RESUMEN
Goserelin is a synthetic decapeptide analogue of luteinising hormone-releasing hormone (LHRH). For experimental purposes it has been administered subcutaneously as an aqueous solution, but for therapeutic use it is formulated as subcutaneous depots releasing goserelin over periods of 1 (3.6 mg) or 3 (10.8 mg) months. Pharmacokinetic data have been generated using a specific radioimmunoassay. When administered as a solution, goserelin is rapidly absorbed and eliminated from serum with a mean elimination half-life (t1/2beta) of 4.2 hours in males and 2.3 hours in females. The shapes of the observed serum goserelin profiles following administration of the depots are primarily determined by the rate of goserelin release from the biodegradable lactide-glycolide copolymer matrix over periods of 1 or 3 months. There is no clinically relevant accumulation of goserelin during multiple administration of these depots. Goserelin is extensively metabolised prior to excretion. Its pharmacokinetics are unaffected by hepatic impairment, but the mean t1/2beta increases to 12.1 hours in patients with severe renal impairment. This suggests that the total renal clearance (renal metabolism and unchanged drug) is decreased in patients with renal dysfunction. It is unnecessary to adjust the dose or administration interval when the depot formulations are administered to elderly patients or to those with impaired renal or hepatic function. Administration of a goserelin 3.6 mg or 10.8 mg depot results in an initial increase of luteinising hormone (LH) levels and in increases of serum testosterone or oestradiol levels in males and females, respectively. This is followed by a decrease in serum LH levels and suppression of testosterone or oestradiol to within the castrate or menopausal range, respectively. Subsequently, throughout treatment with goserelin depots, serum testosterone or oestradiol levels remain suppressed. Clinical outcomes following treatment of patients with prostate cancer, breast cancer and benign gynaecological conditions with goserelin are described briefly.
Asunto(s)
Antineoplásicos Hormonales/farmacocinética , Goserelina/farmacocinética , Anciano , Antineoplásicos Hormonales/administración & dosificación , Antineoplásicos Hormonales/uso terapéutico , Goserelina/administración & dosificación , Goserelina/uso terapéutico , Humanos , Neoplasias/tratamiento farmacológicoRESUMEN
OBJECTIVES: To evaluate the efficacy, tolerability, endocrinological effects and the pharmacokinetics of Casodex, when given as monotherapy during daily dosing of 10-200 mg to patients with advanced prostate cancer. METHODS: A total of 390 patients with advanced prostate cancer were treated for a minimum of 12 weeks with a daily monotherapy dose of Casodex. The doses ranged from 10 to 200 mg. Objective assessments of efficacy included: review of measurable metastases, prostate dimension, prostatic acid phosphatase and prostate-specific antigen (PSA) levels. Subjective assessments of efficacy included review of urological symptoms, performance status, bone scan and analgesic requirement. Pharmacokinetic samples were taken at various time points up to 3 months, and assayed using an achiral HPLC method. RESULTS: Clear objective responses were observed, particularly at doses of 50 mg and above. Specifically, the median percentage decrease in PSA at 50 mg was 90.0%, and at 100 and 200 mg it was 93.4 and 94.8%, respectively. Up to 53% of symptomatic patients demonstrated a subjective response at 3 months. Casodex was well tolerated at all doses with no effect on haematological or cardiovascular parameters and no effect on renal function. The expected pharmacological effects of potent antiandrogen therapy, such as breast tenderness (58%), gynaecomastia (48%), and hot flushes (17%), were reported, but these incidences reflected the direct eliciting of these events. The intrinsic efficacy of Casodex was demonstrated despite increases of 60% in testosterone levels. However, this increase reached a plateau after 4-12 weeks of therapy, but the majority of values remained within the normal range. Casodex has a half-life of approximately 1 week, enabling once-daily dosing with no effect of age or renal impairment on its pharmacokinetics. CONCLUSION: Casodex has a favourable side effect profile compared with the known safety profiles of other antiandrogens and has demonstrated intrinsic efficacy. Casodex warrants further investigation as a monotherapy for the management of advanced prostate cancer.
