RESUMEN
Inhalation of hypertonic saline (HS) acutely enhances mucociliary clearance (MC) in both health and disease. In patients with cystic fibrosis (CF), repeated use of HS causes a sustained improvement in MC as well as clinical benefit. The pharmacodynamic duration of activity on MC may be an important determinant of its therapeutic potential in other airways diseases. Before moving toward testing the clinical benefits of HS for non-CF indications, we sought to assess the duration of pharmacodynamic effects of HS in healthy subjects by performing radiotracer clearance studies at baseline, 30-min post-HS administration, and 4-h post-HS administration. Indeed, acceleration of MC was observed when measured 30 min after HS inhalation. This acceleration was most pronounced in the first 30 min after inhaling the radiotracer in the central lung region (mean Ave30Clr = 15.5 vs. 8.6% for 30-min post-HS treatment vs. mean baseline, respectively, P < 0.005), suggesting that acute HS effects were greatest in the larger bronchial airways. In contrast, when MC was measured 4 h after HS administration, all indices of central lung region MC were slower than at baseline: Ave30Clr = 5.9% vs. 8.6% (P = 0.10); Ave90Clr = 12.4% vs. 16.8% (P < 0.05); clearance through 3 h = 29.4 vs. 43.7% (P < 0.002); and clearance through 6 h = 39.4 vs. 50.2% (P < 0.02). This apparent slowing of MC in healthy subjects 4-h post-HS administration may reflect depletion of airway mucus following acute HS administration.
Asunto(s)
Pulmón/efectos de los fármacos , Depuración Mucociliar/efectos de los fármacos , Solución Salina Hipertónica/farmacología , Administración por Inhalación , Adulto , Bronquios/efectos de los fármacos , Femenino , Volumen Espiratorio Forzado , Voluntarios Sanos , Humanos , Pulmón/diagnóstico por imagen , Masculino , Moco/metabolismo , Cintigrafía , Radiofármacos/farmacocinética , Solución Salina Hipertónica/administración & dosificación , Solución Salina Hipertónica/farmacocinética , Adulto JovenRESUMEN
Sumatriptan exhibits low oral bioavailability partly due to presystemic metabolism, which may vary with regional differences in metabolic activity throughout the gastrointestinal tract. This study evaluated sumatriptan absorption in humans after administration orally and by oroenteric tube into the jejunum and cecum. Because the site of cecal administration varied, pharmacokinetic parameters for sumatriptan and its major metabolite were compared statistically only after oral and jejunal administration. One-half of the oral dose was recovered in the urine as parent (3%) and metabolite (46%). Sumatriptan was absorbed throughout the gastrointestinal tract; absorption was similar after oral and jejunal administration, and less after cecal administration. The metabolite AUC and the AUC ratio (metabolite/parent) were significantly lower after jejunal compared to oral administration; the AUC ratio was two-fold lower after cecal administration. Results suggest that presystemic metabolism of sumatriptan varies throughout the gastrointestinal tract and/or regional differences exist in the absorption of metabolite formed within the gastrointestinal tract.
Asunto(s)
Sistema Digestivo/metabolismo , Absorción Intestinal , Sumatriptán/farmacocinética , Administración Oral , Adulto , Ciego/metabolismo , Humanos , Intubación Gastrointestinal , Yeyuno/metabolismo , Masculino , Sumatriptán/administración & dosificación , Sumatriptán/sangreRESUMEN
3TC is a dideoxy-nucleoside analogue that has demonstrated in-vitro activity against human immunodeficiency virus (HIV). 3TC concentrations in humans were predicted before the initiation of clinical trials by interspecies scaling of pharmacokinetic parameters observed in animal species. Clearance and volume of distribution were estimated for humans using linear regression on a log-log scale of each parameter versus body weight for rats and dogs. The concentration-time profile and the average serum concentration at steady state after various dosage regimens were estimated as a basis for initial dose selection for clinical trials. The predicted parameters (clearance of 16.3 L/hr and volume of distribution of 40 L for a 70-kg man) were compared with that observed (mean clearance of 24 L/hr and mean volume of distribution of 96 L, mean weight of 74 kg) in 20 asymptomatic, HIV positive, volunteers after single intravenous doses of 3TC. Interspecies scaling was applied prospectively as a rationale for dose selection of 3TC in clinical trials.
