RESUMEN
The pharmacokinetics of promethazine hydrochloride after administration of rectal suppositories at three dosage strengths and oral syrup were studied. The study had an open-label, randomized, crossover design. At intervals of five to nine days, healthy volunteers were given two 12.5-mg promethazine rectal suppositories, one 25-mg suppository, one 50-mg suppository, or 50 mg (10 mL) of promethazine oral syrup. Blood samples were collected before each dose and at intervals from 0.5 to 48 hours afterward. Promethazine concentration was determined by high-performance liquid chromatography, and pharmacokinetic values were calculated with noncompartmental methods. Thirty-six subjects (18 men and 18 women) completed the study. Absorption was highly variable for all the formulations. On average, absorption was more rapid and the maximum plasma concentration (Cmax) higher for the syrup than for the suppositories. Cmax was significantly lower for the 50-mg suppository (mean, 9.04 ng/mL) than for the syrup (19.3 ng/mL). The time to Cmax (tmax) was significantly shorter for the syrup (mean, 4.4 hours) than for the suppositories (6.7-8.6 hours). There were no significant differences in dose-normalized Cmax among the three suppository treatments. Area under the concentration-versus-time curve (AUC) was comparable between the syrup and the 50-mg suppository and between the treatments with two 12.5-mg suppositories and the 25-mg suppository. Elimination profiles were similar among all treatments (mean half-life [t1/2], 16-19 hours). There were no significant differences in pharmacokinetics on the basis of sex or race. The mean relative bioavailability for the three suppository treatments ranged from 70% to 97%. Individual relative bioavailabilities ranged from 4% to 343%. The pharmacokinetics of promethazine administered in oral syrup and rectal suppositories were highly variable, but, in general, the suppositories produced a lower Cmax and later tmax than the syrup. All formulations were comparable in terms of dose-normalized AUC and t1/2, and the three suppository treatments were comparable in terms of dose-normalized Cmax.
Asunto(s)
Antagonistas de los Receptores Histamínicos H1/farmacocinética , Prometazina/farmacocinética , Administración Oral , Administración Rectal , Adulto , Análisis de Varianza , Área Bajo la Curva , Disponibilidad Biológica , Cromatografía Líquida de Alta Presión , Estudios Cruzados , Relación Dosis-Respuesta a Droga , Femenino , Semivida , Antagonistas de los Receptores Histamínicos H1/administración & dosificación , Humanos , Masculino , Prometazina/administración & dosificación , SupositoriosRESUMEN
STUDY OBJECTIVE: To assess the effect of bromfenac sodium, a nonnarcotic analgesic drug under development, on the pharmacokinetics and pharmacodynamics of glyburide in patients with type II diabetes. DESIGN: Randomized, double-blind, placebo-controlled, multiple-dose study with a two-period crossover design. PATIENTS: Eleven men and one woman (age 36-64 yrs) whose diabetes was responsive to oral sulfonylurea therapy. INTERVENTIONS: Placebo or bromfenac 50 mg was given as a single oral dose 3 times/day for the first 3 days of the study. On days 4-6, patients received the alternative treatment. For at least 3 months before and during the study, patients took their usual single daily dose of glyburide 10 mg. MEASUREMENTS AND MAIN RESULTS: Bromfenac concentrations were measured by high-performance liquid chromatography with ultraviolet detection. Glyburide concentrations were measured by gas chromatography with nitrogen-phosphorus detection. Glycemia was measured repeatedly on day 3 of each treatment. Pharmacokinetic analysis was performed with noncompartmental techniques. No significant differences in the pharmacokinetics of glyburide or in the pharmacodynamic response of serum glucose levels were observed between placebo and bromfenac. Intersubject variability of concentrations was modest for glyburide and glucose, with a CV of 43% or less. CONCLUSION: Glyburide levels are not changed during concomitant administration of bromfenac.
