RESUMEN
Due to the prevalence of both gastrointestinal and cardiovascular diseases, it is likely that patients may be coprescribed gastric parietal cell proton pump inhibitors and beta-adrenergic antagonists. Therefore, the objectives of this phase I study were to assess the potential effects of the coadministration of lansoprazole on the pharmacokinetics of propranolol and to evaluate the safety of propranolol with concomitant lansoprazole dosing. In a double-blind fashion, 18 healthy male nonsmokers were initially randomized to receive either 60 mg oral lansoprazole, each morning for 7 days, or an identical placebo (period 1). On day 7, all subjects were concomitantly administered oral propranolol, 80 mg. After a minimum of 1 week following the last dose of either lansoprazole or placebo, subjects were crossed over to the opposite treatment for another 7 days (period 2). Subjects were again administered oral propranolol on day 7. During both treatment periods, blood samples for the determination of plasma propranolol and 4-hydroxy-propranolol were obtained just before the dose and at 0.5, 1, 2, 3, 4, 6, 8 12, 16, 20, and 24 hours postdose. Plasma propranolol and 4-hydroxy-propranolol concentrations were determined by using HPLC with fluorescence detection. The Cmax, tmax, AUC0-infinity, and t1/2 values for propranolol, as well as the AUC0-infinity for 4-hydroxy-propranolol, were calculated and compared between the lansoprazole and placebo regimens. The mean age of the 15 subjects who successfully completed the study was 31 years (range: 24-38 years), and their average weight was 174.8 pounds (range: 145-203 pounds). There were no statistically significant differences between the lansoprazole and placebo regimens for the propranolol Cmax, tmax, AUC0-infinity, and t1/2 values. Also, there were no statistically significant differences between regimens for the 4-OH-propranolol AUC0-infinity. Safety evaluations, which included adverse events, vital signs, clinical laboratory determinations, ECG, and physical examinations, revealed no unexpected clinically significant findings and did not suggest a drug-drug interaction. In conclusion, lansoprazole does not significantly alter the pharmacokinetics of propranolol, suggesting that it does not interact with the CYP2D6- or CYP2C19-mediated metabolism of propranolol. Modification of a propranolol dosage regimen in the presence of lansoprazole is not indicated, based on the pharmacokinetic analysis and the lack of a clinically significant alteration in the pharmacodynamic response.
Asunto(s)
Antagonistas Adrenérgicos beta/farmacocinética , Antiulcerosos/farmacología , Omeprazol/análogos & derivados , Propranolol/farmacocinética , Inhibidores de la Bomba de Protones , 2-Piridinilmetilsulfinilbencimidazoles , Antagonistas Adrenérgicos beta/efectos adversos , Antagonistas Adrenérgicos beta/farmacología , Adulto , Antiulcerosos/efectos adversos , Estudios Cruzados , Método Doble Ciego , Interacciones Farmacológicas , Humanos , Lansoprazol , Masculino , Omeprazol/efectos adversos , Omeprazol/farmacología , Propranolol/efectos adversos , Propranolol/farmacologíaRESUMEN
The objective of this randomized, double-blind, two-period crossover study was to investigate whether concomitant steady-state lansoprazole influences the pharmacokinetics of CYP2C9 substrates using single intravenously dosed phenytoin as a model substrate. In addition, the safety of concomitant administration of these two drugs was evaluated. Twelve healthy, nonsmoking, adult male subjects received 60 mg lansoprazole or placebo once daily for 9 days during each study period. On the morning of day 7, each subject received a single 250 mg intravenous phenytoin dose. There were no statistically significant differences between the two regimens for mean phenytoin Cmax or tmax. There was a minor (< 3%) but statistically significant difference between the two regimens for phenytoin AUC resulting from a very low intrasubject coefficient of variation (2.3%). The treatment and control mean plasma concentration phenytoin profiles were virtually super-imposable. In conclusion, concomitant multidose lansoprazole administration is unlikely to have any clinically significant effect on the pharmacokinetics of CYP2C9 substrates in general or intravenous phenytoin specifically.
