RESUMEN

ETHNOPHARMACOLOGICAL RELEVANCE: Propolis has been employed extensively in many cultures since ancient times as antiseptic, wound healing, anti-pyretic and others due to its biological and pharmacological properties, such as immunomodulatory, antitumor, anti-inflammatory, antioxidant, antibacterial, antiviral, antifungal, antiparasite activities. But despite its broad and traditional use, there is little knowledge about its potential interaction with prescription drugs. AIM OF THE STUDY: The main objective of this work was to study the potential herbal-drug interactions (HDIs) of EPP-AF® using an in vivo assay with a cocktail approach. MATERIALS AND METHODS: Subtherapeutic doses of caffeine, losartan, omeprazole, metoprolol, midazolam and fexofenadine were used. Sixteen healthy adult volunteers were investigated before and after exposure to orally administered 125 mg/8 h (375 mg/day) EPP-AF® for 15 days. Pharmacokinetic parameters were calculated based on plasma concentration versus time (AUC) curves. RESULTS: After exposure to EPP-AF®, it was observed decrease in the AUC0-∞ of fexofenadine, caffeine and losartan of approximately 18% (62.20 × 51.00 h.ng/mL), 8% (1085 × 999 h.ng/mL) and 13% (9.01 × 7.86 h.ng/mL), respectively, with all 90% CIs within the equivalence range of 0.80-1.25. On the other hand, omeprazole and midazolam exhibited an increase in AUC0-∞ of, respectively, approximately 18% (18.90 × 22.30 h.ng/mL) and 14% (1.25 × 1.43 h.ng/mL), with the upper bounds of 90% CIs slightly above 1.25. Changes in pharmacokinetics of metoprolol or its metabolite α-hydroxymetoprolol were not statistically significant and their 90% CIs were within the equivalence range of 0.80-1.25. CONCLUSIONS: In conclusion, our study shows that EPP-AF® does not clinically change CYP1A2, CYP2C9, CYP2C19, CYP2D6 and CYP3A activities, once, despite statistical significant, the magnitude of the changes in AUC values after EPP-AF® were all below 20% and therefore may be considered safe regarding potential interactions involving these enzymes. Besides, to the best of our knowledge this is the first study to assess potential HDIs with propolis.

Asunto(s)

Cafeína/farmacocinética , Losartán/farmacocinética , Metoprolol/farmacocinética , Midazolam/farmacocinética , Omeprazol/farmacocinética , Própolis , Terfenadina/análogos & derivados , Subfamilia B de Transportador de Casetes de Unión a ATP/metabolismo , Adulto , Cafeína/sangre , Estudios Cruzados , Sistema Enzimático del Citocromo P-450/genética , Sistema Enzimático del Citocromo P-450/metabolismo , Interacciones Farmacológicas , Femenino , Humanos , Losartán/sangre , Masculino , Metoprolol/sangre , Midazolam/sangre , Omeprazol/sangre , Terfenadina/sangre , Terfenadina/farmacocinética

RESUMEN

AIMS: The aim of the present study was to investigate the impact of human visceral leishmaniasis (VL) and curative chemotherapy on the activity of cytochrome P450 (CYP) 3A, CYP2C9 and CYP2C19 in patients from an endemic region in Brazil. METHODS: Adult patients with parasitologically confirmed VL were given a CYP phenotyping cocktail, comprising midazolam, omeprazole and losartan, immediately before (Study phase 1), 2-3 days (phase 2) and 3-6 months (phase 3) after curative VL chemotherapy. CYP activity was assessed by the apparent clearance of midazolam (CYP3A), omeprazole/5-hydroxyomeprazol ratio in plasma (CYP2C19) and losartan/E3174 ratio in urine (CYP2C9). RESULTS: Mean values (95% confidence interval) in phases 1, 2 and 3 were, respectively: log apparent midazolam clearance, 1.21 (1.10-1.31), 1.45 (1.32-1.57) and 1.35 (1.26-1.44) ml min(-1) kg(-1) ; omeprazole/5-hydroxyomeprazole ratio, 0.78 (0.61-0.94), 0.45 (0.27-0.63) and 0.37 (0.20-0.55); losartan/E3174 ratio, 0.66 (0.39-0.92), 0.35 (0.20-0.50) and 0.35 (0.16-0.53). Analysis of variance revealed significant differences in CYP3A (P = 0.018) and CYP2C19 (P = 0.008), but not CYP2C9 (P = 0.11) phenotypic activity, across the three study phases. CONCLUSION: The phenotypic activities of CYP3A4 and CYP2C19 were significantly reduced during acute VL compared with post-chemotherapy. We propose that increased plasma concentrations of proinflammatory cytokines during active disease account for the suppression of CYP activity. The failure to detect significant changes in CYP2C9 activity in the overall cohort may reflect differential effects of the inflammatory process on the expression of CYP isoforms, although the possibility of insufficient statistical power cannot be dismissed.