Asunto(s)
Antivirales/farmacocinética , Inhibidores de la Transcriptasa Inversa , Zalcitabina/análogos & derivados , Animales , Antivirales/administración & dosificación , Peso Corporal/fisiología , Estudios Cruzados , Perros , Seropositividad para VIH/metabolismo , Humanos , Infusiones Intravenosas , Lamivudine , Masculino , Ratas , Especificidad de la Especie , Zalcitabina/administración & dosificación , Zalcitabina/farmacocinéticaRESUMEN
Cefuroxime axetil tablets have proved effective for the treatment of a variety of community-acquired infections. A suspension formulation has been developed for use in children. Two studies have been conducted to determine if the cefuroxime axetil formulations are bioequivalent. In the initial randomized, two-period crossover study, 24 healthy men received 250-mg doses of suspension and tablet formulations of cefuroxime axetil every 12 h after eating for seven doses. Each treatment period was separated by 4 days. Comparisons of serum and urine pharmacokinetic parameters indicated that the suspension and tablet formulations of cefuroxime axetil are not bioequivalent. Following the initial bioequivalency study, 0.1 % sodium lauryl sulfate (SLS) was added to the suspension to assure the homogeneity of the granules during the manufacturing process. In the subsequent randomized, three-period crossover study, 24 healthy men received single 250-mg doses of three cefuroxime axetil formulations: suspension without SLS, suspension with SLS, and tablet. Again each treatment period was separated by 4 days. Pharmacokinetic analyses demonstrated that while the suspension with SLS and suspension without SLS are bioequivalent, bioequivalence between the suspension with SLS and the tablet was not observed. Thus, the addition of the SLS surfactant to the suspension did not alter the bioavailability of the formulation.
Asunto(s)
Cefuroxima/análogos & derivados , Cefalosporinas/farmacocinética , Adulto , Disponibilidad Biológica , Cefuroxima/administración & dosificación , Cefuroxima/farmacocinética , Humanos , MasculinoRESUMEN
STUDY OBJECTIVE: To compare the frequency, severity, and time course of venous irritation after administration of a single intravenous dose of phenytoin with an equimolar dose of fosphenytoin, a water-soluble phenytoin prodrug. DESIGN: Randomized, double-blind, two-period, crossover study. SETTING: University hospital clinical research unit. PATIENTS: Twelve healthy volunteers within 15% of ideal body weight and with no clinically significant abnormalities on physical examination, medical history, or laboratory assessment. INTERVENTIONS: Volunteers randomly received a 30-minute infusion of phenytoin sodium 250 mg (250 mg/5 ml) or an equimolar dose of fosphenytoin 375 mg (375 mg/5 ml). Subjects returned for the crossover treatment 14-21 days later. MEASUREMENTS AND MAIN RESULTS: Subjects assessed venous irritation (pain, burning, itching), and investigators evaluated phlebitis (erythema, swelling, tenderness), induration, exudation, and cording. Phenytoin was associated with a significantly higher degree of pain at the infusion site in all subjects and a significant degree of phlebitis in eight subjects (p < 0.05); cording occurred in six subjects. The time course of phenytoin-induced phlebitis was bimodal. Erythema and tenderness were prominent at the end of the infusion and again at 24 hours. Cording was first noted between 24 hours and 1 week after infusion. In contrast, fosphenytoin was associated with mild pain in two subjects, one incident of phlebitis, and no erythema or cording. CONCLUSIONS: Fosphenytoin administration resulted in significantly less venous irritation and phlebitis compared with an equimolar dose of phenytoin. The clinical use of this water-soluble phenytoin prodrug should minimize the frequency and severity of infusion-site reactions and should allow convenient, rapid, intravenous administration of drug, undiluted or admixed with intravenous solutions.