Asunto(s)
Antiulcerosos/farmacocinética , Anticonvulsivantes/farmacocinética , Omeprazol/análogos & derivados , Fenitoína/farmacocinética , 2-Piridinilmetilsulfinilbencimidazoles , Adulto , Antiulcerosos/efectos adversos , Antiulcerosos/farmacología , Anticonvulsivantes/efectos adversos , Anticonvulsivantes/farmacología , Estudios Cruzados , Sistema Enzimático del Citocromo P-450/metabolismo , Método Doble Ciego , Interacciones Farmacológicas , Humanos , Inyecciones Intravenosas , Lansoprazol , Masculino , Tasa de Depuración Metabólica , Omeprazol/efectos adversos , Omeprazol/farmacocinética , Omeprazol/farmacología , Fenitoína/efectos adversos , Fenitoína/farmacologíaRESUMEN
AIMS: To assess the effects of the protease inhibitor ritonavir on the pharmacokinetics of ethinyl oestradiol in healthy female volunteers. METHODS: This was an open-label, single centre study in 23 subjects who received two single doses of oral contraceptive containing 50 microg ethinyl oestradiol on Day 1 (alone) and on Day 29 during concomitant ritonavir. Each subject received 16 days of every 12 h doses of ritonavir from Day 15 through Day 30. Blood samples were collected for serum ethinyl oestradiol concentrations for 48 h after each dose and for plasma ritonavir on Day 29 at 0 and 4 h postdose. RESULTS: Statistically significant decreases in ethinyl oestradiol mean Cmax (-32%) and mean AUC (-41%), and a statistically significant increase in the mean terminal elimination rate constant (+31%) were observed during concomitant ritonavir. The harmonic mean terminal half-life decreased from 17 h to 13 h during concomitant ritonavir. No statistically significant change was noted in tmax. The ratios of means (95% confidence intervals) for Cmax and AUC were 0.682 (0.612-0.758) and 0.595 (0.506-0.694), respectively. The changes in ethinyl oestradiol pharmacokinetics were consistent with an increase in clearance from enzymatic induction of glucuronidation and/or cytochrome P450 hydroxylation. Mean steady-state ritonavir concentrations of 6.5 and 13.4 microg ml(-1) were observed at 0 and 4 h postdose, respectively. CONCLUSIONS: Considering the extent of the decrease in ethinyl oestradiol concentrations, the use of alternate contraceptive measures should be considered when ritonavir is being administered.
PIP: The protease inhibitor ritonavir has demonstrated broad-spectrum ability against HIV 1 and 2. The present study investigated the drug interaction potential of steady-state ritonavir on single dose ethinyl estradiol pharmacokinetics. 23 healthy women (mean age, 34 years) received an oral contraceptive (OC) containing 50 mcg of ethinyl estradiol and 1 mg of ethynodiol on days 1 and 29, while 500 mg of ritonavir was administered every 12 hours on days 15-30. After administration of a single dose of OC, serum ethinyl estradiol concentrations peaked at 4 hours and declined thereafter, with a typical half-life of 17 hours. Administration of the second OC on day 29, after 16 days of continuous ritonavir, resulted in a 32% lower ethinyl estradiol mean maximum concentration (p 0.001) and a 41% lower mean area under curve (p 0.001) compared with OC administration alone. In addition, the mean terminal elimination rate constant increased by 31% (p 0.001) with concomitant ritonavir. The changes in ethinyl estradiol pharmacokinetics were consistent with an increase in clearance from enzymatic induction of glucuronidation and/or cytochrome P450 hydroxylation. Mean steady-state ritonavir concentrations of 6.5 and 13.4 mcg/ml were observed at 0 and 4 hours post-dose, respectively. The interaction observed in this study is likely to be clinically significant, with an increased risk of OC failure. Thus, use of alternate contraceptive measures should be recommended when ritonavir is being administered.
Asunto(s)
Fármacos Anti-VIH/farmacología , Anticonceptivos Orales/farmacocinética , Congéneres del Estradiol/farmacocinética , Etinilestradiol/farmacocinética , Inhibidores de la Proteasa del VIH/farmacología , Ritonavir/farmacología , Adulto , Área Bajo la Curva , Interacciones Farmacológicas , Femenino , Semivida , Humanos , Persona de Mediana EdadRESUMEN
To evaluate the potential for an interaction between clarithromycin and loratadine, healthy male volunteers (n = 24) received each of the following regimens according to a randomized crossover design: 500 mg of clarithromycin orally every 12 h (q12h) for 10 days, 10 mg of loratadine orally q24h for 10 days, and the combination of clarithromycin and loratadine. A washout interval of 14 days separated regimens. The addition of loratadine did not statistically significantly affect the steady-state pharmacokinetics of clarithromycin or its active metabolite, 14(R)-hydroxy-clarithromycin. However, the addition of clarithromycin statistically significantly altered the steady-state maximum observed plasma concentration and the area under the plasma concentration-time curve over a dosing interval for loratadine (+36 and +76%, respectively) and for descarboethoxyloratadine (DCL), the active metabolite of loratadine (+69 and +49%, respectively). Clarithromycin probably inhibits the oxidative metabolism of loratadine and DCL by the cytochrome P-450 3A subfamily. Electrocardiograms (n = 12) were obtained over 24-h periods at baseline and steady state (day 10). The mean maximum QTc interval and area under the QTc interval-time curve on day 10 were modestly increased (<3%) from baseline for all three regimens, but no QTc interval exceeded 439 ms for any subject. Elevated steady-state concentrations of loratadine and DCL do not appear to be associated with adverse cardiovascular effects related to prolongation of the QTc interval. Loratadine and clarithromycin were well tolerated, alone and in combination.