Asunto(s)

Sistema Enzimático del Citocromo P-450/metabolismo , Leishmaniasis Visceral/tratamiento farmacológico , Leishmaniasis Visceral/enzimología , Losartán/farmacocinética , Midazolam/farmacocinética , Omeprazol/farmacocinética , Adolescente , Adulto , Brasil , Citocromo P-450 CYP2C19/metabolismo , Citocromo P-450 CYP2C9/metabolismo , Citocromo P-450 CYP3A/metabolismo , Femenino , Humanos , Losartán/orina , Masculino , Midazolam/sangre , Persona de Mediana Edad , Omeprazol/sangre , Adulto Joven

Asunto(s)

Cardiotónicos/sangre , Digoxina/sangre , Insuficiencia Cardíaca/sangre , Omeprazol/sangre , Inhibidores de la Bomba de Protones/sangre , Adulto , Cardiotónicos/farmacocinética , Cardiotónicos/uso terapéutico , Digoxina/farmacocinética , Digoxina/uso terapéutico , Interacciones Farmacológicas/fisiología , Insuficiencia Cardíaca/tratamiento farmacológico , Humanos , Masculino , Persona de Mediana Edad , Omeprazol/farmacocinética , Estudios Prospectivos , Inhibidores de la Bomba de Protones/farmacocinética , Adulto Joven

RESUMEN

BACKGROUND: Some studies have reported a decreased absorption of mycophenolic acid (MPA) from mycophenolate mofetil (MMF) in renal transplanted (RTx) patients under proton-pump inhibitors (PPIs). There is still a lack of information regarding (1) whether this effect occurs when MMF is administered with either tacrolimus or cyclosporine A [calcineurin inhibitors (CNIs)], (2) whether the effect has the same amplitude during the first year after RTx, and finally (3) whether this decrease in exposure is clinically relevant. METHODS: We retrospectively analyzed the omeprazole effect in 348 12-hour pharmacokinetic samplings [area under the curve (AUC)(0-12h)] performed on days 7, 14, 30, 60, 180, and 360 after RTx in 77 patients who participated in previous trials. RESULTS: For all periods, the groups with and without PPI did not differ in all variables. By mixed-model analysis of variance, PPI reduced the MPA AUC(0-12h) (P < 0.0008) in the patients under both CNIs mainly due to decreased absorption (P = 0.049). In the tacrolimus group, a lower exposure seemed also due to a decreased MPA reabsorption at 10-12 hours. The PPI effect remains throughout the first year but was clinically more important on day 7. By Cox analysis, the use of PPI was associated with a 25% less chance of being adequately exposed to MPA (95% confidence interval 0.58-0.99, P = 0.04). Similarly, the number of patients underexposed to MPA (AUC < 30 ng·h/mL) was higher at most periods in the PPI group but again not statistically significant. CONCLUSIONS: These data indicate that PPI decreases the MPA exposure when associated with both CNIs but particularly in the first week after RTx. In this period, the MMF dose should be increased. This effect lasts throughout the first year but does not seem to be clinically relevant after the first week.