Asunto(s)
Antagonistas de Andrógenos/uso terapéutico , Anilidas/uso terapéutico , Antineoplásicos/uso terapéutico , Neoplasias de la Próstata/tratamiento farmacológico , Fosfatasa Ácida/sangre , Antagonistas de Andrógenos/farmacocinética , Anilidas/administración & dosificación , Anilidas/farmacocinética , Antineoplásicos/farmacocinética , Relación Dosis-Respuesta a Droga , Estradiol/sangre , Hormona Folículo Estimulante/sangre , Humanos , Pruebas de Función Hepática , Hormona Luteinizante/sangre , Masculino , Invasividad Neoplásica/patología , Metástasis de la Neoplasia , Estadificación de Neoplasias , Nitrilos , Antígeno Prostático Específico/sangre , Neoplasias de la Próstata/sangre , Neoplasias de la Próstata/patología , Testosterona/sangre , Compuestos de TosiloRESUMEN
We have investigated the pharmacokinetics and pharmacodynamics of propofol in 11 patients with end-stage renal disease (ESRD) compared with nine healthy patients during and after a manually controlled three-stage infusion of propofol 21, 12 and 6 mg kg-1 h-1 lasting a minimum of 2 h. Mean total body clearance was not reduced significantly in the ESRD group (30.66 (SD 8.47) ml kg-1 min-1) compared with the control group (33.75 (7.8) ml kg-1 min-1). ESRD patients exhibited a greater, but not statistically significant, volume of distribution at steady state compared with patients in the control group (11.25 (8.86) vs 5.79 (2.14) litre kg-1, respectively). Elimination half-life values were unchanged by renal failure. Mean times to induction of anaesthesia were similar in both groups: 177 (SD 57) and 167 (58) s for the ESRD and control groups, respectively. Waking time after cessation of propofol infusion was significantly shorter in the ESRD group (474 (156) s) compared with the control group (714 (240) s) (P < 0.05). Mean plasma concentrations on waking were similar. We conclude that the pharmacokinetic and pharmacodynamic profiles of propofol after infusion were not markedly affected by renal failure.
Asunto(s)
Anestésicos Intravenosos/sangre , Fallo Renal Crónico/sangre , Propofol/sangre , Adulto , Periodo de Recuperación de la Anestesia , Anestesia Intravenosa , Anestésicos Intravenosos/farmacocinética , Estado de Conciencia/efectos de los fármacos , Femenino , Semivida , Humanos , Infusiones Intravenosas , Masculino , Persona de Mediana Edad , Propofol/farmacocinéticaRESUMEN
'Casodex' (bicalutamide) is an orally active, non-steroidal, pure antiandrogen; it is a racemate with antiandrogenic activity residing predominantly in the (R)-enantiomer. Healthy male volunteers (n = 15) were administered single oral doses of bicalutamide (50 mg) after food and after fasting as part of a three-treatment, three-period, randomized cross-over study, with a 9 week washout. After fasting, plasma concentrations of (R)-bicalutamide were much higher than those of (S)-bicalutamide; the mean (R)-enantiomer Cmax (734 ng mL-1) was about nine times higher than the (S)-enantiomer value (84 ng mL-1). The corresponding tmax values were 19 and 3 h for (R)- and (S)-bicalutamide, respectively. Elimination of (R)-bicalutamide from plasma was monoexponential and slow (t1/2 = 5.8 d). Elimination of (S)-bicalutamide was biphasic in some volunteers but monophasic in others (terminal t1/2 =1.2 d; n = 11). There was no significant effect of food on AUC, tmax, or t1/2 data for either enantiomer. The observed slightly higher values of Cmax for (R)-bicalutamide (14%) and (S)-bicalutamide (19%), when dosing with food, achieved statistical significance. However, differences of this magnitude are unlikely to to be of any clinical relevance. These data indicate that 'Casodex' can be taken without reference to meal times; this may be of particular relevance for its indication in a disease of the elderly.
Asunto(s)
Antagonistas de Andrógenos/farmacocinética , Anilidas/farmacocinética , Interacciones Alimento-Droga , Administración Oral , Adulto , Análisis de Varianza , Antagonistas de Andrógenos/administración & dosificación , Antagonistas de Andrógenos/sangre , Anilidas/administración & dosificación , Anilidas/sangre , Animales , Área Bajo la Curva , Grasas de la Dieta/administración & dosificación , Ingestión de Alimentos , Ayuno/sangre , Humanos , Absorción Intestinal , Masculino , Persona de Mediana Edad , Nitrilos , Ratas , Estereoisomerismo , Compuestos de TosiloRESUMEN
Casodex (bicalutamide, Zeneca Ltd), has been developed for prostate cancer therapy. Its preclinical, pharmacokinetic, pharmacodynamic, clinical efficacy and tolerability data are described. Casodex is a potent and specific non-steroidal antiandrogen. Clinical studies indicated that Casodex is orally bioavailable and well absorbed, with a plasma half-life of around 1 week. A Casodex dose of 50 mg daily decreased prostatic acid phosphatase comparable with castration. This dose was, therefore, evaluated initially as monotherapy and later as a component of maximal androgen blockade. Using prostate specific antigen as an end point, Casodex 150 mg daily was well-tolerated with demonstrable evidence of activity. Casodex 150 mg monotherapy was less effective than castration in terms of efficacy in patients with metastatic disease at entry. However, in patients non-metastatic at entry, Casodex 150 mg monotherapy appeared to be equivalent to castration in terms of time to death (data immature). Casodex was well-tolerated. In combination treatment, Casodex at 50 mg daily was at least as effective as 750 mg flutamide (Eulexin, Schering-Plough International) with respect to time to treatment failure, equivalent in terms of survival, and better tolerated with respect to diarrhoea. In conclusion, Casodex is a good option for the antiandrogen component of maximal androgen blockade.