Asunto(s)
Antialérgicos/farmacocinética , Antibacterianos/farmacocinética , Claritromicina/farmacocinética , Loratadina/farmacocinética , Adolescente , Adulto , Análisis de Varianza , Antialérgicos/farmacología , Antibacterianos/administración & dosificación , Antibacterianos/efectos adversos , Antibacterianos/sangre , Claritromicina/administración & dosificación , Claritromicina/efectos adversos , Claritromicina/sangre , Estudios Cruzados , Método Doble Ciego , Combinación de Medicamentos , Interacciones Farmacológicas , Electrocardiografía/efectos de los fármacos , Humanos , Loratadina/efectos adversos , Loratadina/farmacología , MasculinoRESUMEN
OBJECTIVE: The pharmacokinetics of an N-hydroxyurea analog, ABT-761 in asthmatic pediatric patients with asthma were investigated. METHODS: A total of 24 patients were enrolled into this 8-day single- and multiple-dose study. Patients received daily doses of ABT-761 according to their body weight: patients of 20-38 kg received 50 mg; patients >38 kg but < or = 55 kg received 100 mg, and patients >55 kg received 150 mg. RESULTS: The mean values for the terminal phase t1/2 were 16-17 h after multiple-dose administration. When normalized for body weight, the mean day 8 Cl(f) values for 50-, 100-mg, and 150-mg doses were 0.57 (n=13), 0.51 (n=10), and 0.43 (n=1) ml x min(-1) x kg(-1), respectively, while the mean Vz/f values ranged from 0.75 to 0.77 l x kg(-1). The mean accumulation ratio observed (day 8 to day 1 AUC0-24 ratio) of ABT-761 was approximately 1.7, which is consistent with the t1/2 of this drug. Body weight, age, and body surface area were virtually identical in explaining the variability in dose-normalized Cmax and AUC values (R2=0.61-0.68). The percents of variance explained by these three variables were within a range of 3% for each pharmacokinetic parameter. CONCLUSIONS: The pharmacokinetics of ABT-761 in children were similar to those previously reported in adults. Body weight, age, or body surface area can be used to provide dosing adjustment for ABT-761 in pediatric patients.
Asunto(s)
Asma/metabolismo , Hidroxiurea/análogos & derivados , Inhibidores de la Lipooxigenasa/farmacocinética , Adolescente , Área Bajo la Curva , Superficie Corporal , Peso Corporal/fisiología , Niño , Cromatografía Líquida de Alta Presión , Femenino , Semivida , Humanos , Hidroxiurea/farmacocinética , MasculinoRESUMEN
OBJECTIVES: The effects of zileuton on terfenadine pharmacokinetics, and the effects of terfenadine alone and the combination on the duration of the QTc interval and the morphology of the TU complex were examined. METHODS: The study was double-blind, randomized, placebo-controlled, two period cross-over in 16 healthy volunteers. During each period, subjects received 60 mg of terfenadine every 12 h on days 1 to 7 and 600 mg of either zileuton or placebo for zileuton every 6 h on days 1 to 10. Blood samples were obtained on days 7 to 10 and serial ECGs were performed on days -1 and 7 in both periods. RESULTS: The combination of zileuton and terfenadine was well tolerated. Coadministration of zileuton with terfenadine resulted in a significant increase in the mean AUC and Cmax of terfenadine by approximately 35% and the mean AUC and Cmax of carboxyterfenadine by approximately 15%. The maximum concentration of terfenadine observed in the study was 9.6 ng.ml-1. The addition of zileuton to terfenadine did not result in significant changes in the evaluated ECG-recordings (QTc interval and morphology of TU complex). The difference in means for both maximum and average QTc interval was very small (< or = 2.3 ms), and there were no clinically significant changes in individual values. CONCLUSIONS: The relatively small pharmacokinetic effect of zileuton on terfenadine metabolism, with no change in the QTc interval, is unlikely to be of clinical significance. The interaction is minimal in comparison to the background variability of the population.
Asunto(s)
Antiinflamatorios no Esteroideos/farmacología , Antagonistas de los Receptores Histamínicos H1/farmacocinética , Hidroxiurea/análogos & derivados , Inhibidores de la Lipooxigenasa/farmacología , Terfenadina/farmacología , Adulto , Análisis de Varianza , Antiinflamatorios no Esteroideos/farmacocinética , Estudios Cruzados , Método Doble Ciego , Sinergismo Farmacológico , Electrocardiografía/efectos de los fármacos , Humanos , Hidroxiurea/farmacocinética , Hidroxiurea/farmacología , Inhibidores de la Lipooxigenasa/farmacocinética , Masculino , Terfenadina/análogos & derivados , Terfenadina/farmacocinéticaRESUMEN
The pharmacokinetic interaction potential of the new proton-pump inhibitor lansoprazole and theophylline was assessed in a double-blind, two-period (13-day duration per period), multiple-dose crossover study in 14 healthy male volunteers. Lansoprazole 60 mg or placebo once daily was coadministered with anhydrous theophylline 200 mg four times daily. Plasma theophylline concentrations were quantitated via high-performance liquid chromatography. Lansoprazole did not appear to affect substantially the absorption profile or clearance of theophylline. Theophylline area under the plasma concentration-versus-time curve over the 6-h dosing interval decreased slightly (13%) but statistically significantly during lansoprazole coadministration. As the magnitude of this effect was small, this interaction is likely to be clinically insignificant.
