RESUMEN
A novel electrochemical sensor is reported for the detection of the antiviral drug favipiravir based on the core-shell nanocomposite of flower-like molybdenum disulfide (MoS2) nanospheres and molecularly imprinted polymers (MIPs). The MoS2@MIP core-shell nanocomposite was prepared via the electrodeposition of a MIP layer on the MoS2 modified electrode, using o-phenylenediamine as the monomer and favipiravir as the template. The selective binding of target favipiravir at the MoS2@MIP core-shell nanocomposite produced a redox signal in a concentration dependent manner, which was used for the quantitative analysis. The preparation process of the MoS2@MIP core-shell nanocomposite was optimized. Under the optimal conditions, the sensor exhibited a wide linear response range of 0.01 ~ 100 nM (1.57*10-6 ~ 1.57*10-2 µg mL-1) and a low detection limit of 0.002 nM (3.14*10-7 µg mL-1). Application of the sensor was demonstrated by detecting favipiravir in a minimum amount of 10 µL biological samples (urine and plasma). Satisfied results in the recovery tests indicated a high potential of favipiravir monitoring in infectious COVID-19 samples.
Asunto(s)
Amidas/análisis , Antivirales/análisis , Disulfuros/química , Polímeros Impresos Molecularmente/química , Molibdeno/química , Nanocompuestos/química , Nanosferas/química , Pirazinas/análisis , Amidas/sangre , Amidas/uso terapéutico , Amidas/orina , Antivirales/sangre , Antivirales/uso terapéutico , Antivirales/orina , COVID-19/virología , Técnicas Electroquímicas/métodos , Humanos , Límite de Detección , Oxidación-Reducción , Pirazinas/sangre , Pirazinas/uso terapéutico , Pirazinas/orina , Reproducibilidad de los Resultados , SARS-CoV-2/aislamiento & purificación , Tratamiento Farmacológico de COVID-19RESUMEN
In light of the recent pandemic, favipiravir (Avigan®), a purine nucleic acid analog and antiviral agent approved for use in influenza in Japan, is being studied for the treatment of coronavirus disease 2019 (COVID-19). Increase in blood uric acid level is a frequent side effect of favipiravir. Here, we discussed the mechanism of blood uric acid elevation during favipiravir treatment. Favipiravir is metabolized to an inactive metabolite M1 by aldehyde oxidase and xanthine oxidase, and excreted into urine. In the kidney, uric acid handling is regulated by the balance of reabsorption and tubular secretion in the proximal tubules. Favipiravir and M1 act as moderate inhibitors of organic anion transporter 1 and 3 (OAT1 and OAT3), which are involved in uric acid excretion in the kidney. In addition, M1 enhances uric acid reuptake via urate transporter 1 (URAT1) in the renal proximal tubules. Thus, favipiravir is thought to decrease uric acid excretion into urine, resulting in elevation of uric acid levels in blood. Elevated uric acid levels were returned to normal after discontinuation of favipiravir, and favipiravir is not used for long periods of time for the treatment of viral infection. Thus, the effect on blood uric acid levels was subclinical in most studies. Nevertheless, the adverse effect of favipiravir might be clinically important in patients with a history of gout, hyperuricemia, kidney function impairment (in which blood concentration of M1 increases), and where there is concomitant use of other drugs affecting blood uric acid elevation.
Asunto(s)
Amidas/efectos adversos , Antivirales/efectos adversos , Infecciones por Coronavirus/tratamiento farmacológico , Hiperuricemia/inducido químicamente , Neumonía Viral/tratamiento farmacológico , Pirazinas/efectos adversos , Ácido Úrico/sangre , Aldehído Oxidasa/metabolismo , Amidas/farmacocinética , Amidas/orina , Antivirales/farmacocinética , Biotransformación , COVID-19 , Interacciones Farmacológicas , Humanos , Hiperuricemia/fisiopatología , Riñón/metabolismo , Enfermedades Renales/metabolismo , Estructura Molecular , Proteína 1 de Transporte de Anión Orgánico/antagonistas & inhibidores , Transportadores de Anión Orgánico/metabolismo , Transportadores de Anión Orgánico Sodio-Independiente/antagonistas & inhibidores , Proteínas de Transporte de Catión Orgánico/metabolismo , Pandemias , Pirazinas/farmacocinética , Pirazinas/orina , Xantina Oxidasa/metabolismoRESUMEN
SCOPE: Coffee is a complex mixture of over 1000 compounds, including diverse heteroaromatic compounds such as alkylpyrazines. Little is known about the intake, metabolism, and bodily distribution of these compounds. Therefore, a human intervention study is conducted to investigate the excretion of alkylpyrazine metabolites in urine after the ingestion of brewed coffee containing alkylpyrazines. METHODS AND RESULTS: After consuming a diet without heat-processed food, ten volunteers consumed 500 mL of freshly brewed coffee prepared from coffee pads, providing intakes of 2-methylpyrazine (2-MeP), 2,5-dimethylpyrazine (2,5-DMeP), and 2,6-dimethylpyrazine (2,6-DMeP) amounting to 17.2, 4.4, and 4.9 µmol, respectively. These alkylpyrazines are metabolized into the corresponding pyrazine carboxylic acids, namely pyrazine-2-carboxylic acid (PA), 5-hydroxypyrazine-2-carboxylic acid (5-OHPA), 5-methylpyrazine-2-carboxylic acid (5-MePA), and 6-methylpyrazine-2-carboxylic acid (6-MePA). In total, 64% of the ingested 2-MeP is excreted as PA, as well as 26% as 5-OHPA, while 91% and 97% of the ingested 2,5-DMeP and 2,6-DMeP are recovered as 5-MePA and 6-MePA, respectively, in urine samples collected after coffee consumption. CONCLUSION: This study provides evidence that alkylpyrazines are rapidly metabolized into the corresponding carboxylic acids and excreted via urine by humans, which is consistent with earlier rodent studies.
