RESUMEN
We investigate biodistribution of gallium-labeled hydroxyethylidenediphosphonic acid (68Ga-HEDP) and diethylenetriaminepentakis(methylenephosphonic acid) (68Ga-DTPMP) in intact Wistar rats. It was shown that 68Ga-DTPMP accumulated mainly in the bone tissue providing high femur/blood and femur/muscle ratios and had high stability in vivo. In contrast, 68Ga-HEDP was characterized by low stability and high uptake of radioactivity in blood throughout the study. So 68Ga-DTPMP can be considered as a new prospective radiotracer in oncology for imaging bone tissue metastasis by positron emission tomography.
Asunto(s)
Ácido Etidrónico/farmacocinética , Fémur/diagnóstico por imagen , Radioisótopos de Galio/farmacocinética , Ácidos Fosforosos/farmacocinética , Radiofármacos/farmacocinética , Animales , Disponibilidad Biológica , Ácido Etidrónico/sangre , Femenino , Radioisótopos de Galio/sangre , Especificidad de Órganos , Ácidos Fosforosos/sangre , Tomografía de Emisión de Positrones/métodos , Radiofármacos/sangre , Ratas , Ratas Wistar , Distribución TisularRESUMEN
Risedronate is widely used clinically to treat osteoporosis, Paget's disease, hypercalcemia, bone metastasis, and multiple myeloma. However, its oral efficacy is restricted due to its low bioavailability and severe gastrointestinal adverse effects. This study was designed to evaluate the effect of deoxycholic acid derivatives on the permeability and oral bioavailability of risedronate by increasing its lipophilicity and affinity to bile transporters. We synthesized two bile acid derivatives, N(α)-deoxycholyl-L-lysyl-methylester (DCK) and N(α)-deoxycholyl-L-lysyl-hydroxide (HDCK) as oral absorption enhancers. After ionic complex formation with the bile acid derivatives, the complexes were characterized by powder X-ray diffraction. Their artificial membrane permeabilities and bioavailabilities in rats were investigated in comparison with pure risedronate. Complex formation with DCK or HDCK demonstrated that risedronate existed in an amorphous form in the complex. A physical complex of risedronate with DCK enhanced the apparent membrane permeability of risedronate significantly but pure risedronate was not permeable. An in vivo study revealed that the C max and AUClast of risedronate/DCK (1:2) complex were 1.92- and 2.64-fold higher than those of pure risedronate, respectively. Thus, the risedronate/DCK complex can improve the oral absorption of risedronate and patient compliance by reducing dose frequency and adverse reactions.
Asunto(s)
Conservadores de la Densidad Ósea/farmacocinética , Ácido Desoxicólico/análogos & derivados , Portadores de Fármacos/química , Ácido Etidrónico/análogos & derivados , Absorción Intestinal/efectos de los fármacos , Animales , Disponibilidad Biológica , Conservadores de la Densidad Ósea/administración & dosificación , Conservadores de la Densidad Ósea/sangre , Conservadores de la Densidad Ósea/química , Proteínas Portadoras/metabolismo , Ácido Desoxicólico/química , Relación Dosis-Respuesta a Droga , Ácido Etidrónico/administración & dosificación , Ácido Etidrónico/sangre , Ácido Etidrónico/química , Ácido Etidrónico/farmacocinética , Iones , Masculino , Glicoproteínas de Membrana/metabolismo , Membranas Artificiales , Estructura Molecular , Permeabilidad , Ratas Sprague-Dawley , Ácido Risedrónico , Solubilidad , Propiedades de Superficie , Factores de TiempoRESUMEN
A method for the simultaneous determination of alendronate, pamidronate, ibandronate and risedronate using ion chromatography with integrated pulsed amperometric detection (IPAD) has been developed. The electrochemical behavior showed the catalytic currents of these bisphosphonates are based on the oxidation of amines in their structures. Because the bisphosphonates are polar compounds and present as anions under alkaline condition, therefore, they can be separated by anion exchange chromatography. A Dionex AS18 column (250 mm x 2 mm) and an AG18 column (50 mm x 2 mm) and 24 mmol/L NaOH solution were used for the separation. Multi-step potential waveform parameters were optimized to maximize the signal-to-noise ratio (S/N), which exhibited adsorption/desorption catalytic features at the gold electrode surface in alkaline solution. Utilizing the optimized waveform, the method showed good linearity (r2 = 0.9972 - 0.9995), satisfactory repeatability (relative standard deviations (RSDs) of the peak areas in the range of 0.84% - 1.37%) and sufficient sensitivity (limits of detection of 0.061 - 0.18 microg/mL) for the identification of the four bisphosphonates. The recoveries were 80.81% - 97.32% with the RSDs of 1.46% - 3.02%. It is demonstrated that this method is a rapid and simple one for the determination of the four bisphosphonates in human plasma.