Asunto(s)
Fenitoína/análogos & derivados , Fenitoína/efectos adversos , Flebitis/inducido químicamente , Adolescente , Adulto , Método Doble Ciego , Edema/inducido químicamente , Eritema/inducido químicamente , Humanos , Infusiones Intravenosas , Masculino , Dolor/inducido químicamente , Fenitoína/administración & dosificación , Prurito/inducido químicamenteRESUMEN
Remifentanil is a newly synthesized 4-anilido-piperidine with an ester side chain susceptible to esterase metabolism. We evaluated the safety, analgesic efficacy, and pharmacokinetics of remifentanil in 48 male volunteers. Volunteers were randomized to receive increasing doses of remifentanil, alfentanil, or placebo. Analgesic efficacy was evaluated by increasing tolerance to a spring-loaded rod measured at the tibia and sternum at multiple time points. Respiratory depression was measured by changes in arterial blood gas tensions and peripheral hemoglobin oxygen saturation. Hemodynamics were continuously monitored by means of an intra-arterial catheter. Both remifentanil and alfentanil produced a dose-dependent increase in analgesia and respiratory depression. Remifentanil was 20 to 30 times more potent (milligram to milligram) than alfentanil when assessed by either analgesic efficacy or respiratory measures. The pharmacokinetics of remifentanil were best described by a biexponential decay curve. Remifentanil had a small volume of distribution of 0.39 (SD, +/- 0.25) L/kg (alfentanil, 0.52 +/- 2 L/kg), with a rapid distribution phase of 0.94 (SD, +/- 0.57) min and an extremely short elimination half-life of 9.5 (SD, +/- 4) min compared with an elimination half-life of alfentanil of 58 (SD, +/- 7.6) min. The t1/2 ke0 (half-time for equilibration between plasma and the effect compartment) of remifentanil for analgesia was calculated as 1.3 min. Thus, remifentanil appears to have a pharmacologic profile similar to other potent mu agonists, but with exceptionally short-lasting pharmacokinetics, which is likely to make it a very useful opioid for clinical practice.
Asunto(s)
Analgésicos Opioides/farmacología , Narcóticos/farmacología , Piperidinas/farmacología , Analgésicos Opioides/farmacocinética , Depresión Química , Hemodinámica/efectos de los fármacos , Hemodinámica/fisiología , Humanos , Masculino , Narcóticos/farmacocinética , Piperidinas/farmacocinética , Remifentanilo , Respiración/efectos de los fármacos , Respiración/fisiología , Seguridad , Factores de TiempoRESUMEN
During development of a ranitidine effervescent oral solution dosage form, a marked decrease was observed in the extent of ranitidine absorption relative to the conventional oral tablet. Two studies were conducted in healthy volunteers to confirm the involvement of an excipient, SAPP (sodium acid pyrophosphate), and the mechanism of interaction, altered gastrointestinal transit. The first study (n = 12) involved single-dose crossover comparisons of (A) 150 mg ranitidine with 1132 mg SAPP versus (B) 150 mg ranitidine and (C) 150 mg ranitidine with all the effervescent tablet excipients except SAPP versus (D) a 150-mg ranitidine effervescent tablet, all administered as oral solutions. Serum ranitidine AUC, Cmax, and tmax were compared using two one-sided t test 90% confidence intervals (CI). Comparing treatments A to B and D to C, all 90% CI were below the 80-120% range, indicating significantly less extensive ranitidine absorption (54% based on AUC) from the oral solutions containing SAPP. The second study (n = 12) was a single-dose crossover comparing 50 microCi 111 InCl solutions with and without 1132 mg SAPP. Gastrointestinal transit times, determined by scintigraphic imaging, were compared between treatments. Gastric emptying time was unchanged, but small intestinal transit time was decreased to 56% in the presence of SAPP. More rapid small intestinal transit associated with an excipient of a solution dosage form apparently resulted in a decreased extent of ranitidine absorption. This observation contradicts the conventional wisdom that oral solutions are unlikely to fall short of bioequivalence relative to solid oral formulations.