Asunto(s)
Café/química , Pirazinas/farmacocinética , Adulto , Ácidos Carboxílicos/farmacocinética , Ácidos Carboxílicos/orina , Cromatografía Líquida de Alta Presión , Femenino , Voluntarios Sanos , Humanos , Masculino , Pirazinamida/análogos & derivados , Pirazinamida/farmacocinética , Pirazinas/orina , Espectrometría de Masa por Ionización de ElectrosprayRESUMEN
Chemical communication plays an integral role in social behavior by facilitating social encounters, allowing for the evaluation of social partners, defining territories and advertising information such as species and sex. Odors provide information about the social environment for rodents and other mammals; however, studies identifying chemical compounds and their functions have thus far focused primarily on a few species. In addition, considerably less attention has been focused on how environmental factors and behavioral context alter these compounds during periods of reproductive quiescence. We examined the effects of photoperiod and social context on chemical communication in the seasonally breeding Siberian hamster which displays modest territorial aggression during long "summer-like" days, but increased aggression in short "winter-like" days. We collected urine samples from long- and short-day male hamsters to investigate how photoperiod and subsequent changes in reproductive phenotype alter urinary volatile compound profiles. Next, we identified changes in urinary compounds before and after an aggressive encounter. Male hamsters exhibited a diverse urinary profile across photoperiods; however, long-day reproductive males showed higher levels of individual compounds when compared to short-day non-reproductive males. In addition, individual compounds were altered following an aggressive encounter; some changed only in long days whereas others changed regardless of photoperiod. Further, aggression and circulating levels of testosterone were positively correlated with urinary compounds in long-, but not short-day males. These findings suggest both photoperiod- and aggression-specific physiological regulation of urinary compounds in this species and contribute to a greater understanding of chemical communication more broadly.
Asunto(s)
Agresión/fisiología , Phodopus/orina , Fotoperiodo , Reproducción/fisiología , Compuestos Orgánicos Volátiles/orina , Análisis de Varianza , Animales , Cricetinae , Cromatografía de Gases y Espectrometría de Masas , Cetonas/orina , Masculino , Fenotipo , Phodopus/sangre , Pirazinas/orina , Testosterona/sangreRESUMEN
In an HCl medium (pH 1.5), ligustrazine (2,3,5,6-tetramethylpyrazine, TMP) reacted with 12-tungstophosphoric acid (TP) to form a 3 : 1 ion-association complex. As a result, the intensities of resonance Rayleigh scattering (RRS), second-order scattering (SOS) and frequency doubling scattering (FDS) were greatly enhanced and new scattering spectra appeared. The maximum RRS, SOS and FDS wavelengths of the ion-association complexes were located at 379, 738 and 395 nm, respectively. The scattering intensity increments (ΔIRRS , ΔISOS and ΔIFDS ) were directly proportional to the concentration of ligustrazine within certain ranges. The detection limits (3σ) of RRS, SOS and FDS were 1.6, 3.2 and 2.8 ng/mL. Optimal conditions for the RRS method and factors influencing the method were discussed, and the structure of the ion-association complex and the reaction mechanism were investigated. Transmission electron microscopy (TEM) was used to characterize the structures of the ion-association complex. Based on the ion-association reaction and its spectral response, a rapid, simple and sensitive RRS method for the determination of TMP was developed. It was applied to the determination of TMP in tablet and urine samples with satisfactory results.
Asunto(s)
Ácidos Fosfóricos/química , Pirazinas/análisis , Pirazinas/química , Compuestos de Tungsteno/química , Humanos , Ácido Clorhídrico/química , Interacciones Hidrofóbicas e Hidrofílicas , Límite de Detección , Pirazinas/orina , Dispersión de Radiación , Solventes/química , Espectrofotometría/métodos , Comprimidos/análisisRESUMEN
BACKGROUND: The common grey wolf (Canis lupus) is found throughout the entire Northern hemisphere and preys on many kinds of mammals. The urine of the wolf contains a number of volatile constituents that can potentially be used for predator-prey chemosignalling. Although wolf urine is put to practical use to keep rabbits, rodents, deer and so on at bay, we are unaware of any prior behavioural studies or chemical analyses regarding the fear-inducing impact of wolf urine on laboratory mice. METHODOLOGY/PRINCIPAL FINDINGS: Three wolf urine samples harvested at different times were used in this study. All of them induced stereotypical fear-associated behaviors (i.e., avoidance and freezing) in female mice. The levels of certain urinary volatiles varied widely among the samples. To identify the volatiles that provoked avoidance and freezing, behavioural, chemical, and immunohistochemical analyses were performed. One of the urine samples (sample C) had higher levels of 2,6-dimethylpyrazine (DMP), trimethylpyrazine (TMP), and 3-ethyl-2,5-dimethyl pyrazine (EDMP) compared with the other two urine samples (samples A and B). In addition, sample C induced avoidance and freezing behaviours more effectively than samples A and B. Moreover, only sample C led to pronounced expression of Fos-immunoreactive cells in the accessory olfactory bulb (AOB) of female mice. Freezing behaviour and Fos immunoreactivity were markedly enhanced when the mice were confronted with a mixture of purified DMP, TMP, and EDMP vs. any one pyrazine alone. CONCLUSIONS/SIGNIFICANCE: The current results suggest that wolf urinary volatiles can engender aversive and fear-related responses in mice. Pyrazine analogues were identified as the predominant active components among these volatiles to induce avoidance and freezing behaviours via stimulation of the murine AOB.