Asunto(s)
Inhibidores Enzimáticos/farmacocinética , Omeprazol/análogos & derivados , Inhibidores de la Bomba de Protones , Teofilina/farmacocinética , 2-Piridinilmetilsulfinilbencimidazoles , Absorción , Administración Oral , Adulto , Cromatografía Líquida de Alta Presión , Estudios Cruzados , Método Doble Ciego , Interacciones Farmacológicas , Inhibidores Enzimáticos/administración & dosificación , Inhibidores Enzimáticos/sangre , Semivida , Humanos , Lansoprazol , Masculino , Omeprazol/administración & dosificación , Omeprazol/sangre , Omeprazol/farmacocinética , Teofilina/administración & dosificación , Teofilina/sangreRESUMEN
This study was conducted to determine (i) the effect of omeprazole on steady-state concentrations of clarithromycin and 14-(R)-hydroxyclarithromycin in plasma and gastric mucosa, (ii) the effect of clarithromycin on steady-state concentrations of omeprazole in plasma, and (iii) the effect of clarithromycin on the suppression of gastric acid secretion by omeprazole. Twenty healthy, Helicobacter pylori-negative male subjects completed this three-period, double-blind, randomized crossover study. In period 1, all subjects received 40 mg of omeprazole each morning for 6 days. Twenty-four-hour gastric pH monitoring took place on days -1 and 6. Pharmacokinetic sampling took place on day 6. In periods 2 and 3, subjects were randomly assigned to receive either 40 mg of omeprazole or omeprazole placebo daily for 6 days plus clarithromycin (500 mg) every 8 h for 5 days with a single 500-mg dose on day 6. Gastric tissue and mucus samples were obtained via endoscopy on day 5. Gastric pH monitoring and pharmacokinetic sampling took place on day 6. Two-week washout intervals separated the three study periods. Clarithromycin increased mean omeprazole area under the concentration-time curve from 0 to 24 h from 3.3 +/- 2.0 to 6.3 +/- 4.5 micrograms.h/ml (P < 0.05) and harmonic mean half-life from 1.2 to 1.6 h (P < 0.05) but did not significantly alter the effect of omeprazole on gastric pH. Mean clarithromycin area under the concentration-time curve from 0 to 8 h increased from 22.9 +/- 5.5 (placebo) to 26.4 +/- 5.7 micrograms.h/ml (omeprazole) (P < 0.05) when clarithromycin was administered with omeprazole. Analysis of variance revealed that mean concentrations of clarithromycin in tissue and mucus were statistically significantly higher when clarithromycin was given with omeprazole than when clarithromycin was given with placebo (P <0.001). Mean maximum observed concentrations of clarithromycin in the gastric fundus increased from 20.8 +/- 7.6 (placebo) to 24.3 +/- 6.4 micrograms/g (omeprazole), and those in the gastric mucous from 4.2 +/- 7.7 placebo to 39.3 +/- 32.8 micrograms/g (omeprazole). Similar increases were observed for the 14-(R)-hydroxyclarithromycin. These results show that omeprazole increases concentrations of clarithromycin in gastric tissue and mucus and may provide a mechanism for synergy between clarithromycin ad omeprazole that explains the excellent eradication of H. pylori seen in clinical trials.
Asunto(s)
Antibacterianos/farmacocinética , Antiulcerosos/farmacología , Claritromicina/farmacocinética , Mucosa Gástrica/metabolismo , Omeprazol/farmacología , Adolescente , Adulto , Antibacterianos/sangre , Claritromicina/sangre , Estudios Cruzados , Método Doble Ciego , Interacciones Farmacológicas , Determinación de la Acidez Gástrica , Mucosa Gástrica/efectos de los fármacos , Humanos , Masculino , Persona de Mediana Edad , Moco/metabolismo , Estómago/efectos de los fármacosRESUMEN
The effects of single and multiple oral doses of zileuton on the pharmacokinetics of antipyrine and indocyanine green were studied in 16 healthy, nonsmoking adult men by means of a double-blind, randomized, parallel placebo-controlled design. Indocyanine green disposition was not significantly altered by zileuton. Plasma antipyrine clearance declined by 20% (p < 0.0005) and 52% (p < 0.0005) after single and multiple dose zileuton exposure, respectively. Total urinary recovery of unchanged antipyrine and metabolites decreased with zileuton exposure. Selective declines from baseline of 16% (p = 0.007) and 20% (p = 0.003) after single-dose zileuton and 30% (p < 0.0005) and 43% (p < 0.0005) after multiple-dose zileuton were detected in recovery of 4-hydroxyantipyrine and 3-hydroxymethylantipyrine, respectively. Urinary recovery of the N-demethylantipyrine metabolite norantipyrine and percent of conjugation of 3-hydroxymethylantipyrine were unchanged by zileuton. In conclusion, zileuton therapy has no detectable effect on indocyanine green disposition but exerts marked effects on antipyrine plasma and urine metabolite disposition.