Asunto(s)
Alendronato/sangre , Cromatografía por Intercambio Iónico , Difosfonatos/sangre , Ácido Etidrónico/análogos & derivados , Técnicas Electroquímicas , Ácido Etidrónico/sangre , Humanos , Ácido Ibandrónico , Pamidronato , Ácido RisedrónicoRESUMEN
Risedronate is a commonly prescribed bisphosphonate for the treatment of bone disorders. Due to its high polarity and low oral bioavailability, low concentrations of risedronate are expected in human plasma and therefore a sensitive assay is required to serve in pharmacokinetic studies. Here, we describe the development and validation of an LC-MS/MS assay for the measurement of risedronate concentrations in human plasma. Risedronate and the internal standard, risedronate-d4, were derivatized on an anion exchange solid-phase extraction cartridge. Trimethylsilyl-diazomethane which is a thermally stable and relatively non-toxic derivatization agent was used to methylate the risedronate phosphonic acid groups and decrease analyte polarity. Following extraction, the analytes were separated on a Phenomenex Gemini C18 column (150 mm×2.0 mm, 5 µm), using a gradient of ammonium acetate 10 mM and acetonitrile with a flow rate of 300 µL/min. The assay calibration range was 0.2-25 ng/mL. The calibration curve of risedronate standards spiked in six individual plasma samples was linear (r²=0.9998). Accuracy (percent deviation from nominal) and precision (percent coefficient of variation) at concentrations 0.5, 5 and 20 ng/mL, and at the lower limit of quantification (LLOQ) of 0.2 ng/mL were excellent at <6%. Mean recovery was 54% for risedronate and 51% for the internal standard. Risedronate was stable in human plasma samples for at least 5 h at room temperature, 101 days frozen at -80°C, 72 h in an autosampler at 10°C, and for three freeze/thaw cycles. The validated assay method successfully quantified the concentrations of risedronate in plasma samples from informed consenting healthy volunteers administered a single 35 mg risedronate tablet.
Asunto(s)
Cromatografía Líquida de Alta Presión/métodos , Ácido Etidrónico/análogos & derivados , Extracción en Fase Sólida/métodos , Espectrometría de Masas en Tándem/métodos , Acetaminofén/sangre , Acetaminofén/aislamiento & purificación , Diazometano/análogos & derivados , Estabilidad de Medicamentos , Ácido Etidrónico/sangre , Ácido Etidrónico/química , Ácido Etidrónico/farmacocinética , Hemólisis , Humanos , Ibuprofeno/sangre , Ibuprofeno/aislamiento & purificación , Análisis de Regresión , Reproducibilidad de los Resultados , Ácido Risedrónico , Sensibilidad y Especificidad , Compuestos de TrimetilsililoRESUMEN
Food-drug interactions may reduce the bioavailability of drugs taken after meals (negative food effect). In order to develop pharmaceutical technologies that overcome this problem, the effect of administration site within the gastrointestinal tract on the bioavailability of several model drugs was examined in rats. Bioavailability after oral administration to fed animals was one-fifth to one-tenth of that in the fasted animals because of interactions between drugs and large amounts of food components remaining in the stomach. This strong negative food effect was reduced when drugs were administered directly into any site of the small intestine. Bioavailability was maximized when the drug administration site was the middle small intestine. On the other hand, intracolonic administration did not result in the reduction of the negative food effect. Site-specific drug delivery to the middle small intestine could be a useful approach for reducing the negative food effect on drug absorption with maximized bioavailability.