Asunto(s)
Difosfatos/farmacología , Tránsito Gastrointestinal/efectos de los fármacos , Ranitidina/farmacocinética , Adulto , Disponibilidad Biológica , Cromatografía Líquida de Alta Presión , Humanos , Radioisótopos de Indio , Absorción Intestinal/efectos de los fármacos , Masculino , Soluciones , Espectrofotometría Ultravioleta , ComprimidosRESUMEN
OBJECTIVE: To determine the safety and pharmacokinetics of the nucleoside analogue, 3TC. DESIGN: A Phase I, open-label, single-centre study. METHODS: Twenty asymptomatic, HIV-infected male patients with CD4 lymphocyte counts < 500 x 10(6)/l who had not received previous antiretroviral therapy completed the study. Each patient received a single intravenous dose followed by a single oral dose of 3TC. Four patients were dosed at each of five dose levels (0.25, 1.0, 2.0, 4.0 and 8.0 mg/kg). RESULTS: The most commonly reported adverse event was headache, which was generally reported to be mild. The mean bioavailability of 3TC was 82% following oral administration. The majority of the dose (approximately 70%) was excreted unchanged in the urine. CONCLUSIONS: Overall, 3TC was well tolerated following dosing, and there were no significant changes in the safety parameters measured. Phase I/II clinical trials with 3TC are ongoing to evaluate its safety, pharmacokinetics and preliminary activity.
Asunto(s)
Infecciones por VIH/tratamiento farmacológico , Inhibidores de la Transcriptasa Inversa , Zalcitabina/análogos & derivados , Administración Oral , Adulto , Relación Dosis-Respuesta a Droga , Esquema de Medicación , Tolerancia a Medicamentos , Cefalea/inducido químicamente , Humanos , Infusiones Intravenosas , Lamivudine , Masculino , Persona de Mediana Edad , Zalcitabina/efectos adversos , Zalcitabina/sangre , Zalcitabina/farmacocinética , Zalcitabina/uso terapéuticoRESUMEN
The pharmacokinetics of cefuroxime axetil suspension in 28 infants and children, ranging in age from 3 months to 12 years (mean, 23 months), were studied. Mean maximum serum cefuroxime concentrations of 3.3, 5.1, and 7.0 micrograms/ml were achieved 3.6, 2.7, and 3.1 h after the administration of doses of 10, 15, and 20 mg, respectively, of cefuroxime axetil suspension per kg of body weight together with milk or milk formula. These concentrations exceed the MICs for common respiratory tract pathogens, including beta-lactamase-producing strains of Haemophilus influenzae and Moraxella (Branhamella) catarrhalis. Following a 10- or 15-mg/kg dose, serum cefuroxime concentrations are similar to those achieved in adults following the administration of a 250-mg cefuroxime axetil tablet. There were linear relationships between dose and both maximum serum cefuroxime concentration and area under the serum drug concentration-verus-time curve. The mean half-life of cefuroxime in serum was independent of dose and ranged from 1.4 to 1.9 h. No cefuroxime axetil (intact ester) was detected in the blood. The intact ester in the urine of four children was measured; however, the amount recovered represented less than 0.1% of the administered dose.
