Assuntos
Benzodiazepinas/farmacologia , Sistema Nervoso Central/efeitos dos fármacos , Estradiol/farmacologia , Animais , Ritmo beta/efeitos dos fármacos , Interações Medicamentosas , Eletroencefalografia/efeitos dos fármacos , Moduladores GABAérgicos/farmacologia , Masculino , Midazolam/farmacologia , Progestinas/farmacologia , Ratos , Ratos Wistar , Receptores de GABA-A/efeitos dos fármacosRESUMO
Proton pump inhibitors (PPIs) have been used recently for gastrointestinal esophageal reflux disease (GERD) in children older than one year with good results. However, the pharmacokinetics of PPIs have not been studied in children less than two years old. The aim of our study was to evaluate the frequency of the main phenotypes of the metabolizing enzymes CYP2C19 and CYP3A4 in Mexican infants. Our results indicate no significant difference between the 0.5 and the 1.5 mg/kg doses. The percentage of CYP2C19-poor metabolizers was 17% in babies below 4 months and was not detected in children above 3 months. When a combined CYP2C19- and CYP3A4- phenotype was estimated, omeprazole levels were significantly higher in poor metabolizers than in extended metabolizers. The percentage of ultra-extensive metabolizers in children older than 3 months were 20% and 33% for CYP2C19 and CYP3A4 respectively, compared to only 6% and 9% respectively, in babies between 1 and 3 months old. In general children, under 4 months had higher omeprazole levels and an immature metabolism. Studies in children older than 2 years old have showed similar pharmacokinetics to adults. For children between 1 month old and up to 9 months, we suggest the use of the 0.5 mg/kg dose, since it prevents accumulation in poor metabolizers, caution is recommended to identify ultra-fast metabolizers, but this would require new studies.
Assuntos
Antiulcerosos/farmacocinética , Omeprazol/farmacocinética , 2-Piridinilmetilsulfinilbenzimidazóis , Administração Oral , Antiulcerosos/administração & dosagem , Hidrocarboneto de Aril Hidroxilases/metabolismo , Citocromo P-450 CYP2C19 , Citocromo P-450 CYP3A , Sistema Enzimático do Citocromo P-450/metabolismo , Feminino , Frequência do Gene , Humanos , Lactente , Recém-Nascido , Masculino , México/epidemiologia , Oxigenases de Função Mista/metabolismo , Omeprazol/administração & dosagem , Omeprazol/análogos & derivados , Omeprazol/sangue , FenótipoRESUMO
BACKGROUND: The pharmacokinetic properties of pravastatin, particularlyAUC and Cmax, are variable by population. A description of the pharmacokinetic properties of pravastatin in Mexican mestizos was not found in a search of MEDLINE/PubMed (key terms: pravastatin, Mexican, and pharmacokinetics; years: 1966-2005). Because Mexicans and Japanese have common ancestors (Mongoloid group), they also have a common gene pool. This gene pool was modified by genetic "bottlenecks" that occurred when these populations migrated to the Americas and when the Mexican population mixed with the Spanish population during the 16th and 17th centuries. Previous studies in Japanese subjects showed 5 main mutations on the hepatic drug transporter OATP-C, resulting in higher Cmax and AUC values compared with whites. In the Japanese population, the rates of expression of the (*) 1b and (*) 15 alleles were 46% and 15%, respectively. OBJECTIVE: The aim of this study was to evaluate the pharmacokinetic propertiesof pravastatin in healthy Mexican mestizo volunteers and to compare them with those in white and Japanese populations described in the literature. METHODS: This open-label, uncontrolled pilot study of the pharmacokineticproperties of pravastatin was conducted at the Division of Pharmacology, Center for Research and Advanced Studies, Mexico City, Mexico. Healthy, adult, Mexican volunteers received a single dose of pravastatin 10 mg PO (tablet). High-performance liquid chromatography was used to determine plasma pravastatin concentrations between 15 minutes and 12 hours after dosing. RESULTS: Twenty-four subjects (15 women, 9 men; mean age, 30.6 years)participated in the study. The mean (SD) Cmax was 9.5 (2.4) ng/mL; Tmax, 0.8 (0.3) hours; AUC0-∞ 35.7 (19.7) ng/mL - h; t1/2, 2.7 (1.1) hours; and mean residence time, 3.1 (1.1) hours. One volunteer (4%) had an AUC value that differed substantially from the rest of the study population, producing a bimodal distribution of the pharmacokinetic parameters. No adverse events were observed or reported during the trial. CONCLUSIONS: In this small pilot study of the pharmacokinetic properties of pravastatin in Mexican mestizos, AUC was not statistically significantly different from previous studies, either in a white or Japanese population. However, we did not find the high values reported for Cmax in some Japanese subjects carrying recently reported mutations on the pravastatin transporter.