Asunto(s)

Trasplante de Riñón/fisiología , Ácido Micofenólico/sangre , Omeprazol/sangre , Adulto , Interacciones Farmacológicas/fisiología , Femenino , Humanos , Estudios Longitudinales , Masculino , Persona de Mediana Edad , Ácido Micofenólico/administración & dosificación , Omeprazol/administración & dosificación , Inhibidores de la Bomba de Protones/administración & dosificación , Inhibidores de la Bomba de Protones/sangre , Estudios Retrospectivos , Factores de Tiempo , Resultado del Tratamiento

RESUMEN

This work reports the result of the enantioselective disposition of pantoprazole, omeprazole, and lansoprazole in a same group of Brazilian health subjects. Ten nongenotyped healthy subjects were used for this study. Each subject received a single oral dose of 80 mg of pantoprazole, 40 mg of omeprazole, and 30 mg of lansoprazole, and the plasma concentrations of the enantiomers were measured for 8 h postdose. For pantoprazole and omeprazole, among the 10 volunteers investigated, only one volunteer (Subject # 4) presented higher plasma concentrations of the (+)-enantiomer than those of (-)-enantiomer. Nevertheless, the area under the concentration-time curve of the (+)-lansoprazole was higher than those the (-)-lansoprazole for all subjects. The comparison of proton pump inhibitors' enantiomers disposition from a single group volunteer demonstrated that pantoprazole and omeprazole can be used to differentiate extensive from poor CYP2C19 metabolizer while lansoprazole cannot do it.

Asunto(s)

Inhibidores de la Bomba de Protones/química , Inhibidores de la Bomba de Protones/farmacocinética , 2-Piridinilmetilsulfinilbencimidazoles/sangre , 2-Piridinilmetilsulfinilbencimidazoles/química , 2-Piridinilmetilsulfinilbencimidazoles/farmacocinética , Adolescente , Adulto , Brasil , Humanos , Lansoprazol , Persona de Mediana Edad , Omeprazol/sangre , Omeprazol/química , Omeprazol/farmacocinética , Pantoprazol , Inhibidores de la Bomba de Protones/sangre , Estereoisomerismo , Especificidad por Sustrato , Adulto Joven

RESUMEN

OBJECTIVE: This study compares midazolam with omeprazole as marker drugs for the evaluation of CYP3A activity in nine healthy self-reported white Brazilian volunteers. METHODS: Omeprazole was also used to evaluate the CYP2C19 phenotype. The volunteers received p.o. 20 mg omeprazole, and blood samples were collected 3.5 h after drug administration. After a washout period of 10 days, the volunteers received p.o. 15 mg midazolam maleate, and serial blood samples were collected up to 6 h after administration of the drug. CYP2C19 was genotyped for the allelic variants CYP2C19*1, CYP2C19*2, CYP2C19*3, and CYP2C19*17. Analysis of omeprazole, hydroxyomeprazole, omeprazole sulfone, and midazolam in plasma was carried out by LC-MS/MS. RESULTS: The volunteers genotyped as CYP2C19*1*17, CYP2C19*17*17, CYP2C19*1*1 (n = 8), or CYP2C19*17*2 (n = 1) presented a median hydroxylation index (omeprazole/hydroxyomeprazole) of 1.35, indicating that all of them were extensive metabolizers of CYP2C19. The volunteers (n = 9) presented a 0.12 log of the omeprazole/sulfone ratio and a median oral clearance of midazolam of 17.89 ml min(-1) kg(-1), suggesting normal CYP3A activity. CONCLUSIONS: Orthogonal regression analysis between midazolam clearance and log of the plasma concentrations of the omeprazole/omeprazole sulfone ratio (R = -0.7544, P < 0.05) suggests that both midazolam and omeprazole can be used as markers of CYP3A activity in the population investigated.

Asunto(s)

Antiulcerosos/administración & dosificación , Citocromo P-450 CYP3A/genética , Midazolam/administración & dosificación , Omeprazol/administración & dosificación , Preparaciones Farmacéuticas/administración & dosificación , Adulto , Antiulcerosos/sangre , Antiulcerosos/farmacocinética , Biomarcadores/sangre , Brasil , Citocromo P-450 CYP3A/metabolismo , Femenino , Humanos , Masculino , Tasa de Depuración Metabólica , Midazolam/sangre , Midazolam/farmacocinética , Omeprazol/sangre , Omeprazol/farmacocinética , Fenotipo , Adulto Joven