Asunto(s)
Cefuroxima/análogos & derivados , Adolescente , Cefuroxima/administración & dosificación , Cefuroxima/farmacocinética , Niño , Preescolar , Estudios de Evaluación como Asunto , Semivida , Humanos , Lactante , SuspensionesRESUMEN
The pharmacokinetics of single doses of cefaclor at 250 and 375 mg and cefuroxime axetil at 250 mg administered under optimal conditions (i.e., cefuroxime axetil after food and cefaclor in the fasted state) were studied in 24 healthy male volunteers. Drug concentrations in serum were related to MICs for common respiratory tract pathogens by using data generated from a recently completed national survey. The time the concentrations in serum exceeded the MICs for Haemophilus influenzae, Streptococcus pneumoniae, and Moraxella (formerly Branhamella) catarrhalis were significantly greater (P less than 0.05) for cefuroxime axetil at 250 mg than for cefaclor at 250 or 375 mg. With the recommended dosing regimens (cefuroxime axetil at 250 mg and cefaclor at 375 mg twice daily or cefaclor at 250 mg three times daily), cefuroxime concentrations exceed the MIC for 90% of the strains tested for a greater time period than cefaclor concentrations with either regimen. The reasons for this difference are (i) the greater potency and slower clearance of cefuroxime compared with those of cefaclor and (ii) the greater sensitivity of these pathogens to cefuroxime.
Asunto(s)
Cefaclor/farmacocinética , Cefuroxima/análogos & derivados , Profármacos/farmacocinética , Administración Oral , Adulto , Cefaclor/sangre , Cefuroxima/sangre , Cefuroxima/farmacocinética , Haemophilus influenzae/efectos de los fármacos , Semivida , Humanos , Absorción Intestinal , Masculino , Pruebas de Sensibilidad Microbiana , Moraxella/efectos de los fármacos , Proyectos Piloto , Streptococcus pneumoniae/efectos de los fármacosRESUMEN
The absorption of albuterol from a single 4-mg oral dose of Volmax and Proventil Repetabs was investigated under both fasting and fed conditions in an open-label, randomized, four-period, crossover study in 24 healthy male volunteers. Blood was collected for determination of albuterol plasma concentrations by HPLC over 30 hours postdose. Twenty subjects were evaluable for data analysis. The mean Cmax for Volmax; administered after a meal was 19% lower than that of the drug administered in a fasting state (3.9 ng/mL vs. 4.8 ng/mL; P less than .01). An almost equivalent lowering of the mean Cmax (by 21%) was observed for Proventil Repetabs after administration with a meal versus fasting (4.2 ng/mL vs. 5.3 ng/mL; P less than .01). There were no significant differences between the two formulations in the degree of Cmax reduction due to the presence of food. The tmax occurred significantly later during the fed treatment for Volmax only (4.9 hours fasted vs. 6.4 hours fed; P less than .01). The lag time was significantly greater during the fed treatments for Volmax. No differences were observed in the area under the plasma concentration-time curve (AUC) for either formulation under fasting versus fed conditions, suggesting that the extent of absortion was not altered by food. Overall, food caused a more sustained release of albuterol from both Volmax and Proventil Repetabs.
Asunto(s)
Albuterol/farmacocinética , Alimentos , Administración Oral , Adulto , Albuterol/administración & dosificación , Albuterol/sangre , Preparaciones de Acción Retardada , Esquema de Medicación , Ayuno/sangre , Humanos , MasculinoRESUMEN
A new extended-release formulation of albuterol, Volmax, was developed based on the oral osmotic drug delivery system. Proventil Repetabs, another extended-release formulation of albuterol, is a repeat-action tablet. The steady-state pharmacokinetic profile of Volmax 8 mg orally every 12 hours for 3 days was compared with that of Proventil Repetabs 8 mg orally every 12 hours for 3 days in a randomized, two-way, crossover study in 23 healthy men. Results were determined for both daytime and nighttime dosing intervals. Volmax demonstrated significantly less peak-trough fluctuation during both dosing intervals than Proventil Repetabs (p less than 0.05). Peak plasma concentrations were higher and occurred earlier with Proventil Repetabs. There were no significant differences between the two formulations with respect to reported adverse experiences. Volmax exhibited a more controlled release of albuterol during both daytime and nighttime dosing intervals than Proventil Repetabs.
