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1.
Xenobiotica ; 50(1): 92-100, 2020 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-31601149

RESUMEN

The carboxylesterase drug hydrolysis pathway has been used extensively to improve the oral availability of drugs under the assumption that the high capacity and low substrate specificity of hydrolytic enzymes would ensure rapid, complete, and consistent conversion of prodrugs to their active metabolite. However, a growing body of literature indicates that drug hydrolysis is usually catalyzed by one primary enzyme, either carboxylesterase-1 or carboxlylesterase-2, and that there is wide variability in enzyme activity affecting the metabolism of prodrugs to their active metabolites.This review identifies carboxylesterase substrates and describes our current understanding of the influence of genetic polymorphisms on substrate disposition and clinical effects. Several polymorphisms are described in the literature and included in the personalized medicine database PharmGKB, but there are no carboxylesterase genotypes referenced in Food and Drug Administration approved drug labeling. The limited validation of metabolic pathways for drugs undergoing hydrolysis, and the small number of studies evaluating genotype-drug interactions confirm that this is an emerging field of drug metabolism research.The dependence of prodrugs, many with low therapeutic indexes, on carboxylesterase-mediated hydrolysis indicate that genetic variation plays an important role in prodrug activation, and that carboxylesterase genotyping will become an important component of personalized medicine.


Asunto(s)
Hidrolasas de Éster Carboxílico/genética , Medicina de Precisión , Hidrolasas de Éster Carboxílico/metabolismo , Interacciones Farmacológicas , Genotipo , Humanos , Hidrólisis , Inactivación Metabólica/genética , Tasa de Depuración Metabólica , Polimorfismo Genético , Profármacos , Especificidad por Sustrato
2.
Xenobiotica ; 50(3): 245-251, 2020 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-31039046

RESUMEN

Clopidogrel is widely prescribed in patients with cardiovascular disease. Most research has focused on the role of hepatic CYP450 metabolism as the primary source of response variability despite 85-90% of clopidogrel being hydrolyzed by human carboxylesterase-1 (CES1).The purpose of this study is to determine the effects of the known CES1 inhibitor alcohol on clopidogrel metabolism: (1) in vitro in human recombinant CES1 and human liver S9 (HLS9) fractions and (2) in a plasma carboxylesterase deficient mouse (Es1e) strain administered 25 mg/kg oral clopidogrel alone and with 3 g/kg alcohol.Alcohol significantly inhibited the hydrolysis of clopidogrel (IC50 161 mM) and 2-oxo-clopidogrel (IC50 6 mM). In HLS9, alcohol treatment formed ethylated metabolites via transesterification and an increased formation of the H4 active metabolite. These results were replicated in Es1e mice as alcohol increased clopidogrel (91%) and H4 (22%) AUC and reduced formation of the clopidogrel (48%) and 2-oxo-clopidogrel (42%) carboxylate metabolites.Clopidogrel metabolism is highly sensitive to alterations in CES1 activity. The Es1e mouse may represent a suitable model of human CES1 drug metabolism that can be used to rapidly assess how alterations in CES1 function impact the disposition of substrate drugs.

3.
Drug Metab Rev ; 50(3): 369-397, 2018 08.
Artículo en Inglés | MEDLINE | ID: mdl-30221555

RESUMEN

There will be 642 million people worldwide by 2040 suffering from diabetes mellitus. Long-term multidrug therapy aims to achieve normal glycemia and minimize complications, and avoid severe hypoglycemic events. The appreciation of the drug-metabolizing enzymes and drug transporters as critical players in the treatment of diabetes has attracted much attention regarding their potential alterations in the pathogenesis of the disease. This review discusses pharmacokinetics-based alterations of cytochrome P450 enzymes, phase-II metabolizing enzymes, and membrane transporter proteins, as well as the potential mechanisms underlying these alterations. We also discuss the potential influences of altered enzymes and transporters on the disposition of commonly prescribed glucose-lowering medicines. Future studies should delve into the impact of altered drug-metabolizing enzymes and transporters on the progression toward abnormal glucose homeostasis.