RESUMEN

BACKGROUND: Omeprazole is metabolized by the hepatic cytochrome P450 (CYP) 2C19 enzyme to 5-hydroxyomeprazole. CYP2C19 exhibits genetic polymorphisms responsible for the presence of poor metabolizers (PMs), intermediate metabolizers (IMs) and extensive metabolizers (EMs). The defective mutations of the enzyme and their frequencies change between different ethnic groups; however, the polymorphism of the CYP2C19 gene has not been studied in Colombian mestizos. The aim of this study was to evaluate the genotype and phenotype status of CYP2C19 in Colombian mestizos, in order to contribute to the use of appropriate strategies of drug therapy for this population. METHODS: 189 subjects were genotyped using the multiplex SNaPshot technique and a subgroup of 44 individuals received 20 mg of omeprazole followed by blood collection at 3 hours to determine the omeprazole hydroxylation index by HPLC. RESULTS: 83.6%, 15.3% and 1.1% of the subjects were genotyped as EMs, IMs and PMs, respectively. The frequencies of the CYP2C29*1 and CYP2C19*2 alleles were 91.3% and 8.7% respectively whereas the *3, *4, *5, *6 and *8 alleles were not found. No discrepancies were found between the genotype and phenotype of CYP2C19. CONCLUSION: The frequency of poor metabolizers (1.1%) in the Colombian mestizos included in this study is similar to that in Bolivian mestizos (1%) but lower than in Mexican-Americans (3.2%), West Mexicans (6%), Caucasians (5%) and African Americans (5.4%). The results of this study will be useful for drug dosage recommendations in Colombian mestizos.

Asunto(s)

2-Piridinilmetilsulfinilbencimidazoles/farmacocinética , Indio Americano o Nativo de Alaska/genética , Antiulcerosos/farmacocinética , Hidrocarburo de Aril Hidroxilasas/genética , Genética de Población , Hígado/enzimología , Oxigenasas de Función Mixta/genética , Omeprazol/farmacocinética , Polimorfismo Genético , 2-Piridinilmetilsulfinilbencimidazoles/sangre , Administración Oral , Adulto , Antiulcerosos/administración & dosificación , Antiulcerosos/sangre , Hidrocarburo de Aril Hidroxilasas/metabolismo , Biotransformación , Cromatografía Líquida de Alta Presión , Colombia , Citocromo P-450 CYP2C19 , Femenino , Frecuencia de los Genes , Genotipo , Humanos , Hidroxilación , Masculino , Persona de Mediana Edad , Oxigenasas de Función Mixta/metabolismo , Omeprazol/administración & dosificación , Omeprazol/sangre , Fenotipo

RESUMEN

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.

Asunto(s)

Antiulcerosos/farmacocinética , Omeprazol/farmacocinética , 2-Piridinilmetilsulfinilbencimidazoles , Administración Oral , Antiulcerosos/administración & dosificación , Hidrocarburo de Aril Hidroxilasas/metabolismo , Citocromo P-450 CYP2C19 , Citocromo P-450 CYP3A , Sistema Enzimático del Citocromo P-450/metabolismo , Femenino , Frecuencia de los Genes , Humanos , Lactante , Recién Nacido , Masculino , México/epidemiología , Oxigenasas de Función Mixta/metabolismo , Omeprazol/administración & dosificación , Omeprazol/análogos & derivados , Omeprazol/sangre , Fenotipo

RESUMEN

A direct injection high-performance liquid chromatographic (HPLC) method, with column-switching, for the determination of omeprazole enantiomers in human plasma is described. A restricted access media (RAM) of bovine serum albumin (BSA) octyl column has been used in the first dimension for separation of the analyte from the biological matrix. The omeprazole enantiomers were eluted from the RAM column onto an amylose tris(3,5-dimethylphenylcarbamate) chiral column by the use of a column-switching valve and the enantioseparation was performed using acetonitrile-water (60:40 v/v) as eluent. The analytes were detected by their UV absorbance at 302 nm. The validated method was applied to the analysis of the plasma samples obtained from 10 Brazilian volunteers who received a 40 mg oral dose of racemic omeprazole and was able to quantify the enantiomers of omeprazole in the clinical samples analyzed. The assay was able to determine the cytochrome P450 2C19 phenotype of the subjects participating in this study.