Asunto(s)
Albuterol/farmacocinética , Administración Oral , Adolescente , Adulto , Albuterol/administración & dosificación , Preparaciones de Acción Retardada , Esquema de Medicación , Humanos , Masculino , ComprimidosRESUMEN
The protein binding and pharmacokinetics of diazepam, ACC-9653 (a phenytoin prodrug), and phenytoin were evaluated in nine healthy male volunteers following administration of diazepam and ACC-9653, alone or concomitantly, in a randomized crossover design. No significant differences were observed in the fraction unbound or pharmacokinetic parameters of ACC-9653, phenytoin, or diazepam when ACC-9653 was administered alone compared to concomitant administration with diazepam. The phenytoin fraction unbound increased significantly with increased concentrations of ACC-9653, indicating displacement of phenytoin from its binding sites by ACC-9653. ACC-9653 also demonstrated concentration dependent binding. The lack of a significant pharmacokinetic drug interaction between ACC-9653 and diazepam suggests that these drugs may be safely administered together, although this conclusion should be confirmed in the intended patient population.
Asunto(s)
Diazepam/farmacocinética , Fenitoína/análogos & derivados , Fenitoína/farmacocinética , Profármacos/farmacocinética , Adulto , Interacciones Farmacológicas , Electrocardiografía , Humanos , Masculino , Fenitoína/efectos adversos , Unión Proteica , UltrafiltraciónRESUMEN
3-Phosphoryloxymethyl phenytoin disodium (ACC-9653) is a water-soluble investigational phenytoin (PHT) prodrug for parenteral administration. The objectives of this investigation were to determine the absolute bioavailability and free fraction of PHT after intravenous (i.v.) administration of ACC-9653. Twelve healthy male volunteers received PHT sodium (250 mg/5 ml; 229.95 mg free acid) and ACC-9653 (375 mg/5 ml; 232.87 mg free acid) i.v. in 30 min in a randomized, double-blind cross-over fashion. The conversion half-life (t 1/2) of ACC-9653 to PHT was 9.3 +/- 2.7 min. ACC-9653 was not detected in urine and greater than 99% of ACC-9653 was converted to PHT. The PHT area under the curve (AUC) was not statistically different between treatments; the bioavailability of PHT after ACC-9653 was 99 +/- 11%. The fraction of unbound converted PHT at the end of the prodrug infusion, in the presence of 44 micrograms/ml ACC-9653, was significantly higher than at 180 min, when the concentration of ACC-9653 was 0.1 microgram/ml. ACC-9653 was shown to be a bioequivalent PHT prodrug exhibiting less irritation at the injection site than the current marketed PHT.
Asunto(s)
Fenitoína/análogos & derivados , Fenitoína/farmacocinética , Disponibilidad Biológica , Humanos , Inyecciones Intravenosas , Masculino , Concentración Osmolar , Fenitoína/sangre , Fenitoína/farmacología , Profármacos , Factores de TiempoRESUMEN
Diazepam 10 mg/2 mL iv was administered undiluted over five minutes to nine healthy men on two separate occasions. The infusion site was evaluated before and after each infusion by subject assessment of pain on a severity scale of zero (none) to ten (most). Blood samples were collected at 0, 5, 20, 30, 45, and 60 minutes, and periodically for 72 hours postinfusion. Diazepam plasma concentrations were determined by HPLC. Concentrations at five minutes (end of infusion) ranged from 0 to 889 ng/mL. Maximum plasma concentration (Cmax) was observed at 5 minutes for 10 treatments, at 20 minutes for 7 treatments, and at 30 minutes for 1 treatment. The observed Cmax ranged from 221 to 889 ng/mL. When time to reach peak plasma concentration (tmax) was 5 minutes, the Cmax was significantly greater than when tmax was 20 minutes (670 +/- 87 vs. 267 +/- 40 ng/mL, p less than 0.005). The area under the curve did not differ significantly between these two groups. The pain score at the end of infusion ranged from zero to five and was inversely related to the concentration at five minutes (r2 = 0.45, p = 0.002). The association between venous irritation, a low plasma concentration at the end of the infusion, and a delayed Cmax suggests that diazepam precipitated in the vein.