Asunto(s)
Antagonistas de Andrógenos/uso terapéutico , Anilidas/uso terapéutico , Antineoplásicos Hormonales/uso terapéutico , Neoplasias de la Próstata/tratamiento farmacológico , Antagonistas de Andrógenos/efectos adversos , Antagonistas de Andrógenos/farmacocinética , Anilidas/efectos adversos , Anilidas/farmacocinética , Antineoplásicos Hormonales/efectos adversos , Antineoplásicos Hormonales/farmacocinética , Humanos , Masculino , Nitrilos , Compuestos de TosiloRESUMEN
1. Casodex, a non-steroidal antiandrogen, is a racemic mixture of R-Casodex, the pharmacologically active (-)-enantiomer, and S-Casodex, the inactive (+)-enantiomer. Single oral doses of pseudo-racemic 14C-Casodex (10 mg/kg), prepared from mixtures of either 14C-labelled R-Casodex and unlabelled S-Casodex, or 14C-S-Casodex and unlabelled R-Casodex, were administered to the intact and bile duct-cannulated male rat. 2. Neither enantiomer underwent stereochemical inversion, but the pharmacokinetics of Casodex showed marked enantioselectivity. 3. After dosing R-labelled Casodex, plasma concentrations of R-Casodex increased slowly to reach a peak of 3.50 +/- 0.05 micrograms/ml (mean +/- SEM) at 12 h and, thereafter, declined monoexponentially with an elimination half-life of 24 h. Plasma concentrations of S-Casodex rose rapidly to reach a much lower peak of 0.97 +/- 0.06 microgram/ml at 3 h and, thereafter, declined rapidly, although there were insufficient data to determine the half-life. R-Casodex had a much higher AUC0-24 (66 micrograms.h/ml) than S-Casodex (12 micrograms.h/ml). Plasma drug concentrations measured using an achiral assay were in very good agreement with the sum of the enantiomer concentrations throughout the profile. R-Casodex comprised 94% of the total plasma radioactivity at 12 h, decreasing to 75% at 120 h. 4. Plasma concentration data generated after administration of S-Casodex were similar to those observed after dosing R-labelled Casodex. S-Casodex comprised about 74% of the total plasma radioactivity at 6 h and only 41% at 24 h. 5. The urine of intact animals contained 36 +/- 2 and 48 +/- 3% of the dose respectively up to 48 and 120 h after dosing with R-labelled Casodex, and 33 +/- 4 and 34 +/- 4% respectively after dosing with S-labelled Casodex. The urine and bile of the cannulated rat contained 43 +/- 2 and 21 +/- 2% of the dose respectively up to 48 h after dosing with R-labelled Casodex and 37 (n = 2) and 50% respectively after dosing with S-labelled Casodex. 6. After dosing with R- or S-labelled Casodex, the urinary radioactivity consisted of the carboxylic acid metabolite formed by hydrolytic cleavage at the amide, whereas biliary radioactivity consisted of hydroxy-Casodex and Casodex, mainly conjugated with glucuronic acid. The clearance of R-Casodex by each of these pathways of metabolism was less than that of S-Casodex, with direct glucuronidation and hydroxylation showing greater enantioselectivity than hydrolysis.