Asunto(s)
Antiinflamatorios no Esteroideos/farmacología , Antipirina/farmacocinética , Hidroxiurea/análogos & derivados , Verde de Indocianina/farmacocinética , Inhibidores de la Lipooxigenasa/farmacología , Administración Oral , Adulto , Antiinflamatorios no Esteroideos/administración & dosificación , Antipirina/sangre , Antipirina/orina , Método Doble Ciego , Humanos , Hidroxiurea/administración & dosificación , Hidroxiurea/farmacología , Inhibidores de la Lipooxigenasa/administración & dosificación , MasculinoRESUMEN
The pharmacokinetics of zileuton, a novel selective 5-lipoxygenase inhibitor, were studied in 37 patients with rheumatoid arthritis after administration of 200 mg, 400 mg, and 600 mg, zileuton for 4 weeks. Patients had 6-h pharmacokinetic evaluation of zileuton on day 14. Plasma zileuton concentrations were quantitated using HPLC. Zileuton pharmacokinetic parameters were estimated using standard noncompartmental methods. A population analysis of zileuton pharmacokinetics was also performed with the NONMEM computer program. The pharmacokinetics of zileuton in patients with rheumatoid arthritis were similar to those previously estimated in normal healthy humans. The peak concentrations and the areas under the curves during the dosing interval were dose proportional. The noncompartmental means of the CL/f, terminal-phase half-life, and V/f of zileuton were approximately 545 ml min-1, 1.4 h, and 64.3 1, respectively. The estimate of population typical values of the CL/f for a 70-kg person (540 ml min-1) and V/f for a 70-kg person (64.8 1) from the NONMEM analysis were in agreement with the noncompartmental estimates. Differences in body weight, but not age or gender, helped explain some of the variability in the pharmacokinetics of zileuton in patients. Therefore, there is no pharmacokinetic basis for alteration of the zileuton dose size or the dosing schedule in patients with rheumatoid arthritis.
Asunto(s)
Artritis Reumatoide/tratamiento farmacológico , Hidroxiurea/análogos & derivados , Inhibidores de la Lipooxigenasa/farmacocinética , Administración Oral , Adolescente , Adulto , Anciano , Femenino , Humanos , Hidroxiurea/farmacocinética , Cinética , Masculino , Matemática , Persona de Mediana Edad , Factores de TiempoRESUMEN
The potential pharmacokinetic and pharmacodynamic interactions between zileuton, a 5-lipoxygenase inhibitor, and naproxen, a nonsteroidal anti-inflammatory drug that acts as a cyclo-oxygenase inhibitor, have been investigated in 24 healthy volunteers. Coadministration of these 2 drugs had no effect upon the plasma concentration-time curves of either zileuton (800mg) or naproxen (500mg) when compared with each drug administered alone. Both naproxen plasma concentrations during the elimination phase and area under the plasma concentration-time curve values were statistically significantly raised upon coadministration with zileuton, when compared with naproxen alone. However, these differences in these 2 values were sufficiently small to be of no clinical significance. There is no evidence that the combination of zileuton and naproxen had an effect on leukotriene B4 levels that was different from the inhibitory effect of zileuton alone, or had an effect on serum thromboxane B2 levels that was different from the effect of naproxen alone. Moreover, inhibition of the 5-lipoxygenase pathway by zileuton did not appear to aggravate the gastrointestinal adverse events commonly associated with naproxen administration. It is concluded that zileuton and naproxen may be coadministered with minimal risk of a clinically significant interaction.
Asunto(s)
Antiinflamatorios no Esteroideos/farmacocinética , Inhibidores de la Ciclooxigenasa/farmacocinética , Hidroxiurea/análogos & derivados , Inhibidores de la Lipooxigenasa/farmacocinética , Naproxeno/farmacocinética , Administración Oral , Adolescente , Adulto , Antiinflamatorios no Esteroideos/administración & dosificación , Antiinflamatorios no Esteroideos/efectos adversos , Antiinflamatorios no Esteroideos/sangre , Inhibidores de la Ciclooxigenasa/administración & dosificación , Inhibidores de la Ciclooxigenasa/efectos adversos , Inhibidores de la Ciclooxigenasa/sangre , Sistema Digestivo/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Método Doble Ciego , Interacciones Farmacológicas , Endoscopía , Humanos , Hidroxiurea/administración & dosificación , Hidroxiurea/efectos adversos , Hidroxiurea/sangre , Hidroxiurea/farmacocinética , Mucosa Intestinal/efectos de los fármacos , Mucosa Intestinal/lesiones , Leucotrieno B4/sangre , Inhibidores de la Lipooxigenasa/administración & dosificación , Inhibidores de la Lipooxigenasa/efectos adversos , Inhibidores de la Lipooxigenasa/sangre , Masculino , Naproxeno/administración & dosificación , Naproxeno/efectos adversos , Naproxeno/sangre , Tromboxano B2/sangreRESUMEN
The effects of age and gender on the single and multiple dose pharmacokinetics of zileuton have been examined in a phase I nonblinded study. A total of 27 healthy volunteers were evaluable, 9 in the young group (age range 20 to 40 years; 5 males and 4 females) and 18 in the elderly group (range 65 to 81 years; 9 males and 9 females). A single oral dose of zileuton 600mg was given to all volunteers on day 1 of the study and at 6-hour intervals from days 3 to 7. Analysis of variance showed slight but significant decreases in the mean apparent clearance of total and free drug in the healthy elderly population after a single zileuton dose, but no significant age-related differences after multiple 6-hourly doses. Similarly, zileuton peak and trough plasma concentrations, and values for half-life, volume of distribution and protein binding were not significantly affected by age after either a single dose or multiple administration. Moreover, gender effects on the pharmacokinetics were also absent after correction for bodyweight differences. From the results of the present study, it is concluded that there is no pharmacokinetic basis for alteration of zileuton dosage schedules in elderly patients.