Asunto(s)
Reacción de Prevención , Conducta Animal , Pánico , Pirazinas , Lobos , Animales , Ratones , Odorantes , Bulbo Olfatorio/efectos de los fármacos , Bulbo Olfatorio/metabolismo , Proteínas Proto-Oncogénicas c-fos/metabolismo , Pirazinas/química , Pirazinas/farmacología , Pirazinas/orina , Lobos/orinaRESUMEN
OBJECTIVES: The objectives of this study were to determine if ABCB1 polymorphisms are associated with interindividual variability in sitagliptin pharmacokinetics and if atorvastatin alters the pharmacokinetic disposition of sitagliptin in healthy volunteers. METHODS: In this open-label, randomized, two-phase crossover study, healthy volunteers were prospectively stratified according to ABCB1 1236/2677/3435 diplotype (n = 9, CGC/CGC; n = 10, CGC/TTT; n = 10, TTT/TTT). In one phase, participants received a single 100 mg dose of sitagliptin; in the other phase, participants received 40 mg of atorvastatin for 5 days, with a single 100 mg dose of sitagliptin administered on day 5. A 24-h pharmacokinetic study followed each sitagliptin dose, and the study phases were separated by a 14-day washout period. RESULTS: Sitagliptin pharmacokinetic parameters did not differ significantly between ABCB1 CGC/CGC, CGC/TTT, and TTT/TTT diplotype groups during the monotherapy phase. Atorvastatin administration did not significantly affect sitagliptin pharmacokinetics, with geometric mean ratios (90 % confidence intervals) for sitagliptin maximum plasma concentration, plasma concentration-time curve from zero to infinity, renal clearance, and fraction of sitagliptin excreted unchanged in the urine of 0.93 (0.86-1.01), 0.96 (0.91-1.01), 1.02 (0.93-1.12), and 0.98 (0.90-1.06), respectively. CONCLUSIONS: ABCB1 CGC/CGC, CGC/TTT, and TTT/TTT diplotypes did not influence sitagliptin pharmacokinetics in healthy volunteers. Furthermore, atorvastatin had no effect on the pharmacokinetics of sitagliptin in the setting of ABCB1 CGC/CGC, CGC/TTT, and TTT/TTT diplotypes.
Asunto(s)
Miembro 1 de la Subfamilia B de Casetes de Unión a ATP/genética , Inhibidores de la Dipeptidil-Peptidasa IV/farmacocinética , Ácidos Heptanoicos/efectos adversos , Inhibidores de Hidroximetilglutaril-CoA Reductasas/efectos adversos , Polimorfismo de Nucleótido Simple , Pirazinas/farmacocinética , Pirroles/efectos adversos , Triazoles/farmacocinética , Subfamilia B de Transportador de Casetes de Unión a ATP , Miembro 1 de la Subfamilia B de Casetes de Unión a ATP/metabolismo , Adulto , Atorvastatina , Biotransformación/efectos de los fármacos , Estudios de Cohortes , Colorado , Estudios Cruzados , Inhibidores de la Dipeptidil-Peptidasa IV/sangre , Inhibidores de la Dipeptidil-Peptidasa IV/orina , Interacciones Farmacológicas , Femenino , Estudios de Asociación Genética , Semivida , Ácidos Heptanoicos/sangre , Ácidos Heptanoicos/farmacocinética , Humanos , Inhibidores de Hidroximetilglutaril-CoA Reductasas/sangre , Inhibidores de Hidroximetilglutaril-CoA Reductasas/farmacocinética , Masculino , Tasa de Depuración Metabólica/efectos de los fármacos , Persona de Mediana Edad , Pirazinas/sangre , Pirazinas/orina , Pirroles/sangre , Pirroles/farmacocinética , Fosfato de Sitagliptina , Triazoles/sangre , Triazoles/orina , Adulto JovenRESUMEN
A new, simple and rapid gas chromatography-mass spectrometry (GC-MS) method for the determination of sitagliptin (STG) in human urine was developed and fully validated. STG was derivatized by N-methyl-trimethylsilyltrifluoroacetamide prior to GC-MS analysis and converted to its N-TMS amine derivative. It was extracted from urine by using carbonate buffer (pH 9.0) and ether. The method was validated in terms of specificity, limit of quantitation (LOQ), linearity, accuracy, precision, stability, recovery, robustness and ruggedness. LOQ was found to be 50 ng mL(-1). The calibration curve was linear in the range of 50-600 ng mL(-1) with a coefficient of determination (r(2)) above 0.997. The intra- and inter-day precisions were less than 8.76%, and the intra- and inter-day accuracies were found between 0.83 and 4.53%. The method was successfully applied to urine samples obtained from diabetic patients.