Asunto(s)
Ácido Etidrónico/análogos & derivados , Interacciones Alimento-Droga , Absorción Intestinal , Naftalenos/farmacocinética , Propionatos/farmacocinética , Trientina/farmacocinética , Animales , Disponibilidad Biológica , Ácido Etidrónico/administración & dosificación , Ácido Etidrónico/sangre , Ácido Etidrónico/química , Ácido Etidrónico/farmacocinética , Tránsito Gastrointestinal , Infusiones Intravenosas , Mucosa Intestinal/metabolismo , Masculino , Estructura Molecular , Naftalenos/administración & dosificación , Naftalenos/sangre , Naftalenos/química , Propionatos/administración & dosificación , Propionatos/sangre , Propionatos/química , Ratas , Ratas Wistar , Ácido Risedrónico , Trientina/administración & dosificación , Trientina/sangre , Trientina/químicaRESUMEN
UNLABELLED: 188Re-Hydroxyethylidene diphosphonate ((188)Re-HEDP) was used in previous studies for the palliative treatment of metastatic bone pain. However, the kinetic and radiation-absorbed doses have not been well documented. Therefore, the aim of this study was to gather dosimetric data for (188)Re-HEDP. METHODS: Thirteen prostate cancer patients with skeletal involvement were treated with 2,700-3,459 MBq (mean dose, 3,120 MBq) (188)Re-HEDP. Patients underwent whole-body scans 3, 20, and 28 h after therapy. The effective half-life, residence time, and radiation-absorbed dose values were calculated for the whole body, bone marrow, kidneys, and bladder as well as for 29 bone metastases. The urinary excretion rate was determined in 6 urine samples of each patient collected over 48 h at 8-h intervals beginning immediately after the administration of (188)Re-HEDP. After injection of (188)Re-HEDP, blood samples were taken weekly for 6 wk, and platelet and leukocyte counts were performed. RESULTS: The mean effective half-life was 15.9 +/- 3.5 h in bone metastases, 10.9 +/- 2.1 h in the bone marrow, 11.6 +/- 2.1 h in the whole body, 12.7 +/- 2.2 h in the kidneys, and 7.7 +/- 3.4 h in the bladder. The following radiation-absorbed doses were calculated: 3.83 +/- 2.01 mGy/MBq for bone metastases, 0.61 +/- 0.21 mGy/MBq for the bone marrow, 0.07 +/- 0.02 mGy/MBq for the whole body, 0.71 +/- 0.22 mGy/MBq for the kidneys, and 0.99 +/- 0.18 mGy/MBq for the bladder. (188)Re-HEDP showed a rapid urinary excretion within the first 8 h after therapy, with 41% of the (188)Re-HEDP administered being excreted. Forty-eight hours after therapy, the excretion rate was 60% +/- 12%. Only 1 patient showed a decrease of platelet count below 100 x 10(9) counts/L. None of the patients presented with a decrease of leukocyte count below 3.0 x 10(9) counts/L. CONCLUSION: (188)Re-HEDP is an effective radiopharmaceutical used in the palliative treatment of metastatic bone pain. The radiation-absorbed dose is acceptable for bone pain palliation with low doses for the normal bone marrow and the whole body.
Asunto(s)
Neoplasias Óseas/metabolismo , Neoplasias Óseas/secundario , Ácido Etidrónico/farmacocinética , Neoplasias de la Próstata/patología , Renio/farmacocinética , Recuento Corporal Total/métodos , Anciano , Anciano de 80 o más Años , Carga Corporal (Radioterapia) , Médula Ósea/metabolismo , Ácido Etidrónico/administración & dosificación , Ácido Etidrónico/sangre , Ácido Etidrónico/orina , Semivida , Humanos , Inyecciones Intravenosas , Riñón/metabolismo , Masculino , Tasa de Depuración Metabólica , Persona de Mediana Edad , Compuestos Organometálicos , Dosis de Radiación , Radiometría/métodos , Renio/administración & dosificación , Renio/sangre , Renio/orina , Distribución Tisular , Vejiga Urinaria/metabolismoRESUMEN
The synthesis and preliminary evaluation of novel alkyl and acyloxymethyl esters of etidronic acid as etidronate prodrugs is reported. Tetramethyl ester of etidronic acid was found be isomerized at pH 7.4 and P-C-P bridge was rearranged to P-C-O-P. This unwanted process was prevented via acylation of the bridging carbon's alcohol group. Acylation showed to be stable if one or more phosphonic OH- groups were substituted. However, when none of the phosphonic OH- groups were substituted, the acylation was chemically hydrolysed and the parent drug was released. This finding was successfully applied in the design of tetrapivaloyloxymethyl ester of acetylated etidronic acid which released etidronic acid via enzymatic (first step) and chemical (second step) hydrolysis in liver homogenate. However, the corresponding tri-substituted pivaloyloxymethyl ester having adequate water-solubility and lipophilicity (logP(app) 0.6 at pH 7.4), is probably the most potential prodrug candidate reported to enhance the oral bioavailability of etidronate.