Asunto(s)
Envejecimiento/metabolismo , Hidroxiurea/análogos & derivados , Inhibidores de la Lipooxigenasa/farmacocinética , Administración Oral , Adulto , Anciano , Anciano de 80 o más Años , Análisis de Varianza , Cromatografía Líquida de Alta Presión , Colorantes/química , Relación Dosis-Respuesta a Droga , Femenino , Semivida , Humanos , Hidroxilación , Hidroxiurea/administración & dosificación , Hidroxiurea/sangre , Hidroxiurea/farmacocinética , Verde de Indocianina/química , Inhibidores de la Lipooxigenasa/administración & dosificación , Inhibidores de la Lipooxigenasa/sangre , Circulación Hepática , Masculino , Reproducibilidad de los Resultados , Caracteres SexualesRESUMEN
In controlled trials involving asthma patients, zileuton - a selective 5-lipoxygenase inhibitor - has significantly improved pulmonary function and reduced symptoms. Since theophylline is frequently prescribed for asthma, we designed a placebo-controlled randomised crossover trial to examine the influence of zileuton on theophylline pharmacokinetics. 16 healthy adult males were given theophylline (Slo-Phyllin) 200mg 4 times daily for 5 days and either zileuton 800mg twice daily or a matching placebo. After a 15-day washout period, theophylline was resumed and the other study drugs reversed. During coadministration with zileuton, mean peak theophylline levels rose from 12.14 to 20.99 mg/L (p < 0.001), while the apparent plasma clearance dropped from 3.74 to 1.91 L/h (p < 0.001). The time to the peak theophylline concentration was delayed by 0.5 hours and the half-life was significantly prolonged by 1.5 hours. 14 volunteers reported 44 mild or moderately severe adverse events, possibly or probably related to coadministration of zileuton, and 8 volunteers reported 8 such events with placebo coadministration. Three volunteers receiving theophylline plus zileuton withdrew from the trial prematurely. Thus, a pharmacokinetic interaction that may produce theophylline toxicity exists between zileuton and theophylline. Accordingly, theophylline dosages in patients receiving zileuton should be adjusted to maintain levels within the therapeutic range. Upon initiation of zileuton, the typical asthma patient may require dosage reductions of one-half, and monitoring of plasma theophylline concentrations is recommended.
Asunto(s)
Broncodilatadores/farmacocinética , Hidroxiurea/análogos & derivados , Inhibidores de la Lipooxigenasa/farmacología , Teofilina/farmacocinética , Administración Oral , Adulto , Análisis de Varianza , Broncodilatadores/administración & dosificación , Broncodilatadores/efectos adversos , Broncodilatadores/sangre , Cromatografía Líquida de Alta Presión , Estudios Cruzados , Relación Dosis-Respuesta a Droga , Método Doble Ciego , Interacciones Farmacológicas , Semivida , Humanos , Hidroxiurea/administración & dosificación , Hidroxiurea/sangre , Hidroxiurea/farmacocinética , Hidroxiurea/farmacología , Inhibidores de la Lipooxigenasa/administración & dosificación , Inhibidores de la Lipooxigenasa/sangre , Inhibidores de la Lipooxigenasa/farmacocinética , Masculino , Teofilina/administración & dosificación , Teofilina/efectos adversos , Teofilina/sangreRESUMEN
The pharmacokinetics of single oral doses of zileuton 200 to 800mg, its R(+) and S(-) enantiomers, and its N-dehydroxylated and glucuronide metabolites have been investigated in a randomised study in 16 normal male healthy volunteers. Zileuton was 93.4% bound to plasma proteins. The overall dispositional pharmacokinetics of zileuton racemate appeared to be linear. The mean dose-normalised area under the concentration-time curve from zero to infinity (AUC0-infinity) remained constant, while the mean dose-normalised peak plasma concentration (Cmax) decreased with the increase in dose, possibly because of dissolution rate-limited absorption at the higher doses. The R(+) and S(-) enantiomers of zileuton may have similar absorption profiles, although the apparent total plasma clearance of the S(-) enantiomer was 49 to 76% higher than the corresponding values for the R(+) enantiomer. The AUC0-infinity of each enantiomer increased proportionately with dose. The pharmacokinetics of the N-dehydroxylated metabolite of zileuton were highly variable, with a more than dose-proportional increase in the mean dose-normalised Cmax and area under the concentration-time curve from zero to 24 hours. The elimination of the glucuronide metabolites of the R(+) and S(-) enantiomers of zileuton was formation rate-limited. The mean percentage of the administered zileuton dose recovered in urine as glucuronide metabolites ranged from 73.1 to 76.5% and showed no dose-related differences. The renal clearance of the glucuronide metabolites of zileuton exceeded the normal glomerular filtration rate, suggesting that these metabolites may be excreted through renal tubular secretion in addition to filtration.