Asunto(s)
Antagonistas de Andrógenos/metabolismo , Anilidas/metabolismo , Antagonistas de Andrógenos/farmacocinética , Anilidas/sangre , Anilidas/farmacocinética , Animales , Heces/química , Glucuronatos/metabolismo , Hidroxilación , Masculino , Nitrilos , Ratas , Estereoisomerismo , Compuestos de TosiloRESUMEN
1. Five healthy male volunteers received a single oral dose (50 mg; 42 microCi) of 14C-Casodex, a racemic compound, which has its antiandrogen activity predominantly in R-Casodex, the (-)-enantiomer, with little activity in S-Casodex, the (+)-enantiomer. 2. Plasma concentrations of R-Casodex increased slowly in all subjects to reach a peak of 559-970 ng/ml between 15 and 48 h after dosing and, thereafter, declined monoexponentially with a mean half-life of 4.2 days. Plasma concentrations of S-Casodex rose rapidly to reach a peak of 32-66 ng/ml within the first 2-5 h, and then declined monoexponentially with a mean half-life of 19 h. Plasma concentrations of the racemate were in very good agreement with the sum of the enantiomer concentrations throughout the study and were very similar to concentrations of total radioactivity over the first 4 days. 3. About 80% of the radioactive dose was recovered in urine (35.8 +/- 1.7%; mean +/- SEM) and faeces (42.6 +/- 2.9%) during a total collection over 9 days; this incomplete recovery was consistent with the slow elimination of R-Casodex. 4. T.l.c. of urine extracts indicated extensive metabolism of Casodex to two polar metabolites identified as the glucuronide conjugates of Casodex and hydroxy-Casodex; almost no parent compound was observed. Virtually all of the Casodex glucuronide excreted in urine during the first 2 days was derived from S-Casodex, consistent with the relatively low plasma concentrations and rapid elimination of this enantiomer. 5. T.l.c. of faecal extracts showed the presence of both Casodex and hydroxy-Casodex; these may have been eliminated in bile as the glucuronide conjugates, with subsequent hydrolysis in the intestinal tract.
Asunto(s)
Antagonistas de Andrógenos/metabolismo , Anilidas/metabolismo , Administración Oral , Adulto , Antagonistas de Andrógenos/química , Antagonistas de Andrógenos/farmacocinética , Anilidas/química , Anilidas/farmacocinética , Heces/química , Glucuronidasa/metabolismo , Semivida , Humanos , Hidrólisis , Masculino , Espectrometría de Masas , Persona de Mediana Edad , Nitrilos , Estereoisomerismo , Compuestos de TosiloRESUMEN
1. Casodex is a novel non-steroidal antiandrogen being developed for the treatment of prostatic cancer. The antiandrogenic activity is predominantly in the R(-) enantiomer with little, if any, activity in the S(+) enantiomer. 2. The pharmacokinetics of the enantiomers of Casodex have been investigated over 28 days following a single oral dose of Casodex (50 mg) to 10 male subjects with histologically verified liver cirrhosis or fatty liver with fibrosis. Ten age matched male subjects with normal hepatic function served as a control group. 3. For both groups plasma concentrations of (S)-Casodex were lower than those for (R)-Casodex; this difference was about 10-fold at early time points and increased to about 25-fold by 24 h after dosage. 4. The kinetics of (R)-Casodex were similar in subjects with and without liver disease (Cmax: 750 vs 848 ng ml(-1); tmax: 24 - 30 h; t(1/2): 7.40 vs 7.22 days; AUC: 182 vs 225 microg ml(-1) h). 5. The kinetics of (S)-Casodex could not be described in the majority of subjects; in the remainder the mean terminal phase half-life for both groups was less than 1 day.
Asunto(s)
Antagonistas de Andrógenos/farmacocinética , Anilidas/farmacocinética , Antineoplásicos/farmacocinética , Hígado Graso/metabolismo , Cirrosis Hepática/metabolismo , Antagonistas de Andrógenos/sangre , Anilidas/sangre , Antineoplásicos/sangre , Humanos , Masculino , Nitrilos , Estereoisomerismo , Compuestos de TosiloRESUMEN
1. Propofol glucuronide (PG) is the major human metabolite of the i.v. anaesthetic propofol, 2,6-diisopropylphenol. 2. Bolus i.v. doses of 14C-PG (1 mg/kg) to rat and dog were eliminated in urine (40 and 66% respectively) and faeces (48 and 19%); 25 and 48% of the dose were excreted unchanged in urine. 3. In dog, PG was distributed from plasma (t 1/2 4 min) into a volume equivalent to extracellular water and eliminated with t 1/2 80 min. Total body clearance was 1.8 ml/min per kg, and renal clearance about 20% GFR. In rat, plasma 14C concentrations were about one-tenth those in dog, thus PG levels were not quantified. 4. Propofol was not detected in the plasma showing that PG is hydrolytically stable. Enterohepatic circulation of PG occurred in rat and to a lesser extent in dog. Metabolites, mainly side-chain hydroxylation products, were evident in both species from 4 h after dosing. 5. Bolus i.v. doses of PG (200 mg/kg) showed no hypnotic activity in mice.
