inibidores de Ciclo-Oxigenase/sangue , Inibidores de Ciclo-Oxigenase/química , Inibidores de Ciclo-Oxigenase/farmacocinética , Fenoprofeno/sangue , Masculino , Taxa de Depuração Metabólica , Ratos , Ratos Wistar , EstereoisomerismoRESUMO
BACKGROUND: The purpose of this study was to evaluate the effect of a selective cyclooxygenase-2 inhibitor on the progression of alveolar bone loss in an experimental periodontitis model in rats. METHODS: One hundred eighty (180) Wistar rats were separated into 3 experimental groups. Cotton ligatures were placed at the gingival margin level of lower right first molars. The rats were randomly assigned to one of the following groups that received: a daily oral dose of 10 mg/kg body weight of celecoxib (Ce1); 20 mg/kg body weight of celecoxib (Ce2); or 10 ml/kg of saline solution (C). Serum levels of celecoxib and white blood cell count were determined. Standardized digital radiographs were taken after sacrifice at 3, 5, 10, 18, and 30 days to measure the amount of bone loss around the mesial root surface of the first molar tooth in each rat. RESULTS: Two-way analysis of variance (ANOVA) indicated that groups treated with celecoxib had significantly less bone loss compared to controls (P < 0.0001) and that there was a significant interaction between treatment with celecoxib and time (P < 0.03). Post-hoc comparisons showed that in both groups treated with celecoxib, the bone loss became significant only after 10 days of ligature placement, while in the control group it was already significant after 5 days. However, differences in mean bone loss between control and Ce1 were significant only at 18 days and, between control and Ce2, at 5 and 18 days. There was no significant difference in bone loss among experimental groups at the end of the experimental period. CONCLUSION: These data provide evidence that systemic therapy with celecoxib can modify the progression of experimentally induced periodontitis in rats.