Asunto(s)
Cromatografía de Gases y Espectrometría de Masas/normas , Cromatografía de Gases y Espectrometría de Masas/tendencias , Pirazinas/química , Pirazinas/orina , Triazoles/química , Triazoles/orina , Femenino , Humanos , Masculino , Fosfato de SitagliptinaRESUMEN
A novel water-compatible molecularly imprinted solid-phase extraction (MISPE) combined with zwitterionic hydrophilic interaction liquid chromatography (ZIC-HILIC) method for selective extraction and determination of sitagliptin in rat serum and urine was developed and validated. The effects of progenic solvents, pH, cross linker and amount of monomer were studied to optimize the efficiency and selectivity. The adsorption kinetics and isotherms were measured. The molecularly imprinted polymer (MIP) showed good specific adsorption capacity with an optimum of 180 mg/g at pH 7.5 and selective extraction of sitagliptin from rat plasma and urine. The recovery of sitagliptin from rat urine and plasma was >98%. The limits of detection (LOD) and quantification (LOQ) were 0.03 and 0.10 µg/L respectively. The proposed method overcomes the matrix effects of phospholipids generally encountered while preparation of plasma samples by precipitation of proteins.
Asunto(s)
Análisis Químico de la Sangre/métodos , Fraccionamiento Químico/métodos , Impresión Molecular/métodos , Polímeros/síntesis química , Pirazinas/análisis , Pirazinas/aislamiento & purificación , Triazoles/análisis , Triazoles/aislamiento & purificación , Urinálisis/métodos , Adsorción , Animales , Calibración , Cromatografía Líquida de Alta Presión , Concentración de Iones de Hidrógeno , Interacciones Hidrofóbicas e Hidrofílicas , Cinética , Límite de Detección , Modelos Lineales , Pirazinas/sangre , Pirazinas/orina , Ratas , Reproducibilidad de los Resultados , Fosfato de Sitagliptina , Solventes/química , Triazoles/sangre , Triazoles/orinaRESUMEN
The objective of this study was to assess the physiologically based pharmacokinetic (PBPK) model for predicting plasma concentration-time profiles of orally available cMet kinase inhibitors, (R)-3-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-5-(1-piperidin-4-yl-1H-pyrazol-4-yl)-pyridin-2-ylamine (PF02341066) and 2-[4-(3-quinolin-6-ylmethyl-3H-[1,2,3]triazolo[4,5-b]pyrazin-5-yl)-pyrazol-1-yl]-ethanol (PF04217903), in humans. The prediction accuracy of pharmacokinetics (PK) by PBPK modeling was compared with that of a traditional one-compartment PK model based on allometric scaling. The predicted clearance values from allometric scaling with the correction for the interspecies differences in protein binding were used as a representative comparison, which showed more accurate PK prediction in humans than the other methods. Overall PBPK modeling provided better prediction of the area under the plasma concentration-time curves for both PF02341066 (1.2-fold error) and PF04217903 (1.3-fold error) compared with the one-compartment PK model (1.8- and 1.9-fold errors, respectively). Of more importance, the simulated plasma concentration-time profiles of PF02341066 and PF04217903 by PBPK modeling seemed to be consistent with the observed profiles showing multiexponential declines, resulting in more accurate prediction of the apparent half-lives (t(1/2)): the observed and predicted t(1/2) values were, respectively, 10 and 12 h for PF02341066 and 6.6 and 6.3 h for PF04217903. The predicted t(1/2) values by the one-compartment PK model were 17 h for PF02341066 and 1.9 h for PF04217903. Therefore, PBPK modeling has the potential to be more useful and reliable for the PK prediction of PF02341066 and PF04217903 in humans than the traditional one-compartment PK model. In summary, the present study has shown examples to indicate that the PBPK model can be used to predict PK profiles in humans.
Asunto(s)
Evaluación Preclínica de Medicamentos/métodos , Modelos Moleculares , Inhibidores de Proteínas Quinasas/farmacocinética , Proteínas Proto-Oncogénicas c-met/antagonistas & inhibidores , Administración Oral , Adulto , Animales , Disponibilidad Biológica , Células Cultivadas , Crizotinib , Perros , Semivida , Hepatocitos/metabolismo , Humanos , Macaca fascicularis , Masculino , Tasa de Depuración Metabólica , Microsomas Hepáticos/metabolismo , Persona de Mediana Edad , Inhibidores de Proteínas Quinasas/administración & dosificación , Inhibidores de Proteínas Quinasas/sangre , Inhibidores de Proteínas Quinasas/orina , Pirazinas/administración & dosificación , Pirazinas/sangre , Pirazinas/farmacocinética , Pirazinas/orina , Pirazoles/administración & dosificación , Pirazoles/sangre , Pirazoles/farmacocinética , Pirazoles/orina , Piridinas/administración & dosificación , Piridinas/sangre , Piridinas/farmacocinética , Piridinas/orina , Ratas , Ratas Sprague-Dawley , Triazoles/administración & dosificación , Triazoles/sangre , Triazoles/farmacocinética , Triazoles/orina , Adulto JovenRESUMEN
(S)-5-Chloro-1-(1-cyclopropylethyl)-3-(2,6-dichloro-4-(trifluoromethyl)phenylamino)pyrazin-2(1H)-one (BMS-665053), a pyrazinone-containing compound, is a potent and selective antagonist of corticotropin-releasing factor receptor-1 (CRF-R1) that showed efficacy in the defensive withdrawal model for anxiety in rats, suggesting its use as a potential treatment for anxiety and depression. In vitro metabolism studies of BMS-665053 in rat and human liver microsomes revealed cytochrome P450-mediated oxidation of the pyrazinone moiety, followed by ring opening, as the primary metabolic pathway. Detection of a series of GSH adducts in trapping experiments suggested the formation of a reactive intermediate, probably as a result of epoxidation of the pyrazinone moiety. In addition, BMS-665053 (20 mg/kg i.v.) underwent extensive metabolism in bile duct-cannulated (BDC) rats. The major drug-related materials in rat plasma were the pyrazinone oxidation products. In rat bile and urine (0-7 h), only a trace amount of the parent drug was recovered, whereas significant levels of the pyrazinone epoxide-derived metabolites and GSH-related conjugates were detected. Further evidence suggested that GSH-related conjugates also formed at the dichloroarylamine moiety possibly via an epoxide or a quinone imine intermediate. Other major metabolites in BDC rat bile and urine included glucuronide conjugates. To reduce potential liability due to metabolic activation of BMS-665053, a number of pyrazinone analogs with different substituents were synthesized and investigated for reactive metabolite formation, leading to the discovery of a CRF-R1 antagonist with diminished in vitro metabolic activation.