Asunto(s)
Propofol/farmacología , Propofol/farmacocinética , Animales , Cromatografía Líquida de Alta Presión , Perros , Heces , Glucuronatos/metabolismo , Semivida , Inyecciones Intravenosas , Masculino , Ratones , Propofol/administración & dosificación , Conejos , Ratas , Ratas Endogámicas , Ratas WistarRESUMEN
SIPHAR and MKMODEL in their extended least squares modes have been compared when fitting a triexponential declining function to simulated data. The data were simulated on SAS incorporating normally distributed random error, having coefficients of variation (CV) of 5, 10, 15, and 25 per cent. At each error level 100 data sets, consisting of 21 data pairs, were simulated. Non-parametric tests were used to compare the accuracy and precision of the estimates produced by the packages. The comparison was repeated with two different sets of exponent values incorporating error at the 15 per cent level. MKMODEL was also compared to ELSFIT and ELSMOS at the same error level. SIPHAR was consistently less accurate and less precise than MKMODEL in estimating the structural model parameters. SIPHAR was also sensitive to the concentration units used for the input data. Estimates of the variance model power produced by SIPHAR were very variable while those from MKMODEL covered a much tighter range. For both packages there was generally a linear increase in the CV on each mean parameter estimate with increase in the CV on the error model. Good agreement was observed between MKMODEL, ELSFIT, and ELSMOS. The presence of an additive constant in the variance model used in SIPHAR was shown to be responsible for its poorer accuracy and precision.
Asunto(s)
Análisis de los Mínimos Cuadrados , Modelos Estadísticos , Farmacocinética , Algoritmos , SemividaRESUMEN
The pharmacokinetics of propofol administered as long term infusions were determined in 12 intensive care unit patients (two female; mean age 58 yr, mean weight 66.9 kg) requiring sedation during mechanical ventilation. Patients were recruited after having been administered propofol for 24 h. Blood samples for analysis of propofol were taken during the infusion (mean duration 85.6 h; mean rate 2.58 mg kg-1 h-1) and for up to about 42 h after its termination. The median propofol total body clearance, derived from the apparent steady state propofol blood concentrations during infusion, was 2.11 litre min-1. One patient died during the infusion, from multi-organ failure secondary to a pre-existing septicaemia, and in one other patient no sampling was possible during the first 30 min after infusion; full elimination data were obtained for 10 patients. After termination of the infusion, propofol blood concentrations declined rapidly, with an overall mean decrease of 50% over the first 10 min; thereafter the decline was more gradual. The elimination profile was triphasic in seven patients and biphasic in three patients. Mean half-lives for the three phases were 1.81 (n = 10) min, 70.9 (n = 7) min and 1411 (n = 11) min. There was no apparent trend in the terminal phase half-life with the duration of sampling after infusion.
Asunto(s)
Anestesia Intravenosa/métodos , Cuidados Críticos/métodos , Propofol/farmacocinética , Respiración Artificial/métodos , Adulto , Anciano , Femenino , Semivida , Humanos , Infusiones Intravenosas , Masculino , Tasa de Depuración Metabólica , Persona de Mediana Edad , Propofol/administración & dosificación , Propofol/sangre , Factores de TiempoRESUMEN
1. The pharmacokinetics of propofol in an emulsion formulation ('Diprivan') have been studied after single bolus doses to rats, dogs, rabbits and pigs, and after single and multiple infusions to dogs. Venous blood propofol concentrations were determined by h.p.l.c. with u.v. or fluorescence detection. Curve fitting was performed using ELSFIT. 2. The distribution of propofol in blood and its plasma protein binding have been studied in rat, dog, rabbit and man. Protein binding was high (96-98%), and in most species propofol showed appreciable association with the formed elements of blood. 3. Where an adequate sampling period was employed the pharmacokinetics of propofol were best described by a three-compartment open 'mammillary' model. Propofol was distributed into a large initial volume (1-21/kg) and extensively redistributed (Vss = 2-10 x body weight) in all species. Clearance of propofol by all species was rapid, ranging from about 30-80 ml/kg per min in rats, dogs and pigs to about 340 ml/kg per min in rabbits.