Asunto(s)
Hidroxiurea/análogos & derivados , Inhibidores de la Lipooxigenasa/farmacocinética , Absorción , Administración Oral , Adulto , Análisis de Varianza , Disponibilidad Biológica , Proteínas Sanguíneas/metabolismo , Cromatografía Líquida de Alta Presión , Estudios Cruzados , Relación Dosis-Respuesta a Droga , Tasa de Filtración Glomerular , Glucuronatos/sangre , Glucuronatos/orina , Semivida , Humanos , Hidroxilación , Hidroxiurea/administración & dosificación , Hidroxiurea/metabolismo , Hidroxiurea/farmacocinética , Túbulos Renales Proximales/metabolismo , Inhibidores de la Lipooxigenasa/administración & dosificación , Inhibidores de la Lipooxigenasa/metabolismo , Masculino , Persona de Mediana Edad , Unión Proteica , Estereoisomerismo , Urea/administración & dosificación , Urea/análogos & derivados , Urea/metabolismo , Urea/farmacocinéticaRESUMEN
The effects of zileuton (Abbott-64077) on the pharmacokinetics of sulfasalazine (SASP) and its metabolites, sulfapyridine (SP) and N-acetylsulfapyridine (ASP), were studied in a randomised double-blind placebo-controlled study enrolling 14 healthy male volunteers. All subjects received SASP 1 g every 12 hours for 8 days and zileuton 800mg or placebo administered twice daily from day 4 to day 8 inclusive. Coadministration of zileuton did not significantly affect the area under the plasma concentration-time curve, the maximum (Cmax) or minimum (Cmin) plasma concentration and the time to Cmax of SASP, SP or ASP. Likewise, zileuton did not modify the terminal elimination half-life of SASP. It is concluded that coadministration of zileuton 1.6 g/day has no significant effects on the pharmacokinetics of SASP 2 g/day or its metabolites, SP and ASP.
Asunto(s)
Antiinfecciosos/farmacocinética , Antiinflamatorios/farmacocinética , Hidroxiurea/análogos & derivados , Inhibidores de la Lipooxigenasa/farmacología , Sulfasalazina/farmacocinética , Administración Oral , Adulto , Antiinfecciosos/administración & dosificación , Antiinfecciosos/sangre , Antiinflamatorios/administración & dosificación , Antiinflamatorios/sangre , Cromatografía Líquida de Alta Presión , Método Doble Ciego , Interacciones Farmacológicas , Semivida , Humanos , Hidroxiurea/administración & dosificación , Hidroxiurea/sangre , Hidroxiurea/farmacología , Inhibidores de la Lipooxigenasa/administración & dosificación , Inhibidores de la Lipooxigenasa/sangre , Masculino , Persona de Mediana Edad , Sulfapiridina/análogos & derivados , Sulfapiridina/sangre , Sulfapiridina/farmacocinética , Sulfasalazina/sangreRESUMEN
The pharmacokinetics and pharmacodynamics of AA-2414 [(+-)-7-(3,5,6-trimethyl-1,4-benzoquinon-2-yl)-7-phenylheptano+ ++ ic acid] were evaluated in 39 healthy male subjects after four different oral multiple-dosing regimens. Population pharmacokinetic analysis with NONMEM showed plasma concentration-time profiles of AA-2414 to be best characterized by a two-compartment open model with zero-order input and first-order elimination. The final estimates for oral clearance, volume of distribution, and steady-state volume of distribution were 10.7 ml/hr/kg, 92.8 ml/kg, and 280 ml/kg, respectively; the corresponding coefficients of variation for interindividual variability were 21%, 10%, and 9%. The pharmacokinetic parameters were associated only with body weight. The residual variability was 25%. The ex vivo platelet aggregation response to U-46619, a thromboxane A2 mimetic, was significantly inhibited by AA-2414. The effect was found to be linearly related to plasma concentration with population estimates of 2.3 mumol/L and 2.38 for the baseline effect and slope, respectively; the corresponding coefficients of variation for interindividual variability were 22% and 38%. The residual variability was 39%. The leukotriene B4, thromboxane B2, and anti-platelet aggregation factor activity measurements were not significantly affected by administration of AA-2414.