Asunto(s)
Pirazinas/química , Receptores de Hormona Liberadora de Corticotropina/antagonistas & inhibidores , Animales , Bilis/química , Biotransformación , Ácido Glucurónico/metabolismo , Glutatión/metabolismo , Humanos , Hígado/enzimología , Espectroscopía de Resonancia Magnética , Masculino , Espectrometría de Masas , Microsomas Hepáticos/enzimología , Modelos Químicos , Estructura Molecular , Pirazinas/sangre , Pirazinas/metabolismo , Pirazinas/orina , Ratas , Ratas Sprague-Dawley , Espectrofotometría UltravioletaRESUMEN
High turbulence liquid chromatography (HTLC, or turbulent flow online extraction) and tandem mass spectrometry (MS/MS) methods for the determination of sitagliptin in human urine and hemodialysate were developed and validated to support clinical studies. A narrow bore large particle size reversed-phase column (Cyclone, 50 mm x 1.0 mm, 60 microm) and a BDS Hypersil C18 column (30 mm x 2.1 mm, 3 microm) were used as extraction and analytical columns, respectively. For the urine assay, the LLOQ was 0.1 microg/ml, the linear calibration range was 0.1 to 50 microg/ml, the interday precision (R.S.D.%, n=5) was 2.3-6.5%, and the accuracy was 96.9-106% of the nominal value. For the urine quality control samples (QCs), the intraday precision (R.S.D.%, n=5) and accuracy were 1.8-2.6% and 96.2-106% of the nominal value, respectively. The interday precision (R.S.D.%) for 56 sets of urine QCs over a 6-month period varied from 3.8% to 5.5% and the accuracy from 102% to 105% of the nominal value. For the hemodialysate assay, the LLOQ was 0.01 ng/ml, the linear dynamic range was 0.01-5.0 ng/ml, the interday precision was 1.6-4.1%, and the accuracy was 89.8-104% of the nominal value. For hemodialysate QCs, the intraday precision and accuracy varied from 2.3% to 8.9% and from 99.8% to 111% of the nominal value, respectively. These results demonstrated that both methods are selective, accurate, precise, reproducible, and suitable for quantifying sitagliptin in hemodialysate and human urine samples.
Asunto(s)
Cromatografía Liquida/métodos , Soluciones para Hemodiálisis/análisis , Pirazinas/análisis , Espectrometría de Masas en Tándem/métodos , Triazoles/análisis , Calibración , Estabilidad de Medicamentos , Humanos , Pirazinas/orina , Sensibilidad y Especificidad , Fosfato de Sitagliptina , Triazoles/orinaRESUMEN
The purpose of this study was to determine the absolute bioavailability of sitagliptin, an orally active, potent and highly selective dipeptidyl peptidase-4 inhibitor recently approved in the United States for the treatment of type 2 diabetes. The effect of a high fat meal on sitagliptin pharmacokinetics was also assessed. The study was performed in two parts. Intravenous doses (2 h infusion) of 25, 50 and 100 mg were administered double-blind to 10 (8 active, 2 placebo) subjects in a fixed-sequence manner in Part I. In Part II, 12 subjects were randomized to each of three open-label treatments: an intravenous 100 mg dose; a single oral 100 mg final market image tablet administered following a high fat meal and a single oral 100 mg final market image tablet administered fasted. Following each dose, plasma and urine were collected at pre-specified times for evaluation of sitagliptin pharmacokinetics. All doses were generally well tolerated in both parts of the study. Following rising intravenous doses of sitagliptin, AUC(0-infinity) increased dose-proportionally, indicating that plasma clearance is independent of dose over the dose range evaluated. Renal clearance of unchanged sitagliptin accounted for approximately 70% of the total plasma clearance of sitagliptin, indicating that sitagliptin is primarily cleared via renal excretion. Averaged across doses, the mean total plasma clearance was 416 ml/min. The mean absolute bioavailability of sitagliptin was 87% with a 90% CI of (81%, 93%). The AUC(0-infinity) and C(max) geometric mean ratios (fed/fasted) and 90% CIs were 1.03 (0.97, 1.11) and 0.94 (0.86, 1.03), respectively, and were contained within the bounds of (0.80, 1.25). Additionally, the high-fat meal had no significant effect on T(max) or apparent terminal t(1/2). Thus, food does not affect the pharmacokinetics of sitagliptin and therefore can be administered without regard to food.