Asunto(s)
Propofol/farmacocinética , Animales , Perros , Emulsiones , Femenino , Infusiones Intravenosas , Masculino , Tasa de Depuración Metabólica , Propofol/administración & dosificación , Propofol/sangre , Unión Proteica , Conejos , Ratas , Especificidad de la Especie , Porcinos , Porcinos EnanosRESUMEN
1. An i.v. dose of 14C-propofol (0.53 mg/kg) was administered to three male and three female patients during the anhepatic phase of liver transplantation, which lasted 30-56 min after dosing. Arterial and venous blood samples, bile (T-tube drainage) and urine were collected at various times afterwards and submitted to h.p.l.c. and radioassay or specific fluorescence detection for the unchanged drug. 2. Extrahepatic metabolism was apparent during the anhepatic phase, since at 30 min post-dose, unchanged propofol comprised only 42-89% of the blood radioactivity. 3. Examination of the plasma radioactivity during the anhepatic phase in two subjects showed evidence of propofol glucuronide and 4-quinol sulphate, confirming extrahepatic metabolism of the drug. Quinol glucuronides were only detected in the liver reperfusion phase. 4. There was no evidence that the lungs contribute to the extrahepatic metabolism of propofol, since drug concentrations in the arterial blood were not less than in central venous samples. 5. During the first 24 h period, urine collected from five patients contained 7-74% dose, whilst the bile contained 0.1-0.9%. In three patients with normal renal function recovery in urine was 66-74% dose. Examination of urinary radioactivity in one subject showed the main component to be propofol glucuronide during the anhepatic phase.
Asunto(s)
Trasplante de Hígado , Propofol/farmacocinética , Adulto , Bilis/metabolismo , Femenino , Glucuronatos/metabolismo , Humanos , Cinética , Masculino , Persona de Mediana Edad , Propofol/sangre , Propofol/orina , Reperfusión , Sulfatos/metabolismoRESUMEN
1. Bolus i.v. doses of 14C-propofol (7-10 mg/kg) to rat, dog and rabbit, or an infusion dose (0.47 mg/kg per min for 6 h) to dog were eliminated primarily in urine (60-95% dose); faecal elimination (13-31%) occurred for rat and dog, but was minimal (less than 2%) for rabbit. 2. After bolus administration, blood 14C concentrations were maximal (8-30 micrograms equiv./ml) at 2-15 min; these declined rapidly during the 0-2 h period and thereafter more slowly. Propofol concentrations were maximal (4-16 micrograms/ml) at 2 min and the profiles were best fitted by a tri-exponential (rat and dog) or bi-exponential (rabbit) equation. Duration of sleep ranged from 5 to 8 min. 3. Infusion of 14C-propofol in dog gave a blood 14C concentration of 117 micrograms equiv./ml at the end of the 6 h infusion period; this declined at a similar rate to that after the bolus dose. Propofol concentration on termination of infusion was 13 micrograms/ml; thereafter, propofol concentrations declined less rapidly than after the bolus dose. Waking occurred about 44 min post-infusion. 4. Propofol was cleared by conjugation of the parent molecule or its quinol metabolite; hydroxylation of an isopropyl group also occurred in rat and rabbit. Biliary excretion leading to enterohepatic recirculation, and in turn increased sulphate conjugation, occurred in rat and dog, but not rabbit, resulting in a marked interspecies variation in drug clearance and metabolite profiles.
Asunto(s)
Propofol/sangre , Animales , Bilis/metabolismo , Perros , Femenino , Glicoconjugados/metabolismo , Infusiones Intravenosas , Inyecciones Intravenosas , Masculino , Tasa de Depuración Metabólica , Embarazo , Propofol/administración & dosificación , Propofol/metabolismo , Conejos , Ratas , Especificidad de la EspecieRESUMEN
1. Bolus i.v. doses of 14C-propofol (9 mg/kg) were administered to female rats for measurement of tissue levels of total 14C and propofol from 2 min to 24 h post-dose; whole-body autoradiography was studied at 6 min, 2 h and 24 h post-dose, and also involved 15-day pregnant rats. 2. The blood propofol concentration-time profile was fitted by a tri-exponential function corresponding to a three-compartment open model. Data show rapid distribution during the mixing period into highly perfused tissues and muscle, comprising the central compartment, and slower uptake into less well-perfused skin and adipose tissues comprising the deeper compartments. 3. The initial decline in blood propofol concentration was associated with redistribution (t1/2 4 min), the second decline (15-240 min post-dose) was associated with metabolism (t1/2 33 min) and the third decline reflected slow depletion of drug from deep tissue compartments (t1/2 6.4 h). 4. Blood and brain propofol concentrations on waking (at 7 min post-dose) were 4 micrograms/ml and 9 micrograms/g respectively; the model shows that, at this time, 30% of the dose was lost from the central compartment by redistribution and a similar amount by metabolism. 5. Tissue profiles of total 14C and propofol diverged for highly perfused tissues (other than brain) because of slow clearance of metabolites, accentuated by enterohepatic recirculation.