Asunto(s)
Ácido Etidrónico/síntesis química , Profármacos/síntesis química , Animales , Difosfonatos/sangre , Difosfonatos/síntesis química , Difosfonatos/farmacocinética , Ácido Etidrónico/sangre , Ácido Etidrónico/farmacocinética , Humanos , Hígado/metabolismo , Profármacos/farmacocinética , ConejosRESUMEN
The aim of the study was to find out whether bisphosphonates transform into insoluble material in human blood and serum in vitro. Samples of fresh blood and serum were incubated with various concentrations of 14C-labelled clodronate, etidronate, pamidronate and tiludronate for 2 h and 8 h at 37 degrees C. The presence of unfiltrable material in the plasma separated from the blood, and in the serum were studied with 1) 100, 300 and 1,000 kd (kilo Daltons) filter tubes centrifuged at 3,000 g for 60 min, and 2) high-speed centrifugation at 13,000 g for 30 min. The radioactivities in the ultrafiltrates and supernatants were compared to those in the native plasma or serum. All bisphosphonates transformed into unfiltrable material, which was separated from the samples with the 100 and 300 kd filters but not with the 1,000 kd filter. The material was not sedimented with the high-speed centrifugation. The lengthening of the incubation time from 2 h to 8 h increased the unfiltrable fraction, which generally was dependent on the drug concentration in the blood, too. However, the fraction of the unfiltrable material did not seem to increase with time when the drug was incubated with serum instead of blood. Since drug binding to plasma proteins is generally a very rapid process, some factors other than proteins only, e.g. cations or cation residues, present in the blood but not in the serum, should be involved in transforming of bisphosphonates into insoluble material in the blood.
Asunto(s)
Difosfonatos/sangre , Analgésicos no Narcóticos/sangre , Analgésicos no Narcóticos/farmacocinética , Antineoplásicos/sangre , Antineoplásicos/farmacocinética , Biotransformación , Radioisótopos de Carbono , Ácido Clodrónico/sangre , Ácido Clodrónico/farmacocinética , Difosfonatos/farmacocinética , Ácido Etidrónico/sangre , Ácido Etidrónico/farmacocinética , Femenino , Humanos , Técnicas In Vitro , Masculino , PamidronatoRESUMEN
PURPOSE: Two studies were conducted to compare the absorption of risedronate administered as a solution to three different gastrointestinal sites (study A) and to determine the extent of absorption of risedronate solution administered by rapid and slow infusion to the second part of the duodenum (study B). METHODS: Each study was designed as a single-dose, crossover (three periods, study A; two periods, study B) trial in healthy male subjects, with a 14-day washout period between dosing. Subjects fasted overnight before drug administration and for 4 hours after drug administration. In study A, a risedronate solution of 40 mg in 30 mL of water was administered directly into the stomach, the second part of the duodenum, or the terminal ileum over 1 minute via a nasoenteral tube in a three-period crossover design. In study B, a risedronate solution of 40 mg in 30 mL of water was administered directly into the second part of the duodenum over 1 minute and over 1 hour in a randomized, two-period crossover design. Serum and urine samples were obtained for 48 hours after dosing for risedronate analysis. RESULTS: Eight subjects completed each study. No statistically significant site-specific differences in any pharmacokinetic parameter were observed (study A). Based on the area under the serum concentration-time profile and the amount of drug excreted in the urine unchanged, the extent of risedronate absorption did not differ significantly following a rapid or a slow infusion (study B). Only minor symptomatic complaints were reported by subjects, such as headaches and body aches. CONCLUSIONS: These studies indicate that the rate and extent of risedronate absorption are independent of the site of administration along the gastrointestinal tract, and that the extent of absorption is not affected by the rate of administration.