Asunto(s)
Inhibidores de la Dipeptidil-Peptidasa IV , Pirazinas/farmacocinética , Triazoles/farmacocinética , Administración Oral , Adulto , Área Bajo la Curva , Disponibilidad Biológica , Estudios Cruzados , Dipeptidil Peptidasa 4 , Método Doble Ciego , Inhibidores Enzimáticos/administración & dosificación , Inhibidores Enzimáticos/farmacocinética , Femenino , Semivida , Humanos , Inyecciones Intravenosas , Masculino , Tasa de Depuración Metabólica , Persona de Mediana Edad , Pirazinas/sangre , Pirazinas/orina , Fosfato de Sitagliptina , Comprimidos , Triazoles/sangre , Triazoles/orinaRESUMEN
Sitagliptin is a highly selective orally active dipeptidyl peptidase-4 inhibitor recently approved in the United States for the treatment of type 2 diabetes. Ten healthy subjects received single oral doses of 25, 50, 100, 200 and 400 mg final market image tablets in five separate treatment periods in randomized fashion to assess dose proportionality. Blood (up to 72 h post-dose) and urine (up to 24 h post-dose) samples for sitagliptin pharmacokinetic analysis were collected at pre-specified times following administration of sitagliptin. Dose-proportionality of AUC(0-infinity), C(max) and C(24 h) was assessed using a power-law model. The results of this study indicate that plasma AUC(0-infinity) increased in a dose-proportional manner over the 25-400 mg dose range. Over the same dose range, plasma C(max) increased in a greater than dose-proportional manner and C(24 h) increased in a modestly less than dose proportional manner. No clinically meaningful differences in T(max) or apparent t(1/2) were noted across the dose range. Differences in the percentage of the sitagliptin dose excreted unchanged in urine (72.5% pooled across doses) and renal clearance (344 ml/min pooled across doses) were not statistically significant. Sitagliptin was generally well tolerated at all the doses evaluated.
Asunto(s)
Inhibidores de la Dipeptidil-Peptidasa IV , Pirazinas/farmacocinética , Triazoles/farmacocinética , Administración Oral , Adulto , Análisis de Varianza , Área Bajo la Curva , Cromatografía Líquida de Alta Presión , Estudios Cruzados , Dipeptidil Peptidasa 4 , Relación Dosis-Respuesta a Droga , Inhibidores Enzimáticos/administración & dosificación , Inhibidores Enzimáticos/farmacocinética , Femenino , Semivida , Humanos , Masculino , Persona de Mediana Edad , Pirazinas/sangre , Pirazinas/orina , Fosfato de Sitagliptina , Comprimidos , Espectrometría de Masas en Tándem , Triazoles/sangre , Triazoles/orinaRESUMEN
Two novel metabolites of the dipeptidyl peptidase inhibitor sitagliptin (MK-0431, (2R)-4-oxo-4-[3-(trifluoromethyl)-5,6-dihydro[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl]-1-(2,4,5-trifluorophenyl)-butan-2-amine), were identified after purification from dog urine. The metabolites (referred to as M2 and M5) were characterized by hydrogen/deuterium exchange tandem mass spectrometry and NMR spectroscopy nuclear Overhauser effect experiments as the cis and trans stereoisomers formed by cyclization of the primary amino group with the alpha carbon of the piperazine ring, following oxidative desaturation.
Asunto(s)
Inhibidores Enzimáticos/metabolismo , Hipoglucemiantes/metabolismo , Pirazinas/metabolismo , Triazoles/metabolismo , Animales , Biotransformación , Ciclización , Dipeptidil Peptidasa 4/metabolismo , Inhibidores de la Dipeptidil-Peptidasa IV , Perros , Inhibidores Enzimáticos/farmacología , Inhibidores Enzimáticos/orina , Hipoglucemiantes/farmacología , Hipoglucemiantes/orina , Espectroscopía de Resonancia Magnética , Estructura Molecular , Oxidación-Reducción , Pirazinas/farmacología , Pirazinas/orina , Fosfato de Sitagliptina , Espectrometría de Masa por Ionización de Electrospray , Estereoisomerismo , Espectrometría de Masas en Tándem , Triazoles/farmacología , Triazoles/orinaRESUMEN
The metabolism and excretion of [(14)C]sitagliptin, an orally active, potent and selective dipeptidyl peptidase 4 inhibitor, were investigated in humans after a single oral dose of 83 mg/193 muCi. Urine, feces, and plasma were collected at regular intervals for up to 7 days. The primary route of excretion of radioactivity was via the kidneys, with a mean value of 87% of the administered dose recovered in urine. Mean fecal excretion was 13% of the administered dose. Parent drug was the major radioactive component in plasma, urine, and feces, with only 16% of the dose excreted as metabolites (13% in urine and 3% in feces), indicating that sitagliptin was eliminated primarily by renal excretion. Approximately 74% of plasma AUC of total radioactivity was accounted for by parent drug. Six metabolites were detected at trace levels, each representing <1 to 7% of the radioactivity in plasma. These metabolites were the N-sulfate and N-carbamoyl glucuronic acid conjugates of parent drug, a mixture of hydroxylated derivatives, an ether glucuronide of a hydroxylated metabolite, and two metabolites formed by oxidative desaturation of the piperazine ring followed by cyclization. These metabolites were detected also in urine, at low levels. Metabolite profiles in feces were similar to those in urine and plasma, except that the glucuronides were not detected in feces. CYP3A4 was the major cytochrome P450 isozyme responsible for the limited oxidative metabolism of sitagliptin, with some minor contribution from CYP2C8.