Asunto(s)
Propofol/farmacocinética , Tejido Adiposo/metabolismo , Animales , Autorradiografía , Femenino , Inyecciones Intravenosas , Tasa de Depuración Metabólica , Modelos Biológicos , Músculos/metabolismo , Propofol/administración & dosificación , Propofol/metabolismo , Ratas , Ratas Endogámicas , Distribución TisularRESUMEN
1. The pharmacokinetics of Casodex, a novel, non-steroidal antiandrogen, have been investigated following single oral and i.v. doses and during daily oral dosing to male and female rats and male dogs. 2. The binding of 14C-Casodex to rat, dog and human plasma proteins, determined by equilibrium dialysis, was high with values greater than 95%; in dog there was evidence for decreased binding at concentrations greater than 12 micrograms/ml. 3. Casodex was slowly absorbed over prolonged periods and its bioavailability decreased with increase in dose from 72% and 88% in male and female rats respectively at 1 mg/kg to 10% and 12% at 250 mg/kg; in dog bioavailability decreased from 100% at 0.1 mg/kg to 31% at 100 mg/kg. 4. Elimination of Casodex from plasma was slow with terminal elimination half-lives of about 1 day in rat and about 6 days in dog. On daily administration to rats Casodex accumulates slightly in plasma at 10 mg/kg but not at 250 mg/kg; in dog appreciable accumulation (9-12-fold), calculated from the ratio of trough plasma concentrations at steady state to those after a single dose, was observed at 2.5 and 10 mg/kg, but at 100 mg/kg the accumulation ratio was much lower (4-fold).
Asunto(s)
Anilidas/farmacocinética , Administración Oral , Antagonistas de Andrógenos/administración & dosificación , Antagonistas de Andrógenos/sangre , Antagonistas de Andrógenos/farmacocinética , Anilidas/administración & dosificación , Anilidas/sangre , Animales , Proteínas Sanguíneas/metabolismo , Perros , Femenino , Semivida , Inyecciones Intravenosas , Masculino , Tasa de Depuración Metabólica , Nitrilos , Unión Proteica , Ratas , Ratas Endogámicas , Compuestos de TosiloRESUMEN
We have compared the pharmacokinetics of propofol as an infusion in 10 control and 10 patients with cirrhosis. Anaesthesia was induced within 3-4 min during administration of an infusion of propofol 21 mg kg-1 h-1. After 5 min, the infusion was decreased in a stepwise manner to 12 mg kg-1 h-1 and subsequently 6 mg kg-1 h-1. The mean recovery time after discontinuation of the infusion was significantly longer in the cirrhotic group; however, when patients opened their eyes, blood concentrations of propofol were similar in both groups (1 micrograms ml-1). Pharmacokinetic analysis was performed from the beginning of infusion to 8 h after termination. Total body clearance was not reduced significantly in cirrhotic (1.56 (SD 0.48) litre min-1) compared with control (1.75 (0.32) litre min-1) patients. The volume of distribution at steady state was significantly greater in patients with cirrhosis than in control patients (202 (82) litre vs 121 (49) litre). However, this difference did not change terminal elimination half-life. The pharmacokinetics of propofol given by infusion to maintain general anaesthesia were not affected markedly by moderate cirrhosis.