Asunto(s)
Diazepam/efectos adversos , Adulto , Cromatografía Líquida de Alta Presión , Diazepam/administración & dosificación , Diazepam/sangre , Humanos , Infusiones Intravenosas , MasculinoRESUMEN
The bioavailability of phenytoin from ACC-9653 versus intravenously administered sodium phenytoin was determined using a crossover design for intravenous and intramuscular administration of ACC-9653 to healthy volunteers. Absolute bioavailability of phenytoin derived from ACC-9653 in each subject was calculated as the ratio of the phenytoin area under the plasma concentration time curve for time 0 to infinity [AUC(0-inf)] after ACC-9653 divided by the phenytoin AUC(0-inf) after intravenous sodium phenytoin. The mean absolute bioavailability of ACC-9653 was 0.992 after intravenous administration and 1.012 after intramuscular administration. These data establish that the bioavailability of ACC-9653 is complete following intravenous or intramuscular administration in single-dose volunteer studies. The absolute bioavailability of phenytoin derived from ACC-9653 in subjects with therapeutic plasma phenytoin concentrations is being studied in patients given simultaneous infusions of stable isotope-labeled tracer doses of ACC-0653 and sodium phenytoin.
Asunto(s)
Fenitoína/análogos & derivados , Profármacos/metabolismo , Disponibilidad Biológica , Ensayos Clínicos como Asunto , Humanos , Fenitoína/administración & dosificación , Fenitoína/metabolismo , Profármacos/administración & dosificación , Distribución AleatoriaRESUMEN
A new prodrug of phenytoin, the disodium phosphate ester of 3-hydroxymethyl-5,5-diphenylhydantoin (ACC-9653), was administered intravenously over 30 minutes to four different groups of volunteers at doses of 150, 300, 600, and 1200 mg. The prodrug and phenytoin were measured in plasma samples, collected at specified times, by specific high performance liquid chromatography (HPLC) assays. The prodrug, after achieving a maximum concentration at the end of the 30-minute infusion (Cmax 20, 36, 75, 129 micrograms/mL) declined rapidly with a half-life (t1/2) of about 8 minutes. The area under the plasma concentration-time curve (10, 19, 43, 77 mg.hr/L) was proportional to dose whereas the total clearance, 14 L/hr, was independent of dose. The volume of distribution of the prodrug, a polar, water-soluble molecule was about 2.6 L, indicating that most of the dose remained in the plasma. The concentration of phenytoin reached 90% of its maximum about 12 minutes after the end of the infusion of ACC-9653. At the dose of 1200 mg of prodrug, the average peak concentration of phenytoin was about 17 micrograms/mL, near the upper limit of the therapeutic range. Adverse reactions (lightheadedness, nystagmus, incoordination) were minor and attributed to phenytoin. No significant abnormalities in ECG, Holter monitoring, or EEG were noted after the infusion of ACC-9653.
Asunto(s)
Fenitoína/análogos & derivados , Fenitoína/farmacocinética , Profármacos , Adulto , Cromatografía Líquida de Alta Presión , Electrocardiografía , Hemodinámica/efectos de los fármacos , Humanos , Infusiones Intravenosas , Masculino , Fenitoína/administración & dosificación , Fenitoína/efectos adversos , Profármacos/efectos adversos , Espectrofotometría UltravioletaRESUMEN
Ten healthy male volunteers completed a study to determine the effect of cimetidine dose timing on the oral clearance of propranolol. Propranolol HCl 160 mg as tablets, was administered daily at 8 AM for 4 consecutive days on three occasions. In addition, cimetidine HCl 800 mg as tablets, was administered either simultaneously in the morning with propranolol (8 AM), at bedtime (10 PM), or not at all (control). Each treatment was separated by at least a 3-day washout. Propranolol and cimetidine serum samples were measured over the 24-hour dosing interval after the last propranolol dose. Cimetidine administration at 8 AM and 10 PM was associated with significant mean increases in the propranolol area under the serum concentration-time curve of 26% and 41%, respectively (P less than .002). The mean elimination half-life of propranolol was 6.3 hours during all three treatments. There was no significant difference in area under cimetidine serum concentration time curve between 8 AM and 10 PM dosing. Dosing cimetidine at bedtime 10 hours before propranolol does not diminish the magnitude of interaction.