Asunto(s)
Inhibidores de la Adenosina Desaminasa , Inhibidores de la Dipeptidil-Peptidasa IV , Inhibidores Enzimáticos/farmacocinética , Glicoproteínas/antagonistas & inhibidores , Hipoglucemiantes/farmacocinética , Pirazinas/farmacocinética , Triazoles/farmacocinética , Adenosina Desaminasa/metabolismo , Administración Oral , Adulto , Área Bajo la Curva , Hidrocarburo de Aril Hidroxilasas/genética , Hidrocarburo de Aril Hidroxilasas/metabolismo , Biotransformación , Radioisótopos de Carbono , Ciclización , Citocromo P-450 CYP2C8 , Citocromo P-450 CYP3A , Sistema Enzimático del Citocromo P-450/genética , Sistema Enzimático del Citocromo P-450/metabolismo , Dipeptidil Peptidasa 4/metabolismo , Inhibidores Enzimáticos/administración & dosificación , Inhibidores Enzimáticos/sangre , Inhibidores Enzimáticos/orina , Heces/química , Glucurónidos/metabolismo , Glicoproteínas/metabolismo , Humanos , Hidroxilación , Hipoglucemiantes/administración & dosificación , Hipoglucemiantes/sangre , Hipoglucemiantes/orina , Técnicas In Vitro , Riñón/metabolismo , Masculino , Microsomas Hepáticos/metabolismo , Estructura Molecular , Oxidación-Reducción , Pirazinas/administración & dosificación , Pirazinas/sangre , Pirazinas/orina , Proteínas Recombinantes/metabolismo , Valores de Referencia , Fosfato de Sitagliptina , Ésteres del Ácido Sulfúrico/metabolismo , Triazoles/administración & dosificación , Triazoles/sangre , Triazoles/orinaRESUMEN
The pharmacokinetics, metabolism, and excretion of sitagliptin [MK-0431; (2R)-4-oxo-4-[3-(trifluoromethyl)-5,6-dihydro[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl]-1-(2,4,5-trifluorophenyl)butan-2-amine], a potent dipeptidyl peptidase 4 inhibitor, were evaluated in male Sprague-Dawley rats and beagle dogs. The plasma clearance and volume of distribution of sitagliptin were higher in rats (40-48 ml/min/kg, 7-9 l/kg) than in dogs ( approximately 9 ml/min/kg, approximately 3 l/kg), and its half-life was shorter in rats, approximately 2 h compared with approximately 4 h in dogs. Sitagliptin was absorbed rapidly after oral administration of a solution of the phosphate salt. The absolute oral bioavailability was high, and the pharmacokinetics were fairly dose-proportional. After administration of [(14)C]sitagliptin, parent drug was the major radioactive component in rat and dog plasma, urine, bile, and feces. Sitagliptin was eliminated primarily by renal excretion of parent drug; biliary excretion was an important pathway in rats, whereas metabolism was minimal in both species in vitro and in vivo. Approximately 10 to 16% of the radiolabeled dose was recovered in the rat and dog excreta as phase I and II metabolites, which were formed by N-sulfation, N-carbamoyl glucuronidation, hydroxylation of the triazolopiperazine ring, and oxidative desaturation of the piperazine ring followed by cyclization via the primary amine. The renal clearance of unbound drug in rats, 32 to 39 ml/min/kg, far exceeded the glomerular filtration rate, indicative of active renal elimination of parent drug.
Asunto(s)
Inhibidores de la Dipeptidil-Peptidasa IV , Inhibidores Enzimáticos/farmacocinética , Hipoglucemiantes/farmacocinética , Pirazinas/farmacocinética , Triazoles/farmacocinética , Adenosina Desaminasa/metabolismo , Inhibidores de la Adenosina Desaminasa , Administración Oral , Animales , Bilis/metabolismo , Disponibilidad Biológica , Biotransformación , Ciclización , Dipeptidil Peptidasa 4/metabolismo , Perros , Inhibidores Enzimáticos/administración & dosificación , Inhibidores Enzimáticos/sangre , Inhibidores Enzimáticos/orina , Heces/química , Glucurónidos/metabolismo , Glicoproteínas/antagonistas & inhibidores , Glicoproteínas/metabolismo , Haplorrinos , Humanos , Hidroxilación , Hipoglucemiantes/administración & dosificación , Hipoglucemiantes/sangre , Hipoglucemiantes/orina , Técnicas In Vitro , Riñón/metabolismo , Masculino , Microsomas Hepáticos/metabolismo , Estructura Molecular , Oxidación-Reducción , Unión Proteica , Pirazinas/administración & dosificación , Pirazinas/sangre , Pirazinas/orina , Ratas , Ratas Sprague-Dawley , Fosfato de Sitagliptina , Especificidad de la Especie , Ésteres del Ácido Sulfúrico/metabolismo , Triazoles/administración & dosificación , Triazoles/sangre , Triazoles/orinaRESUMEN
Sitagliptin (MK-0431) is an oral, potent, and selective dipeptidyl peptidase-IV (DPP-4) inhibitor developed for the treatment of type 2 diabetes. This multicenter, randomized, double-blind, placebo-controlled study examined the pharmacokinetic and pharmacodynamic effects of sitagliptin in obese subjects. Middle-aged (45-63 years), nondiabetic, obese (body mass index: 30-40 kg/m2) men and women were randomized to sitagliptin 200 mg bid (n = 24) or placebo (n = 8) for 28 days. Steady-state plasma concentrations of sitagliptin were achieved within 2 days of starting treatment, and >90% of the dose was excreted unchanged in urine. Sitagliptin treatment led to approximately 90% inhibition of plasma DPP-4 activity, increased active glucagon-like peptide-1 (GLP-1) levels by 2.7-fold (P < .001), and decreased post-oral glucose tolerance test glucose excursion by 35% (P < .050) compared to placebo. In nondiabetic obese subjects, treatment with sitagliptin 200 mg bid was generally well tolerated without associated hypoglycemia and led to maximal inhibition of plasma DPP-4 activity, increased active GLP-1, and reduced glycemic excursion.