Asunto(s)

Antiulcerosos/sangre , Cromatografía Líquida de Alta Presión/métodos , Inhibidores Enzimáticos/sangre , Omeprazol/sangre , Antiulcerosos/farmacocinética , Área Bajo la Curva , Inhibidores Enzimáticos/farmacocinética , Humanos , Omeprazol/farmacocinética , Reproducibilidad de los Resultados , Sensibilidad y Especificidad , Estereoisomerismo

RESUMEN

A practical and selective HPLC method for the separation and quantification of omeprazole enantiomers in human plasma is presented. C18 solid phase extraction (SPE) cartridges were used to extract the enantiomers from plasma samples and the chiral separation was carried out on a Chiralpak AD column protected with a CN guard column, using ethanol:hexane (70:30) as the mobile phase, at a flow rate of 0.5 ml/min. The detection was carried out at 302 nm. The method proved to be linear in the range of 10-1000 ng/ml for each enantiomer, with a quantification limit of 5 ng/ml. Precision and accuracy, demonstrated by within-day and between-day assays, were lower than 10%.

Asunto(s)

Antiulcerosos/sangre , Omeprazol/sangre , Cromatografía Líquida de Alta Presión/métodos , Humanos , Reproducibilidad de los Resultados , Sensibilidad y Especificidad , Estereoisomerismo

RESUMEN

An analytical method based on liquid chromatography with positive ion electrospray ionization (ESI) coupled to tandem mass spectrometry detection was developed for the determination of lansoprazole in human plasma using omeprazole as the internal standard. The analyte and internal standard were extracted from the plasma samples by liquid-liquid extraction using diethyl-ether-dichloromethane (70:30; v/v) and chromatographed on a C(18) analytical column. The mobile phase consisted of acetonitrile-water (90:10; v/v)+10 mM formic acid. The method has a chromatographic total run time of 5 min and was linear within the range 2.5-2000 ng/ml. Detection was carried out on a Micromass triple quadrupole tandem mass spectrometer by Multiple Reaction Monitoring (MRM). The intra- and inter-run precision, calculated from quality control (QC) samples, was less than 3.4%. The accuracy as determined from QC samples was less than 9%. The method herein described was employed in a bioequivalence study of two capsule formulations of lansoprazole.

Asunto(s)

Antiulcerosos/sangre , Cromatografía Liquida/métodos , Omeprazol/sangre , Espectrometría de Masa por Ionización de Electrospray/métodos , 2-Piridinilmetilsulfinilbencimidazoles , Humanos , Lansoprazol , Omeprazol/análogos & derivados , Estándares de Referencia , Reproducibilidad de los Resultados , Sensibilidad y Especificidad , Equivalencia Terapéutica

RESUMEN

We present a new simple and reliable HPLC method for measuring omeprazole and its two main metabolites in plasma. This can be used for studying CYP2C19 and CYP3A4 genetic polymorphisms using omeprazole as the probe drug. Omeprazole, hydroxyomeprazole and omeprazole sulfone were extracted from plasma samples with phosphate buffer and dichloromethane-ether (95:5). HPLC separation was achieved using an Ultrasphere ODS C(18) (Beckman) column. The mobile phase was acetonitrile-phosphate buffer (24:76, pH 8), containing nonylamine at 0.015%. Retention times were 9.5 min for omeprazole, 3.25 min for hydroxyomeprazole, 7.4 min for omeprazole sulfone and 6.27 min for internal standard (phenacetine). Detection (UV at 302 nm) of analytes was linear in the range from 96 to 864 ng/ml. This is useful for calculating metabolic index for CYP2C19 and CYP3A4 in adults and children. This method is stable, reproducible, improves resolution and has practical advantages such as low cost.

Asunto(s)

Hidrocarburo de Aril Hidroxilasas/genética , Cromatografía Líquida de Alta Presión/métodos , Sistema Enzimático del Citocromo P-450/genética , Oxigenasas de Función Mixta/genética , Omeprazol/sangre , Hidrocarburo de Aril Hidroxilasas/metabolismo , Citocromo P-450 CYP2C19 , Citocromo P-450 CYP3A , Sistema Enzimático del Citocromo P-450/metabolismo , Humanos , Oxigenasas de Función Mixta/metabolismo , Fenotipo , Reproducibilidad de los Resultados , Sensibilidad y Especificidad , Espectrofotometría Ultravioleta

Asunto(s)

Úlcera Duodenal/tratamiento farmacológico , Determinación de la Acidez Gástrica , Omeprazol/administración & dosificación , Esquema de Medicación , Gastrinas/sangre , Reflujo Gastroesofágico/tratamiento farmacológico , Humanos , Omeprazol/sangre