Asunto(s)
Analgésicos/farmacología , Benzofenonas/farmacología , Bromobencenos/farmacología , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Gliburida/administración & dosificación , Hipoglucemiantes/administración & dosificación , Adulto , Anciano , Área Bajo la Curva , Benzofenonas/administración & dosificación , Benzofenonas/farmacocinética , Disponibilidad Biológica , Glucemia/efectos de los fármacos , Bromobencenos/administración & dosificación , Bromobencenos/farmacocinética , Estudios Cruzados , Diabetes Mellitus Tipo 2/metabolismo , Método Doble Ciego , Interacciones Farmacológicas , Quimioterapia Combinada , Femenino , Gliburida/farmacocinética , Semivida , Humanos , Masculino , Tasa de Depuración Metabólica , Persona de Mediana EdadRESUMEN
OBJECTIVE: To estimate absolute bioavailability of bromfenac and to compare its pharmacokinetics after intravenous and oral administration. DESIGN: This was a randomized, open-label, single-dose, crossover study conducted under fasting conditions with a washout period of at least 48 hours between doses. Each subject received a 50-mg dose of bromfenac both intravenously and orally followed by collection of blood samples at specified time intervals. Bromfenac plasma concentrations were measured by using a validated HPLC method with ultraviolet detection. SETTING: The study was conducted at the Drug Evaluation Unit. Hennepin County Medical Center, Minneapolis, MN. SUBJECTS: The participants consisted of 12 healthy subjects between 18 and 45 years of age and within +/-15% of ideal body weight. RESULTS: The mean +/- SD absolute bioavailability of bromfenac was 67% +/- 20%. CONCLUSIONS: The pharmacokinetic parameters of bromfenac were similar after intravenous and oral administration, suggesting that the prototype oral dosage form is optimal and that the observed intersubject variability is due to bromfenac itself, not the type of dosage form.
Asunto(s)
Analgésicos/farmacocinética , Benzofenonas/farmacocinética , Bromobencenos/farmacocinética , Administración Oral , Adolescente , Adulto , Analgésicos/administración & dosificación , Benzofenonas/administración & dosificación , Disponibilidad Biológica , Bromobencenos/administración & dosificación , Estudios Cruzados , Femenino , Humanos , Inyecciones Intravenosas , Masculino , Persona de Mediana EdadRESUMEN
OBJECTIVE: To compare the pharmacokinetic parameters of bromfenac, a nonsteroidal antiinflammatory drug under development, in healthy volunteers of various ages and either gender, after single and multiple doses. DESIGN: Open-label, single- and multiple-dose, nonrandomized, parallel study. PARTICIPANTS: Twenty young (18-45 y), 12 young-elderly (65-74 y), and 12 elderly (75-85 y) subjects were studied. Half of the subjects in each group were women. INTERVENTIONS: Bromfenac was given as a single 50-mg dose and then as 50-mg doses every 12 hours for 3 additional days. Twelve blood samples were collected for 12 hours after the first and last doses. MAIN OUTCOME MEASURES: Bromfenac concentrations were measured by using an HPLC procedure with ultraviolet detection. Unbound bromfenac concentrations were measured by equilibrium dialysis. Pharmacokinetic analysis was performed by noncompartmental techniques. RESULTS: No significant differences related to gender were detected. Significant differences were observed in half-life (t1/2), AUC, clearance, and apparent volume of distribution when the elderly group was compared with the young group and in t1/2 when the elderly group was compared with the young-elderly group, although substantial overlap among groups was observed. CONCLUSIONS: Administration of bromfenac to young-elderly or elderly subjects of either gender does not require a dosage adjustment in acute settings. Consideration should be made to titrating dosages in patients over 75 years of age who require repeated doses.
Asunto(s)
Analgésicos/farmacocinética , Benzofenonas/farmacocinética , Bromobencenos/farmacocinética , Adolescente , Adulto , Factores de Edad , Anciano , Anciano de 80 o más Años , Analgésicos/administración & dosificación , Benzofenonas/administración & dosificación , Bromobencenos/administración & dosificación , Femenino , Humanos , Masculino , Persona de Mediana Edad , Proyectos Piloto , Factores SexualesRESUMEN
OBJECTIVES: To compare the pharmacokinetics of bromfenac among normal subjects and renally compromised patients and patients with end-stage renal disease. METHODS: Bromfenac pharmacokinetics were examined after a single 50 mg oral dose in 18 subjects with normal kidney function, 12 subjects with decreased kidney function, and 10 dialysis-dependent subjects. Protein binding was assessed by equilibrium dialysis. RESULTS: Mean peak concentrations and areas under the concentration versus time curve ranged from 3.3 to 3.9 micrograms/ml and 5.1 to 6.9 micrograms.hr/ml, respectively. The mean unbound fraction in the subjects receiving dialysis (0.29%) was nearly twice that in the subjects with normal kidney function (0.17%) and in the subjects with impaired kidney function (0.16%), but no differences were detected in clearance, volume of distribution, or their free fraction-corrected counterparts. Bromfenac half-life nearly doubled in the impaired and dialysis groups but was shorter than the anticipated 8-hour dose interval. Eight subjects had a total of 11 study events; none were serious and all were self-limited. CONCLUSIONS: These findings suggest that no dosage adjustment is necessary in patients with impaired kidney function, but clinical monitoring appropriate for their individual condition is recommended.