Asunto(s)
Cirrosis Hepática/metabolismo , Propofol/farmacocinética , Adulto , Anestesia Intravenosa , Humanos , Infusiones Intravenosas , Hígado/metabolismo , Hígado/cirugía , Cirrosis Hepática/cirugía , Persona de Mediana Edad , Propofol/administración & dosificaciónRESUMEN
This randomized, double-blind, crossover study in 10 healthy male volunteers compared four single oral doses of ICI 141,292 ('Visacor'), i.e. 50, 100, 200, and 300 mg, with placebo. Venous blood samples were collected pre-dose and at various times after dosing and the concentrations of ICI 141,292 in the plasma were determined by radioimmunoassay. A standardized 4-min bicycle exercise test was also performed and before this the resting haemodynamic parameters were assessed. Peak plasma concentrations of ICI 141,292 and the area under the plasma concentration-time curve increased disproportionately with dose such that after scaling to a dose of 200 mg there remained a significant linear trend with dose. The time to peak plasma concentration displayed an increasing trend with dose and, once again, the linear component of this trend was statistically significant. The mean heart rates during exercise were all significantly reduced compared to placebo for 24 h by each of the doses (range 7.8 to 17.4 beats min-1 at 24 h, p less than 0.01). The increase in heart rate during exercise was inversely related to the logarithm of the ICI 141,292 plasma concentration with higher plasma concentrations being associated with lower heart rate increases. The mean supine resting heart rates were slightly but significantly reduced at 2 and 6 h after dosing by each treatment and by the 300 mg dose at 24 h. Each of the doses of ICI 141,292 was well tolerated.
Asunto(s)
Antagonistas Adrenérgicos beta/farmacocinética , Bencenoacetamidas , Propanolaminas/farmacocinética , Antagonistas Adrenérgicos beta/efectos adversos , Antagonistas Adrenérgicos beta/farmacología , Adulto , Presión Sanguínea/efectos de los fármacos , Ejercicio Físico , Frecuencia Cardíaca/efectos de los fármacos , Humanos , Masculino , Propanolaminas/efectos adversos , Propanolaminas/farmacologíaRESUMEN
1. Epanolol is a novel anti-anginal agent which is a beta 1-adrenoceptor partial agonist exhibiting selective beta 1-adrenoceptor antagonist and selective beta 1-adrenoceptor agonist activity. It is mainly metabolised to conjugates prior to excretion in urine and it was of interest to determine if any accumulation occurred in elderly patients. 2. The pharmacokinetics of epanolol have been studied over 72 h after a single oral dose of 200 mg and then over 24 h after 12 consecutive daily oral doses in 13 elderly patients with stable angina pectoris. 3. The peak plasma concentrations (mean +/- s.d.) after the single dose (25.7 +/- 17.0 ng ml-1) were not significantly different (P = 0.35) from those at steady state (32.4 +/- 20.9 ng ml-1). There was wide inter-individual variation on both occasions. The time to peak did not alter significantly during the study with mean values of 1.5 and 1.2 h on acute and chronic dosing respectively. 4. Plasma concentrations declined biphasically with a mean terminal phase half-life of 17 h and 5 fold inter-individual variation. 5. The mean area under the curve to 24 h was not significantly different (P = 0.26) after the single dose (59.0 +/- 29.8 ng ml-1 h) from that at steady state (78.4 +/- 55.0 ng ml-1 h). There was also wide inter-individual variation in these values. 6. In conclusion, the lack of significant accumulation of epanolol indicates that no alteration of dose is necessary when using epanolol in elderly patients with normal renal and hepatic function.
Asunto(s)
Antagonistas Adrenérgicos beta/farmacocinética , Angina de Pecho/metabolismo , Bencenoacetamidas , Propanolaminas/farmacocinética , Antagonistas Adrenérgicos beta/efectos adversos , Antagonistas Adrenérgicos beta/uso terapéutico , Anciano , Angina de Pecho/tratamiento farmacológico , Angina de Pecho/fisiopatología , Presión Sanguínea/efectos de los fármacos , Femenino , Semivida , Frecuencia Cardíaca/efectos de los fármacos , Humanos , Masculino , Propanolaminas/efectos adversos , Propanolaminas/uso terapéuticoRESUMEN
The pharmacokinetic profile of a single dose of 100 mg of (+/-)-N-[2-[[3-(o-cyanophenoxy)-2-hydroxypropyl]amino]ethyl]- 2-(p-hydroxyphenyl) acetamide (epanolol, Visacor), has been determined in an open study of 15 elderly patients with stable angina pectoris. Haematological, biochemical and physiological measurements demonstrated that epanolol was well tolerated in this group of patients. A mean peak epanolol concentration of 18.4 ng/ml was observed at a mean time of 1.08 h. In about one third of patients, an analytically significant secondary peak was observed. Peak concentrations showed an interindividual variability of 16-fold. Following the peak, plasma concentrations declined biphasically. Epanolol was eliminated from plasma with a mean terminal half-life of 22 h. There was some evidence of a linear relationship between heart rate and logarithmic plasma concentration but this was not statistically significant. These data are consistent with the results of pharmacokinetic studies in healthy young volunteers.