Asunto(s)
Cimetidina/administración & dosificación , Propranolol/farmacocinética , Administración Oral , Adulto , Cimetidina/sangre , Cimetidina/farmacocinética , Cimetidina/farmacología , Interacciones Farmacológicas , Humanos , Cinética , Masculino , Propranolol/sangre , Propranolol/farmacología , Factores de TiempoRESUMEN
Histamine H2-antagonists have the ability to produce fundamental changes in the absorption and disposition of other drugs. However, there are similarities and differences between the H2-antagonists in this respect, depending on the process involved. By increasing the intragastric pH any H2-antagonist has the potential of altering the absorption of weak acids or weak bases. However, since the rise in intragastric pH is not immediate, as with antacids, this type of interaction might be avoided for concomitantly administered, rapidly absorbed drugs. Whereas cimetidine inhibits hepatic mixed-function oxidase drug metabolism, ranitidine does not have this characteristic. Clinical studies have found that cimetidine produces a 20 to 60 percent decrease in the clearance of 23 drugs (such as warfarin, theophylline, quinidine, phenytoin, imipramine, propranolol, nifedipine). Marketed and investigational H2-antagonist drugs differ in their ability to inhibit drug metabolism due to the combined characteristics of cytochrome P-450 binding affinity and therapeutic dosage. Cimetidine also inhibits the renal-tubular secretion of other weak bases (such as procainamide). Management suggestions are presented to help clinicans predict and avoid failure in drug therapy as a result of these drug interactions.
Asunto(s)
Antagonistas de los Receptores H2 de la Histamina/farmacología , Absorción , Disponibilidad Biológica , Cimetidina/metabolismo , Cimetidina/farmacología , Cimetidina/uso terapéutico , Inhibidores Enzimáticos del Citocromo P-450 , Relación Dosis-Respuesta a Droga , Interacciones Farmacológicas , Antagonistas de los Receptores H2 de la Histamina/metabolismo , Antagonistas de los Receptores H2 de la Histamina/uso terapéutico , Humanos , Imidazoles/metabolismo , Imidazoles/farmacología , Imidazoles/uso terapéutico , Riñón/efectos de los fármacos , Riñón/metabolismo , Hígado/efectos de los fármacos , Hígado/metabolismo , Tasa de Depuración Metabólica/efectos de los fármacos , Ranitidina/metabolismo , Ranitidina/farmacología , Ranitidina/uso terapéutico , Distribución TisularRESUMEN
Twelve healthy male volunteers were treated with 1200 mg/day cimetidine, 300 mg/day ranitidine, or no H2-receptor antagonist (control) for seven days in a sequence determined by Latin-square design. Each treatment period was separated by a seven-day washout. On the third day of each treatment period, 80 mg propranolol every 12 hours for nine doses was initiated. Whole blood concentrations of propranolol and 4-hydroxypropranolol were measured at 12 time points during the 12-hour period following administration of the last propranolol dose. Heart rate was measured before each blood sample was withdrawn. Cimetidine treatment was associated with a 47 per cent increase in the area under the propranolol concentration-time curve and a 17 per cent increase in elimination half-life of propranolol. Ranitidine had no significant effect on the concentration-time profile of propranolol. There were no significant differences in the 4-hydroxypropranolol pharmacokinetic parameters during any of the treatments. There was, however, a significant decrease in the average 4-hydroxypropranolol-to-propranolol steady-state concentration ratio during the cimetidine treatment. There was no significant difference in heart rate between any of the treatments. The elevation of propranolol concentrations during cimetidine treatment is likely due to metabolic inhibition by cimetidine.