RESUMEN
Gastrointestinal absorption of bisphosphonates is highly variable from individual to individual (between-subject variation) and from day to day (within-subject variation), a fact that creates problems both in research and in clinical use of these drugs. We conducted a randomized, two-period cross-over pharmacokinetic (phase I) study to assess the relative bioavailability of two different clodronate preparations: an 800 mg tablet and a 400 mg capsule. Urinary excretion of clodronate correlates with gastrointestinal absorption. To minimize the confounding effect of the high variability of gastrointestinal absorption, we chose as the primary parameter the cumulative amount of clodronate excreted into urine (A(e0-t)) during 9 days (7 days of treatment, 2 days of follow-up). The 90% confidence interval calculated for the population medians of A(e0-t) was 0.83-1.09, well within the 90% confidence interval stipulated for bioequivalence for the area under the curve values (0.80-1.25). This new procedure for pooling urinary excretion data offered a clear advantage over previous methods, and thus could presumably be used to study other drugs as well that are not metabolized and may show highly variable gastrointestinal absorption.
Asunto(s)
Analgésicos no Narcóticos/farmacocinética , Ácido Clodrónico/farmacocinética , Administración Oral , Adolescente , Adulto , Analgésicos no Narcóticos/administración & dosificación , Analgésicos no Narcóticos/farmacología , Analgésicos no Narcóticos/orina , Análisis de Varianza , Área Bajo la Curva , Disponibilidad Biológica , Cápsulas/metabolismo , Cápsulas/normas , Ácido Clodrónico/administración & dosificación , Ácido Clodrónico/farmacología , Ácido Clodrónico/orina , Estudios Cruzados , Femenino , Estudios de Seguimiento , Semivida , Humanos , Absorción Intestinal/efectos de los fármacos , Absorción Intestinal/fisiología , Masculino , Estándares de Referencia , Reproducibilidad de los Resultados , Programas Informáticos , Comprimidos/metabolismo , Comprimidos/normas , Equivalencia TerapéuticaRESUMEN
Estramustine phosphate is generally used as a second-line treatment in patients with advanced prostate cancer. The bone metastases due to the cancer are often treated simultaneously with clodronate in order to relieve the bone pain. Therefore, the interaction of clodronate (800 mg orally four times daily) and estramustine phosphate (280 mg orally twice daily) on their bioavailability was studied in twelve patients with prostate carcinoma and bone metastases. The drugs were first given separately, each to six patients, for five days, and then concomitantly for the same period. The bioavailabilities of the drugs were calculated on the last day of each treatment period. When clodronate was given alone, its concentrations in serum and AUC for one dose interval (6 hr) did not differ from those obtained with the drug given concomitantly with estramustine phosphate, nor did the combination of estramustine phosphate change the excretion of clodronate in urine. The serum concentrations of estramustine phosphate were elevated by about 80% when the drug was given together with clodronate. The AUC for one dose interval (12 hr) was also significantly higher for estramustine phosphate with clodronate than without clodronate. The urinary excretion of estrone, a major metabolite of estramustine phosphate, was also significantly higher after the admission with clodronate. The results suggest that clodronate increases the oral bioavailability of estramustine phosphate.
Asunto(s)
Analgésicos no Narcóticos/uso terapéutico , Antineoplásicos Hormonales/uso terapéutico , Ácido Clodrónico/uso terapéutico , Estramustina/uso terapéutico , Neoplasias de la Próstata/tratamiento farmacológico , Administración Oral , Anciano , Anciano de 80 o más Años , Analgésicos no Narcóticos/administración & dosificación , Analgésicos no Narcóticos/farmacocinética , Análisis de Varianza , Antineoplásicos Hormonales/administración & dosificación , Antineoplásicos Hormonales/farmacocinética , Disponibilidad Biológica , Neoplasias Óseas/tratamiento farmacológico , Neoplasias Óseas/secundario , Carcinoma/tratamiento farmacológico , Ácido Clodrónico/administración & dosificación , Ácido Clodrónico/farmacocinética , Ácido Clodrónico/orina , Sinergismo Farmacológico , Quimioterapia Combinada , Estramustina/administración & dosificación , Estramustina/farmacocinética , Estramustina/orina , Cromatografía de Gases y Espectrometría de Masas , Humanos , Masculino , Persona de Mediana Edad , Dolor/tratamiento farmacológicoRESUMEN
OBJECTIVE: The effect of food on the bioavailability of oxybutynin was assessed in a randomised cross-over study in 23 healthy volunteers. A single oral 10 mg dose of a controlled release oxybutynin tablet was administered after a high fat breakfast and to fasting subjects. The AUC, Cmax, tmax, t1/2 and MRT of oxybutynin and its active metabolite N-desethyloxybutynin were determined. RESULTS: Breakfast did not change the AUC of oxybutynin but increased the AUC of N-desethyloxybutynin by about 20%. The Cmax of oxybutynin and N-desethyloxybutynin were two-fold higher when the drug was administered after breakfast compared to the fasting state. CONCLUSION: Breakfast significantly reduced the MRT of oxybutynin and N-desethyloxybutynin.
Asunto(s)
Antagonistas Colinérgicos/farmacocinética , Interacciones Alimento-Droga , Alimentos , Ácidos Mandélicos/farmacocinética , Adulto , Área Bajo la Curva , Disponibilidad Biológica , Estudios Cruzados , Preparaciones de Acción Retardada , Femenino , Semivida , Humanos , MasculinoRESUMEN
The pharmacokinetic parameters describing the fate of one intravenous clodronate (disodium dichloromethane diphosphonate) dose was studied in 24 normal subjects and in 24 patients with different degrees of renal insufficiency. The aim of the study was to derive data for adjustment of dosage in relation to renal function. Disodium clodronate in serum and urine samples was analyzed by capillary gas chromatography with mass-selective detection. The renal clearance (CLR) of clodronate was highly dependent on renal function and declined successively with declining glomerular filtration rate (GFR). Plasma clearance (CLP) declined, too, but to a lesser degree than CLR. The impairment of renal function resulted in decreased cumulative urinary elimination of clodronate and increased total areas under the serum concentration-time curve (AUC0-infinity). Hence, as the renal elimination of clodronate diminishes with decreasing GFR, there is a related retention of the substance. As a result of the present study, the following dosages are recommended: creatinine clearance (CLCr) from 50 to 80 ml/minute, 75-100% of normal dose; CLCr 12-50 ml/minute, 50-75% of normal dose; and ClCr < 12 ml/minute, 50% of normal dose. The results must be interpreted with caution in patients with malignancy and severe skeletal disease, in whom the nonrenal clearance may vary markedly.