RESUMEN
We studied the influence of diclofenac on the pharmacokinetics of cloxacillin in healthy volunteers, 60 years or older, as well as the possible effect of cloxacillin and diclofenac on urinary protein excretion. In a randomized, double-blind, cross-over study 15 subjects were given 1 g cloxacillin, and placebo or 75 mg diclofenac, as single intravenous doses. Plasma concentrations of cloxacillin were followed over 10.5 hr, and urine excretion of cloxacillin over 24 hr. The effect of the drugs on urinary excretion of protein indicators of glomerular (albumin, IgG) and tubular (protein HC) function was also studied. Total plasma clearance of cloxacillin was with placebo 219 +/- 51 (mean +/- S.D.), and with diclofenac 212 +/- 39 ml/min./1.73 m2 (ns); renal clearance was 97 +/- 21 and 96 +/- 24 ml/min./1.73 m2, respectively (ns). The terminal t1/2 of cloxacillin was 1.03 +/- 0.42 hr with placebo, and 1.12 +/- 0.37 with diclofenac (ns). The mean ratio of AUC0-infinity's (cloxacillin plus diclofenac/cloxacillin plus placebo) was 1.03 (90% CI: 0.99, 1.08). Urinary excretion of the proteins was low and was not increased by cloxacillin or diclofenac. In healthy volunteers, 60 years or older, diclofenac does not alter cloxacillin pharmacokinetics, and neither cloxacillin nor diclofenac in single intravenous doses cause renal dysfunction.
Asunto(s)
Antiinflamatorios no Esteroideos/farmacología , Cloxacilina/farmacocinética , Diclofenaco/farmacología , Penicilinas/farmacocinética , Anciano , Anciano de 80 o más Años , Albuminuria , Cloxacilina/sangre , Creatinina/orina , Estudios Cruzados , Método Doble Ciego , Femenino , Humanos , Riñón/efectos de los fármacos , Masculino , Persona de Mediana Edad , Penicilinas/sangre , Proteínas/efectos de los fármacos , Proteínas/metabolismo , Factores de TiempoRESUMEN
To examine the importance of preanalytical factors on the sample concentration of morphine, morphine-3-glucuronide and morphine-6-glucuronide, blood samples were drawn in sets of four from 21 patients who were given morphine due to chronic pain or as premedication prior to surgery. Three different sampling tubes, different combinations of incubation temperature and time, and different temperatures during centrifugation were used and compared to reference standard treatment of blood samples using analysis of variance. Blood samples taken in EDTA tubes produced significantly higher (4.8%) concentrations of morphine compared with the reference levels obtained in heparin glass tubes. Incubation of blood samples at body temperature resulted in significantly higher (4.4%) morphine levels compared to reference levels. None of the other conditions studied influenced the sample concentrations of morphine significantly. The levels of the metabolites were not significantly affected under any of the tested conditions. Even if the preanalytical factors investigated in this study had little influence on the results, a standardised procedure is recommended for handling of blood samples for analysis of morphine and its metabolites.
Asunto(s)
Análisis Químico de la Sangre , Morfina/sangre , Morfina/metabolismo , Análisis Químico de la Sangre/instrumentación , Análisis Químico de la Sangre/métodos , Conservación de la Sangre , Centrifugación , Relación Dosis-Respuesta a Droga , Humanos , Temperatura , Factores de TiempoRESUMEN
The gastrointestinal absorption of a series of vasopressin (VP) analogues with enhanced enzymatic stability was determined in chronically catheterized, conscious rats. The following peptides were used: [Mpa1,D-Arg8]vasopressin (dDAVP), [Mpa1,Asn4,D-Arg8]VP, [Mpa1,Val4,D-Arg8]VP, [Mpa1,(CH3)3Ala4,D-Arg8]VP, [Mpa1,Tyr(ethyl)2,D-Arg8]VP, and [Mpa1,D-Tyr(ethyl)2,Ile3,Val4,D-Arg8]VP. The peptides were administered by gavage feeding and blood samples were taken repeatedly for 3 h. In another series of experiments, plasma clearance rates (Clp) were determined using the constant infusion method. Plasma concentrations were measured by use of a cross-reacting dDAVP antiserum in a radioimmunoassay method. The bioavailability of all peptides was below 0.1%. The Clp values differed sevenfold; the lowest was for [Mpa1,D-Tyr(ethyl)2,Ile3,Val4,D-Arg8]VP and the highest was for [Mpa1,Asn4,D-Arg8]VP. With the exception of dDAVP the Clp values of the analogues showed an inverse relationship with hydrophilicity. Incubations in relatively concentrated intestinal contents for 1 h showed extensive degradation of the analogues except for [Mpa1,D-Tyr(ethyl)2,Ile3,Val4,D-Arg8]VP. It can be concluded that, in the rat, the bioavailability of dDAVP is lower than in other animal species and in man. Increased resistance to peptide degradation by gastrointestinal contents did not improve absorption. Therefore, the permeability properties of the intestinal mucosa are likely to be a more important factor affecting the gastrointestinal absorption of this group of peptides, although postabsorption events, like hepatic extraction, may also play a role.