Asunto(s)
Inhibidores de la Adenosina Desaminasa , Inhibidores de la Dipeptidil-Peptidasa IV , Glicoproteínas/antagonistas & inhibidores , Hipoglucemiantes/farmacocinética , Obesidad/metabolismo , Pirazinas/farmacocinética , Triazoles/farmacocinética , Adenosina Desaminasa/metabolismo , Administración Oral , Glucemia/efectos de los fármacos , Peso Corporal/efectos de los fármacos , Dipeptidil Peptidasa 4/metabolismo , Método Doble Ciego , Femenino , Péptido 1 Similar al Glucagón/sangre , Prueba de Tolerancia a la Glucosa , Glicoproteínas/metabolismo , Humanos , Hipoglucemiantes/sangre , Hipoglucemiantes/farmacología , Hipoglucemiantes/orina , Masculino , Persona de Mediana Edad , Obesidad/sangre , Pirazinas/sangre , Pirazinas/farmacología , Pirazinas/orina , Fosfato de Sitagliptina , Triazoles/sangre , Triazoles/farmacología , Triazoles/orinaRESUMEN
The effects of cysteine on the pharmacokinetics of 2-(allylthio)pyrazine (2-AP) were investigated after intravenous administration of the drug (50 mg/kg) to control (Sprague-Dawley) rats (4-week fed on 23% casein diet), and rats with protein-calorie malnutrition (PCM, 4-week fed on 5% casein diet) and PCMC (PCM with 250 mg/kg of oral cysteine, twice daily starting from the fourth week). In rats with PCM, the area under the plasma concentration-time curve from time zero to time infinity (AUC) of 2-AP was significantly smaller than that in control rats. However, in rats with PCMC, the AUC of 2-AP was significantly greater than that in control rats and rats with PCM. This could be due to significantly greater formation of M4 in rats with PCM and significantly smaller formation of M4 in rats with PCMC than that in control rats. In rats with PCMC, some pharmacokinetic parameters of 2-AP restored fully or more than the levels of control rats. For example, in rats with PCMC, the apparent volume of distribution at steady state of 2-AP (7290, 16,600, and 7050 ml/kg for control rats, and rats with PCM and PCMC, respectively), the percentage of dose excreted in 24-h urine as unchanged 2-AP (0.242, 0.727, and 0.130%), and 'the amount' excreted in 24-h urine as M4 (100, 228, and 51%) were comparable to those in control rats. However, the AUC (739, 434, and 1240 microg/min/ml) and total body clearance (67.7, 115, and 40.2 ml/min/kg) of 2-AP were significantly greater and slower, respectively, than those in control rats. This could be at least partly due to increase in S-methyltransferase activity (to form M4) in rats with PCM and greater restoration of its activity (decrease in its activity) in rats with PCMC.
Asunto(s)
Cisteína/farmacología , Sustancias Protectoras/farmacocinética , Desnutrición Proteico-Calórica/metabolismo , Pirazinas/farmacocinética , Animales , Peso Corporal/efectos de los fármacos , Cromatografía Líquida de Alta Presión , Ingestión de Alimentos/efectos de los fármacos , Inyecciones Intravenosas , Masculino , Tamaño de los Órganos/efectos de los fármacos , Desnutrición Proteico-Calórica/tratamiento farmacológico , Desnutrición Proteico-Calórica/fisiopatología , Pirazinas/sangre , Pirazinas/orina , Ratas , Ratas Sprague-Dawley , Distribución TisularRESUMEN
1. The urinary metabolites of the anti-convulsant compound 4-amino-1-(2,6-difluorobenzyl)-1H-1,2,3-triazolo[4,5-c]-pyridine hydrochloride (GI265080) obtained following a single oral dose to man have been detected and quantified relative to each other using 19F-NMR spectroscopy. 2. The human urinary metabolites of GI265080 were isolated using semipreparative HPLC and unequivocally characterized using 1H-NMR spectroscopy, two-dimensional heteronuclear NMR spectroscopy and mass spectrometry. The assignments of the N-(5)-oxide and the N-(5)-O-glucuronide metabolites of GI265080 were further confirmed by independent synthesis. The urinary metabolites obtained following single oral doses to dog and rat have also been isolated and characterized. 3. The human urinary metabolites of GI265080 comprise the N-(5)-oxide, the quaternary N+-(5)-glucuronide, the 7-hydroxy glucuronide and a glucuronide conjugate of the N-(5)-oxide. The N-(5)-O-glucuronide conjugate is a novel species in human metabolism and is a significant route of elimination of GI265080 in man. 4. The urinary metabolites of the potential anti-convulsant GW273293 (6-amino-3-(2,3,5-trichlorophenyl)pyrazin-2-ylamine) obtained following a single oral dose to man have also been isolated and characterized. The formation of a novel N-O-glucuronide was also observed and was shown to constitute a significant route of elimination of GW273293 in man.