Asunto(s)
Bloqueadores de los Canales de Calcio/farmacocinética , Ácido Etidrónico/análogos & derivados , Absorción Intestinal , Área Bajo la Curva , Bloqueadores de los Canales de Calcio/administración & dosificación , Bloqueadores de los Canales de Calcio/efectos adversos , Bloqueadores de los Canales de Calcio/sangre , Formas de Dosificación , Duodeno/metabolismo , Ácido Etidrónico/administración & dosificación , Ácido Etidrónico/efectos adversos , Ácido Etidrónico/sangre , Ácido Etidrónico/farmacocinética , Mucosa Gástrica/metabolismo , Humanos , Íleon/metabolismo , Masculino , Ácido RisedrónicoRESUMEN
Clodronate, etidronate, and pamidronate are highly hydrophilic bisphosphonates used for the treatment of bone resorption and hypercalcemia. They also inhibit the development of experimental atherosclerosis without influencing serum cholesterol level. We studied the distribution and the accumulation of the carbon 14-labeled bisphosphonates in the aorta and some other tissues of healthy rabbits and in rabbits with diet-induced atherosclerosis. After intravenous injection, clodronate and pamidronate disappeared from circulation more slowly in atherosclerotic than in healthy rabbits, and the drug concentrations in the peripheral tissues were generally lower in atherosclerotic than in healthy animals. At 24 hours after dosing in healthy rabbits, the mean aorta to plasma ratios of clodronate, etidronate, and pamidronate were, respectively, 2.4 to 2.8, 2.4 to 4.0, and 8.6 to 10. The corresponding ratios in atherosclerotic rabbits were, respectively, 13 to 22, 1.5 to 2.2, and 13 to 24. Seven days after the injection the mean clodronate concentration in the aortas of healthy rabbits was 0.5% to 0.9% of the dose given per tissue weight, and the concentration in those of atherosclerotic animals was 3.8% to 5.2% of the dose given per tissue weight. The results indicate that hydrophilic bisphosphonates, known to inhibit the atherogenesis, concentrate markedly in the aortas of healthy and atherosclerotic rabbits.
Asunto(s)
Aorta/metabolismo , Arteriosclerosis/metabolismo , Ácido Clodrónico/farmacocinética , Difosfonatos/farmacocinética , Ácido Etidrónico/farmacocinética , Músculo Liso Vascular/metabolismo , Análisis de Varianza , Animales , Válvula Aórtica/metabolismo , Radioisótopos de Carbono , Ácido Clodrónico/sangre , Difosfonatos/sangre , Ácido Etidrónico/sangre , Masculino , Válvula Mitral/metabolismo , Pamidronato , Conejos , Valores de Referencia , Factores de Tiempo , Distribución TisularRESUMEN
The acute intravenous toxicity of disodium dihydrogen (1-hydroxyethylidene)diphosphonate (etidronate disodium; I) and the mechanism of this toxic response have been investigated in 40 beagle dogs. The intravenous toxicity of I is dependent on the total dose administered and the length of the infusion interval. The toxicity of I is directly related to the ability of the drug to bind or complex with the circulating calcium in the blood. Maximum depressions in ionized calcium coincide in time with peak blood levels of I, and at lethal doses electrocardiographic changes indicative of hypocalcemia are observed. For a 2-min infusion of 2 mg of I/kg, no effect is observed on ionized calcium levels, and the electrocardiogram remains normal. At doses of 16 and 32 mg/kg, coincident with an immediate fall in ionized calcium levels, there is a transient rise in total calcium and a fall in phosphorus levels. The ionized calcium level rises, and total calcium level falls and stabilizes at baseline levels within 30 min after the infusion. However, the phosphorus level rises and exceeds the baseline value, reaching 3-4 times normal by 72 h after the infusion. With proven lethal doses of I (60 mg/kg infused over 2 min) and the simultaneous infusion of an ionized calcium salt such as calcium gluconate (20 mg of Ca2+/kg), electrocardiograms remain normal and death is prevented. Thus, an effective antidote in the event of an overdose or too rapid an infusion of I can be employed to prevent acute toxic effects.