Asunto(s)
Desamino Arginina Vasopresina/farmacocinética , Absorción Intestinal/fisiología , Secuencia de Aminoácidos , Animales , Desamino Arginina Vasopresina/análogos & derivados , Desamino Arginina Vasopresina/sangre , Femenino , Masculino , Tasa de Depuración Metabólica/fisiología , Datos de Secuencia Molecular , Ratas , Ratas Sprague-DawleyRESUMEN
The pharmacologic and pharmacokinetic properties were evaluated in a series of antiuterotonic oxytocin analogs, modified at positions 1, 2, 4, 8 and, in one case, position 9 of the oxytocin (OT) molecule. [Mpa1,D-Tyr2(Et),Val4,Orn8,desGly9]-OT, [Mpa1,Tyr2(Et),Val4,Orn8]-OT and [Mpa1,D-Tyr2,Val4,Orn8]-OT displayed similar plasma clearance rates (Clps) using the constant infusion method in rats. Two analogs, [Mpa1,D-Tyr2(Et),Val4,Orn8]-OT and, particularly, [Mpa1,D-Tyr2(Et),Thr4,Orn8]-OT, were cleared at significantly higher rates compared with the others. [Mpa1, D-Tyr2(Et), Val4, Orn8]-OT and [Mpa1, D-Tyr2(Et), Thr4, Orn8, desGly9]-OT were most potent in eliciting a short-term in vivo antiuterotonic effect, whereas the duration of effect was longest for [Mpa1, D-Tyr2, Val4, Orn8]-OT and [Mpa1, D-Tyr2(Et), Thr4, Orn8, desGly9]-OT. The Clp of [Mpa1, D-Tyr2, Val4, Orn8]-OT was similar regardless of the infusion rate. No relationship between antiuterotonic effect and Clp of the five peptides could be demonstrated, and no significant linear correlation between Clp and effect duration was found. The apparent volumes of distribution for the present analogs were 10-fold larger than the blood volume, a finding to be considered when measuring in vivo antagonistic activity. The 24-h urinary excretion ranged from 14.3 to 25.6% of the i.v. dose and was negatively correlated with peptide lipophilicity. It is concluded that, in addition to diverging pharmacologic properties, peptide analogs may differ markedly in kinetic parameters like Clp, volumes of distribution and urinary excretion despite minor molecular modifications.
Asunto(s)
Oxitocina/farmacología , Oxitocina/farmacocinética , Útero/efectos de los fármacos , Animales , Arginina Vasopresina/farmacocinética , Femenino , Semivida , Técnicas In Vitro , Masculino , Tasa de Depuración Metabólica , Oxitocina/análogos & derivados , Ratas , Ratas Sprague-Dawley , Relación Estructura-Actividad , Contracción Uterina/efectos de los fármacosRESUMEN
Atrial natriuretic peptide (ANP), a 28-residue peptide with cardiovascular and renal effects, is rapidly cleared from the circulation. Beside renal clearance, an extra-renal metabolism by the enzyme neutral endopeptidase-24.11 (NEP-24.11) has been proposed, since specific NEP-24.11-inhibitors increase endogenous plasma-ANP. NEP-24.11 is present in rat lung but its significance for ANP hydrolysis within the lung is unclear. The aim of this study was to investigate a possible degradation of rat ANP in a membrane preparation from rat lung. Hydrolysis products of ANP were separated by HPLC and further characterized by a pulmonary artery bioassay, by radioimmunoassay with different antisera, by peptide sequencing and by masspectrometry. Rat pulmonary membranes degraded ANP to one main metabolite lacking biological activity and with poor cross-reactivity to an antiserum recognising the central ring-structure of the peptide. Formation of the hydrolysis product was prevented by the NEP-24.11-inhibitor phosphoramidon (1 microM). Peptide sequencing of the metabolite revealed a cleavage between Cys7 and Phe8, which was confirmed by mass-spectrometry. The metabolite had an HPLC elution time identical to that of the product formed by purified porcine NEP-24.11. These findings suggest that ANP is metabolized and inactivated by endopeptidase-24.11 in rat lungs, the first organ exposed to ANP released from the heart.