Asunto(s)
Benzoquinonas , Ácidos Heptanoicos , Quinonas/farmacocinética , Receptores de Tromboxanos/antagonistas & inhibidores , Ácido 15-Hidroxi-11 alfa,9 alfa-(epoximetano)prosta-5,13-dienoico , Administración Oral , Adolescente , Adulto , Peso Corporal , Método Doble Ciego , Humanos , Leucotrieno B4/sangre , Masculino , Agregación Plaquetaria/efectos de los fármacos , Inhibidores de Agregación Plaquetaria/farmacología , Endoperóxidos de Prostaglandinas Sintéticos/farmacología , Quinonas/administración & dosificación , Quinonas/sangre , Quinonas/farmacología , Tromboxano A2/análogos & derivados , Tromboxano A2/farmacología , Tromboxano B2/sangreRESUMEN
The biologic aggressiveness of palpable versus nonpalpable prostate cancer was evaluated in 666 patients studied with endosonography over a 24-month period. Biologic aggressiveness was defined by a combined histologic and grade-stage category score. In 314 patients suspected of having prostate cancer 328 biopsies were performed. Carcinoma was detected in 99 patients, by means of both palpation and endosonography (n = 80), endosonography alone (n = 9), and palpation alone (n = 8); two cancers were not detected with either palpation or endosonography. All patients with normal results of digital examination had a combined grade-stage category score lower than 9. Fifty-five of 69 patients (80%) with abnormal results of digital examination and available histologic data had a histologic score of 6 or higher; 38 of these patients (69%) had a combined grade-stage category score of 9 or higher. Although the number of patients is small, these data suggest that nonpalpable cancers are biologically less aggressive than palpable ones and that the advantage of endosonography over palpation in detection of clinically significant cancers is limited.
Asunto(s)
Adenocarcinoma/diagnóstico por imagen , Palpación , Neoplasias de la Próstata/diagnóstico por imagen , Adenocarcinoma/diagnóstico , Adenocarcinoma/patología , Anciano , Biopsia con Aguja , Humanos , Masculino , Persona de Mediana Edad , Próstata/patología , Neoplasias de la Próstata/diagnóstico , Neoplasias de la Próstata/patología , UltrasonografíaRESUMEN
The impact of assay variability on pharmacokinetic modeling was investigated. Simulated replications (150) of three "individuals" resulted in 450 data sets. A one-compartment model with first-order absorption was simulated. Random assay errors of 10, 20, or 30% were introduced and the ratio of absorption rate (Ka) to elimination rate (Ke) constants was 2, 10, or 20. The analyst was blinded as to the rate constants chosen for the simulations. Parameter estimates from the sequential method (Ke estimated with log-linear regression followed by estimation of Ka) and nonlinear regression with various weighting schemes were compared. NONMEM was run on the 9 data sets as well. Assay error caused a sizable number of curves to have apparent multicompartmental distribution or complex absorption kinetic characteristics. Routinely tabulated parameters (maximum concentration, area under the curve, and, to a lesser extent, mean residence time) were consistently overestimated as assay error increased. When Ka/Ke = 2, all methods except NONMEM underestimated Ke, overestimated Ka, and overestimated apparent volume of distribution. These significant biases increased with the magnitude of assay error. With improper weighting, nonlinear regression significantly overestimated Ke when Ka/Ke = 20. In general, however, the sequential approach was most biased and least precise. Although no interindividual variability was included in the simulations, estimation error caused large standard deviations to be associated with derived parameters, which would be interpreted as interindividual error in a nonsimulation environment. NONMEM, however, acceptably estimated all parameters and variabilities. Routinely applied pharmacokinetic estimation methods do not consistently provide unbiased answers. In the specific case of extended-release drug formulations, there is clearly a possibility that certain estimation methods yield Ka and relative bioavailability estimates that would be imprecise and biased.
Asunto(s)
Farmacocinética , Biometría , Modelos Biológicos , Análisis de RegresiónRESUMEN
A standardized endosonographic numeric method has been developed for the detection of prostate cancer. Eighty-six men were examined with a 5-MHz, 96-element linear-array probe. Mean gray-scale amplitudes were produced by a semiautomatic method for periprostatic fat and regions of interest within the external portion of the prostate gland that were visually suspicious for prostate cancer. Mean gray-scale amplitude ratios of visually abnormal areas of prostate to periprostatic fat (Ap/Af) were calculated. Pathologic confirmation of disease was obtained in all patients. Three different numeric Ap/Af ratios were compared with digital palpation and subjective visual interpretation of sonograms. The numeric method resulted in a consistently higher specificity, accuracy, and positive predictive value when compared with palpation and subjective interpretation. The initial results suggest that this technique may also detect atypical hyperplasia.
Asunto(s)
Endoscopía , Neoplasias de la Próstata/diagnóstico , Ultrasonografía , Adenocarcinoma/diagnóstico , Adenocarcinoma/patología , Adulto , Anciano , Anciano de 80 o más Años , Biopsia , Reacciones Falso Negativas , Reacciones Falso Positivas , Humanos , Masculino , Persona de Mediana Edad , Palpación , Próstata/patología , Hiperplasia Prostática/diagnóstico , Hiperplasia Prostática/patología , Neoplasias de la Próstata/patología , Prostatitis/diagnósticoRESUMEN
Suppose that a test formulation and a standard formulation are to be compared in an experiment with a two period crossover design. Suppose that it is desired to obtain a confidence interval for the ratio of the test formulation mean to the standard formulation mean for some variable. Suppose that the measurements on the variable will themselves be analyzed rather than analyzing the logarithms of the measurements. A method for obtaining an exact confidence interval for a rather general model is described. A method has previously been given for obtaining an exact confidence interval under a more restrictive model. The two models are contrasted.