Asunto(s)
Analgésicos no Narcóticos/farmacocinética , Antiinflamatorios no Esteroideos/farmacocinética , Benzofenonas/farmacocinética , Bromobencenos/farmacocinética , Fallo Renal Crónico/sangre , Riñón/fisiopatología , Adulto , Anciano , Femenino , Tasa de Filtración Glomerular , Semivida , Humanos , Fallo Renal Crónico/fisiopatología , Fallo Renal Crónico/terapia , Masculino , Persona de Mediana Edad , Diálisis RenalRESUMEN
An open-label, nonrandomized, multiple-dose, inpatient study was conducted in healthy male volunteers to compare the pharmacokinetics of bromfenac and phenytoin when the drugs are given individually and concomitantly. Twelve men received multiple oral doses of bromfenac for 4 days and then oral phenytoin for up to 14 days followed by concomitant administration of bromfenac and phenytoin for 8 days. Concomitant administration of the two drugs caused an approximate 40% decrease in the mean peak plasma concentration (Cmax) and the interdose area under the concentration-time curve (AUC) of bromfenac. The oral clearance (Clpo) of bromfenac doubled and the volume of distribution increased by 77%. For phenytoin, the mean peak serum concentration and the AUC increased by 9% and 11%, respectively, in the presence of bromfenac. The only change in unbound phenytoin was a 16% increase in the AUC. Although statistically significant, the changes in the pharmacokinetic parameters of phenytoin and unbound phenytoin were small. Adjustments in the dose of phenytoin should not be required during concomitant administration of bromfenac, although each patient's clinical status should be evaluated individually.
Asunto(s)
Analgésicos/farmacocinética , Anticonvulsivantes/farmacocinética , Benzofenonas/farmacocinética , Bromobencenos/farmacocinética , Fenitoína/farmacocinética , Adulto , Área Bajo la Curva , Benzofenonas/efectos adversos , Disponibilidad Biológica , Bromobencenos/efectos adversos , Interacciones Farmacológicas , Semivida , Humanos , Masculino , Tasa de Depuración Metabólica , Faringitis/inducido químicamente , Fenitoína/efectos adversosRESUMEN
OBJECTIVE: To compare the pharmacokinetics of methotrexate (MTX) and bromfenac administered separately or coadministered in patients with rheumatoid arthritis (RA). METHODS: Patients received their usual weekly oral dose of MTX on Days 1 and 8 and bromfenac 50 mg every 8 h from Days 4 to 9. On Days 1 and 8 serial blood and urine samples were collected to study the pharmacokinetics of MTX and 7-hydroxymethotrexate (7-OHMTX). Bromfenac pharmacokinetics were studied on Days 7 and 8. Concentrations of the analytes were assayed using validated high performance liquid chromatography methods. RESULTS: Nine patients, 5 women and 4 men, completed the study. No statistically significant changes were observed in any of the pharmacokinetic variables evaluated for bromfenac with or without MTX. Bromfenac also did not alter the pharmacokinetics of low dose MTX. However, some significant changes were observed in the pharmacokinetics of 7-hydroxymethotrexate: a 30% increase in dose normalized area under the serum concentration time curve (mean +/- SD) to 3102 +/- 1397 micrograms.h/l and a 16% decrease in renal clearance to 10.0 +/- 6.7 ml/h/kg. Eight patients had mild or moderate adverse events: most were considered unrelated to the study drug by the investigator. One patient did not complete the study because of moderate hypertension. No patient had clinically important abnormal laboratory test results. CONCLUSION: No clinically significant changes in MTX pharmacokinetics were detected in patients with RA when bromfenac was added to MTX therapy. Although 7-OHMTX concentrations were elevated, the changes were small and unlikely to be of clinical significance. MTX did not alter the pharmacokinetics of bromfenac.