Asunto(s)
Factor Natriurético Atrial/metabolismo , Pulmón/enzimología , Neprilisina/metabolismo , Secuencia de Aminoácidos , Animales , Factor Natriurético Atrial/antagonistas & inhibidores , Factor Natriurético Atrial/farmacología , Bioensayo , Cromatografía Líquida de Alta Presión , Glicopéptidos/farmacología , Hidrólisis , Técnicas In Vitro , Espectrometría de Masas , Datos de Secuencia Molecular , Arteria Pulmonar/efectos de los fármacos , Arteria Pulmonar/fisiología , Conejos , Radioinmunoensayo , Ratas , Ratas Sprague-DawleyRESUMEN
The biliary excretion of the vasopressin analogue 1-deamino-8-D-arginine vasopressin (dDAVP) was determined in the pig after three administration routes, intrajugular venous, intraportal venous and intraduodenal. In all cases the biliary excretion was less than 1% of the administered dose. The plasma/bile concentration ratio was less than 1:1. A significant first-pass effect was found when the liver was exposed to a high intraportal dose of dDAVP. Possible uptake and degradation/biotransformation was evaluated by incubating [3H]dDAVP with liver tissue slices showing that [3H]dDAVP was rapidly removed from the incubation medium. The following conclusions can be drawn from these experiments: 1) The intestinal mucosa constitutes the major barrier to intestinal absorption of dDAVP. 2) dDAVP is excreted in bile in small amounts. 3) Indirect evidence suggests that the dDAVP molecule is degraded/biotransformed in the liver at its C-terminus.
Asunto(s)
Bilis/metabolismo , Desamino Arginina Vasopresina/farmacocinética , Animales , Desamino Arginina Vasopresina/administración & dosificación , Duodeno , Técnicas In Vitro , Inyecciones , Inyecciones Intravenosas , Venas Yugulares , Hígado/metabolismo , Masculino , Vena Porta , PorcinosRESUMEN
The degradation of the vasopressin analogue dDAVP was studied by reversed phase high-performance liquid chromatography (HPLC) after incubations in pancreatic juice and intestinal mucosa homogenates. dDAVP remained stable in pancreatic juice for a period of 60 min. while the parent hormone arginine vasopressin (AVP) was completely degraded within 5 min. In intestinal mucosa homogenates dDAVP was degraded with half-lives of 9 min. (fast phase) and 161 min. (slow phase), about four times slower than AVP. By amino-acid analysis it was confirmed that the metabolite [Mpa1, Des-D-Arg8-Gly9 NH2]-vasopressin was gradually produced. No other breakdown products were observed. These findings may be of value for the further development of more stable peptide analogues which may be effective upon oral administration.
Asunto(s)
Desamino Arginina Vasopresina/metabolismo , Mucosa Intestinal/metabolismo , Jugo Pancreático/metabolismo , Animales , Arginina Vasopresina/metabolismo , Cromatografía Líquida de Alta Presión/métodos , Conejos , PorcinosRESUMEN
When thyroid hormone secretion in vivo was studied by the release of 125I from thyroid to blood after TSH in mice preloaded with the isotope, only 54.4 +/- 2.0% (+/- SE) of plasma 125I was butanol extractable, indicating low specificity for thyroid hormones. To improve specificity plasma 125I was bound to anti-T4 rabbit antibodies and precipitated with goat antirabbit serum. The intraassay coefficient of variation was 2.5%, and anti-T4 bound radioactivity correlated well with that extractable with butanol (r = 0.95, P less than 0.001). The effect of 40-1000 microU TSH intravenously in mice pretreated with 1 microgram T3 3 times during 2 days to suppress endogenous TSH was evaluated 2 hrs after the injection of TSH by 1) conventional radioimmunoassays of total and free stable T4 in plasma (no preloading with 125I), 2) total blood 125I in mice preloaded with 125I, and 3) anti-T4 bound 125I in plasma in mice preloaded with 125I. Stable T4 increased with TSH doses of 70 microU or higher, but the slope was low and the relation between error variance and slope did not permit a useful bioassay. Total blood 125I responded significantly to 40 microU TSH and showed a favourable relation between error variance and slope, but the specificity may be questioned. Anti-T4 bound 125I in plasma also responded significantly to 40 microU TSH and showed a very good relation between error variance and slope. The new technique of measuring anti-T4 bound radioactivity seems to combine the specificity of radioimmunoassay with a precision and sensitivity well comparable to that of the conventional radioiodine release technique.