Asunto(s)
Ácido Etidrónico/toxicidad , Anestesia , Animales , Calcio/sangre , Gluconato de Calcio/farmacología , Difosfonatos/sangre , Perros , Electrocardiografía , Ácido Etidrónico/administración & dosificación , Ácido Etidrónico/sangre , Femenino , Infusiones Parenterales , Masculino , Fósforo/sangre , Factores de TiempoAsunto(s)
Cromatografía en Gel , Ácido Clodrónico , Difosfonatos , Ácido Etidrónico , Ultrafiltración , Proteínas Sanguíneas/metabolismo , Tampones (Química) , Calcio/farmacología , Ácido Clodrónico/sangre , Difosfatos/sangre , Difosfonatos/sangre , Ácido Etidrónico/sangre , Humanos , Concentración de Iones de Hidrógeno , Unión ProteicaRESUMEN
The biologic and imaging characteristics of Tc-99m MDP and Tc-99m HEDP were compared in ten patients: Tc-99m MDP exhibited lower blood activity, lower 4-hr urinary excretion, and higher normal bone-to-background ratio. Assessment of overall image quality also favored Tc-99m MDP, indicating that the normal skeleton is better visualized with this agent. The total number of lesions seen (18) was not large enough to allow critical comparison of relative lesion-detecting efficacy. However, discrepancies between the two agents were observed, suggesting additional evaluation of the relative lesion-detecting efficacy of these two bone agents.
Asunto(s)
Enfermedades Óseas/diagnóstico por imagen , Difosfonatos , Ácido Etidrónico , Tecnecio , Adulto , Anciano , Neoplasias Óseas/diagnóstico por imagen , Difosfonatos/sangre , Difosfonatos/orina , Ácido Etidrónico/sangre , Ácido Etidrónico/orina , Femenino , Humanos , Masculino , Persona de Mediana Edad , Cintigrafía , Juego de Reactivos para Diagnóstico , Medronato de Tecnecio Tc 99mRESUMEN
The transcapillary extraction of diphosphonate, as [99mTc]EHDP, a substance used in bone scanning and for management of certain metabolic bone diseases, has been examined. The maximum instantaneous extraction for [99mTc]EHDP was 0.27 +/- 0.05 (mean +/- SD, N = 10) and the net extraction at 5 min was 0.18 +/- 0.05 (N = 10). The permeability ratio of [99mTc]EHDP to the freely diffusible compound, sucrose, using the formula PS = -Fs loge (1 - Emax), was 0.71. This is similar to the ratio of diffusion coefficients of EHDP to sucrose, which is estimated to be 0.78. These results suggest that the mechanism by which [99mTc]EHDP passes through the capillaries in bone is passive diffusion. Tissue level estimations of EHDP confirm a rapid blood clearance associated with an increase in the rate of urinary excretion; the level of [99mTc]EHDP in bone, however, remains constant. The fractional excretion of [99mTc]EHDP was 27.3 +/- 2.0% in control dogs and was unchanged by thyroparathyroidectomy and subsequent infusion of parathyroid hormone.
Asunto(s)
Enfermedades Óseas/diagnóstico , Ácido Etidrónico , Cintigrafía , Tecnecio , Animales , Huesos/irrigación sanguínea , Capilares , Permeabilidad Capilar , Difusión , Perros , Ácido Etidrónico/sangre , Ácido Etidrónico/metabolismo , Riñón/metabolismo , Masculino , Matemática , Glándulas Paratiroides/cirugía , Hormona Paratiroidea/farmacología , Radioisótopos de Estroncio/metabolismo , TiroidectomíaRESUMEN
A technique has been developed to measure the diphosphonate ethane-1-hydroxy-1, 1-diphosphonate (EHDP) quantitatively in 5 ml of urine or 2 ml of plasma. The procedure is based on a coprecipitation of EHDP with calcium phosphate, elimination of inorganic phosphate as an insoluble triethylamine-phosphomolybdate complex, decomposition of the P-C-P bond with ultraviolet light and spectrophotometric determination of the inorganic phosphate released. A trace amount of [14C] EHDP is used to correct for losses. The method appears specific for the diphosphonate, exhibits quantitative recoveries, and has a mean coefficient of variation of 3.7% for urine and 7.3% for plasma. The limit of detection is in the order of 2.5 mumol/1 in 5 ml urine and 0.5 mumol/1 in 2 ml of plasma.