RESUMEN
The drug-food and drug-drug interaction between grapefruit juice (GFJ) and ketoconazole (KETO) was evaluated in schizophrenic patients given a single dose of clozapine (CLZ). CLZ is metabolized primarily by CYP isozymes 3A4 and 1A2 to two principal metabolites, desmethylclozapine (DCLZ) and clozapine N-oxide (CNO). GFJ and KETO are well known potent CYP 3A4 inhibitors in the gastrointestinal tract and hepatic isozymes, respectively. Twenty-one schizophrenic patients participated in the co-administration of CLZ 50 mg and GFJ. After a one-week washout, five patients were given double the GFJ (HGFJ) dose for 7 consecutive days. In another group of five patients, ketoconazole (KETO) 400 mg was given for 7 consecutive days. At the end of the 7-day period for both groups, CLZ was coadministered with the HGFJ and KETO groups. CLZ, DCLZ and CNO were assayed by HPLC. GFJ, HGJF and ketoconazole failed to significantly change CLZ disposition. Metabolites DCLZ and CNO concentrations remained unchanged during the study. The only exception was decreased Cmax in DCLZ and CNO concentrations. These results indicate that CYP 3A4 inhibition may not be clinically significant compared to CYP 1A2, as previous studies show a dramatic increase in CLZ plasma concentrations with fluvoxamine (CYP 1A2 inhibitor). The reasons for the lack of drug-food and drug-drug interactions with CLZ and CYP 3A4 inhibitors can be explained by the higher Ki values for gastrointestinal and hepatic CYP 3A4 isozymes.
Asunto(s)
Antipsicóticos/sangre , Bebidas , Citrus , Clozapina/sangre , Inhibidores Enzimáticos del Citocromo P-450 , Oxigenasas de Función Mixta/antagonistas & inhibidores , Esquizofrenia/sangre , Adulto , Antifúngicos/farmacología , Antipsicóticos/uso terapéutico , Clozapina/uso terapéutico , Estudios Cruzados , Citocromo P-450 CYP3A , Sistema Enzimático del Citocromo P-450/fisiología , Interacciones Farmacológicas , Inhibidores Enzimáticos/farmacología , Interacciones Alimento-Droga , Humanos , Cetoconazol/farmacología , Masculino , Oxigenasas de Función Mixta/fisiología , Esquizofrenia/tratamiento farmacológicoRESUMEN
The absolute bioavailability and pharmacokinetics of three formulations of ondansetron hydrochloride 24 mg--an oral tablet, an intravenous solution, and an extemporaneous rectal suppository--were studied. Twelve healthy, nonsmoking volunteers (six men and six women) were given ondansetron in a study with a three-way cross-over design. All subjects received each dosage form on the same day in the following order: oral tablet, rectal suppository, and intravenous infusion. Administrations were separated by one week. Blood sampling times varied, depending on the administration route. Mean absolute bioavailability for the oral tablet and the rectal suppository differed significantly. Absorption of ondansetron was prolonged when it was administered as the rectal suppository. Absolute bioavailability for the 24-mg tablet was similar to that for other tablet strengths in previous studies. All subjects completed the study without significant adverse effects. Absorption of ondansetron from the rectal suppository was prolonged compared with the oral tablet and the i.v. infusion. Bioavailability for the 24-mg suppository formulation was considerably lower than for the 24-mg tablet.
Asunto(s)
Antieméticos/farmacocinética , Ondansetrón/farmacocinética , Disponibilidad Biológica , Estudios Cruzados , Femenino , Semivida , Humanos , Infusiones Intravenosas , Masculino , Ondansetrón/administración & dosificación , Supositorios , ComprimidosRESUMEN
The treatment of Alzheimer's disease is of increasing importance as the population ages and the number of people with the disease increases. The aetiology of Alzheimer's disease is complex and therefore treatment strategies rely on generalised pathological findings. Cholinesterase inhibitors enhance a generalised deficit of central nervous system acetylcholine and are the first class of agents specifically approved for the treatment of Alzheimer's disease. The clinical efficacy of the different cholinesterase inhibitors is similar; however, differences in pharmacodynamic and pharmacokinetic parameters can influence tolerability and safety in the elderly population. Concomitant disease states, significant drug interactions and the altered kinetics and dynamics seen in elderly patients can also affect treatment outcome. Although cholinesterase inhibitors are not 'curative' for Alzheimer's disease, clinical evidence indicates that these drugs can significantly delay the progress of cognitive impairment. Consequently, they represent a useful treatment for the symptoms of Alzheimer's disease in the elderly.
Asunto(s)
Anciano/psicología , Enfermedad de Alzheimer/tratamiento farmacológico , Inhibidores de la Colinesterasa/uso terapéutico , Enfermedad de Alzheimer/psicología , Inhibidores de la Colinesterasa/efectos adversos , Inhibidores de la Colinesterasa/farmacocinética , Interacciones Farmacológicas , HumanosRESUMEN
The drug-drug interaction between fluvoxamine (FLV) and clozapine (CLZ) was evaluated by in-vitro and in-vivo methods. In-vitro studies were conducted using human hepatic microsomal preparations with standard chemical inhibitors of the cytochrome P450 (CYP 450) isozyme system. Furafyline, FLV, troleandomycin (TAO) and erythromycin were used as the chemical inhibitors. For the in-vivo study, nine male schizophrenic patients were administered a single dose of CLZ 50 mg on two separate occasions with a 2-week FLV treatment of 50 mg twice a day in between each CLZ dose. Blood samples were obtained over 48 h following CLZ administration. CLZ and its two principle metabolites, clozapine N-oxide (CNO) and desmethylclozapine (DCLZ), were measured by high performance liquid chromatography with ultraviolet detection for both in-vitro and in-vivo studies. The in-vitro formation of DCLZ was inhibited by furafyline and FLV by 42.0% and 48.5% (P<0.01), respectively. TAO and erythromycin had only modest inhibition effects on DCLZ formation of 18.3% and 21.0% (P = NS), respectively. CNO in-vitro formation was significantly reduced by TAO and erythromycin by 44.5% and 45.0% (P<0.01), respectively. Furafyline and FLV had only modest effects of 19.2% and 8.5% (P = NS), respectively. In schizophrenic patients, FLV resulted in a pronounced increased in CLZ plasma concentrations with the total mean CLZ AUC increased by a factor of 2.58 from 780.8 ng/ml per hour to 2218.0 ng/ml per hour (P<0.001). All patients were sedated during combined FLV and CLZ use. During FLV treatment, CNO and DCLZ AUC both decreased by 18.8% (P = 0.07) and 9.0% (P = NS), respectively. These results indicate that in-vitro evaluations may not always accurately reflect changes in drug-drug interaction observed in-vivo. Careful patient monitoring is recommended during FLV/CLZ co-administration.