Asunto(s)
Tiroxina/sangre , Animales , Butanoles , Femenino , Radioisótopos de Yodo , Ratones , Ratones Endogámicos , RadioinmunoensayoRESUMEN
We have studied the interaction of erythromycin with theophylline. We gave ten healthy volunteers theophylline as an intravenous loading dose (5 mg X kg-1) over 1 h, followed by a maintenance infusion (0.5 mg X kg-1 X h-1) for 5 h. A second infusion of theophylline was given after 9 days of treatment with 1 g erythromycin base daily, and the concentrations of theophylline were determined during the infusion periods. The concentrations of erythromycin were measured for 8 h, after one week of treatment, and also after the last erythromycin dose, simultaneously with the second theophylline infusion. Concentrations within the therapeutic range were obtained with both drugs. A significant increase in both AUC and mean plasma concentrations of theophylline was seen during erythromycin treatment. The plasma clearance of theophylline was reduced in 9 of the 10 subjects. Renal clearance increased correspondingly, but the change was not statistically significant. Serum concentrations of erythromycin fell significantly, by more than 30%, with concurrent theophylline medication. We conclude that an interaction between theophylline and erythromycin, affecting both drugs, can be shown with concentrations of the drugs within the therapeutic range.
Asunto(s)
Eritromicina/administración & dosificación , Teofilina/administración & dosificación , Adulto , Interacciones Farmacológicas , Eritromicina/sangre , Femenino , Humanos , Infusiones Intravenosas , Inyecciones Intravenosas , Riñón/metabolismo , Cinética , Masculino , Tasa de Depuración Metabólica , Persona de Mediana Edad , Teofilina/sangreRESUMEN
The possibility that norepinephrine stimulates basal but inhibits TSH-induced thyroid hormone secretion was explored by the use of in vivo and in vitro techniques. Basal thyroid hormone secretion was defined as TSH-independent secretion, experimentally obtained in vivo by pretreatment with T4 or T3. In mice pretreated with 125I and T4, norepinephrine enhanced baseline blood radioiodine levels, but in control mice, norepinephrine failed to alter basal plasma T4 levels. To study whether the stimulated release of radioiodine truly reflects stimulated thyroid hormone secretion, the nature of the radioiodine that was elevated by norepinephrine after 125I pretreatment was investigated. In controls, the fraction of radioiodine that was bound to thyroid hormones was 24.6 +/- 0.8% (+/- SE) of the total radioiodine. This figure increased to 31.9 +/- 1.1% (P less than 0.001) in response to norepinephrine. Further, by a technique of binding the released radioiodine to specific anti-T4 antiserum, norepinephrine was found to increase secretion of radiolabeled T4 by 22 +/- 2% (P less than 0.001). Thus, it is concluded that norepinephrine stimulates basal thyroid hormone secretion in vivo, and that its failure to alter plasma T4 levels is due to the low sensitivity of the technique. In contrast, it was found that norepinephrine inhibits the thyroid stimulatory effect of TSH in vivo. Under in vitro conditions, norepinephrine was found to increase the release of radioiodine that was bound to thyroid hormones from thyroid glands of mice that had been pretreated with 125I. However, norepinephrine failed to alter the baseline thyroid content of cAMP, yet it inhibited the cAMP-accumulating effect of TSH. In conclusion, the present study demonstrates that norepinephrine exerts a dual effect on thyroid hormone secretion in the mouse; it stimulates basal but inhibits TSH-induced thyroid hormone secretion.