Asunto(s)
Sistema Enzimático del Citocromo P-450/metabolismo , Diabetes Mellitus/metabolismo , Hipoglucemiantes/farmacocinética , Proteínas de Transporte de Membrana/metabolismo , Animales , Diabetes Mellitus/enzimología , Humanos
4.
Expert Opin Drug Metab Toxicol ; 14(2): 131-142, 2018 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-29264996

RESUMEN

INTRODUCTION: Mammalian carboxylesterase enzymes are a highly conserved metabolic pathway involved in the metabolism of endogenous and exogenous compounds including many widely prescribed therapeutic agents. Recent advances in our understanding of genetic polymorphisms affecting enzyme activity have exposed potential therapeutic implications. Areas covered: The aims of this review are to provide an overview of carboxylesterase 1 (CES1) and carboxylesterase 2 (CES2) gene structure, to summarize the known polymorphism affecting substrate-drug metabolism, and to assess the potential therapeutic implications of genetic variations affecting enzyme function. Expert opinion: Genetic variability in carboxylesterase drug metabolism is a nascent area of research with only a handful of the thousands of SNPs investigated for their potential effects of enzyme activity or carboxylesterase-substrate disposition and therapeutics. It remains to be determined if the wide variability in enzyme activity can be explained by genetic variation, and used in personalized medicine to improve clinical outcomes.


Asunto(s)
Carboxilesterasa/genética , Hidrolasas de Éster Carboxílico/genética , Preparaciones Farmacéuticas/metabolismo , Carboxilesterasa/metabolismo , Hidrolasas de Éster Carboxílico/metabolismo , Variación Genética , Humanos , Preparaciones Farmacéuticas/administración & dosificación , Polimorfismo de Nucleótido Simple
5.
Br J Clin Pharmacol ; 83(12): 2687-2694, 2017 12.
Artículo en Inglés | MEDLINE | ID: mdl-28758694

RESUMEN

AIMS: To determine the disposition and effects of caffeine after administration using a new dosage form (AeroShot) that delivers caffeine by inspiration of a fine powder into the oral cavity and compare it to an equivalent dose of an oral solution (energy drink) as the reference standard. METHODS: Healthy human subjects (n = 17) inspired a 100 mg caffeine dose using the AeroShot device or consumed an energy drink on separate study days. Heart rate, blood pressure and subject assessments of effects were measured over an 8-h period. Plasma concentrations of caffeine and its major metabolites were determined by liquid chromatography-mass spectrometry. Pharmacokinetic, cardiovascular and perceived stimulant effects were compared between AeroShot and energy drink phases using a paired t test and standard bioequivalency analysis. RESULTS: Caffeine disposition was similar after caffeine administration by the AeroShot device and energy drink: peak plasma concentration 1790 and 1939 ng ml-1 , and area under the concentration-time curve (AUC) 15 579 and 17 569 ng ml-1 × h, respectively, but they were not bioequivalent: AeroShot AUC of 80.3% (confidence interval 71.2-104.7%) and peak plasma concentration of 86.3% (confidence interval 62.8-102.8%) compared to the energy drink. Female subjects did have a significantly larger AUC compared to males after consumption of the energy drink. The heart rate and blood pressure were not significantly affected by the 100 mg caffeine dose, and there were no consistently perceived stimulant effects by the subjects using visual analogue scales. CONCLUSION: Inspiration of caffeine as a fine powder using the AeroShot device produces a similar caffeine profile and effects compared to administration of an oral solution (energy drink).


Asunto(s)
Cafeína/administración & dosificación , Cafeína/farmacocinética , Bebidas Energéticas , Administración por Inhalación , Administración Oral , Adolescente , Adulto , Área Bajo la Curva , Presión Sanguínea/efectos de los fármacos , Cafeína/efectos adversos , Bebidas Energéticas/efectos adversos , Femenino , Frecuencia Cardíaca/efectos de los fármacos , Humanos , Masculino , Persona de Mediana Edad , Polvos , Factores Sexuales , Tennessee , Equivalencia Terapéutica , Adulto Joven
6.
Biomed Chromatogr ; 31(6)2017 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-27864843

RESUMEN

Caffeine is a mild stimulant with significant potential for abuse, being consumed in larger doses with the widespread availability of energy drinks and by novel routes of administration such as inspired powder, oral sprays and electronic cigarettes. How these recent changes in caffeine consumption affecting caffeine disposition and abuse potential is of growing concern. In the study of caffeine disposition in humans, it is common to only measure the caffeine concentration; however, caffeine's three major metabolites (paraxanthine, theobromine and theophylline) retain central nervous system stimulant activity that may contribute to the overall pharmacological activity and toxicity. Therefore, it would be scientifically more rigorous to measure caffeine and its major metabolites in the evaluation of caffeine disposition in human subjects. Herein, we report a method for the simultaneous quantification of caffeine and its three major metabolites in human plasma by high-performance liquid chromatography coupled to electrospray tandem mass spectrometry (HPLC-ESI-MS/MS). Human plasma samples were treated by simple protein precipitation and the analytes were separated using a 6 min gradient program. Precision and accuracy were well within in the 15% acceptance range. The simple sample preparation, short runtime, sensitivity and the inclusion of caffeine's major metabolites make this assay methodology optimal for the study of caffeine's pharmacokinetics and pharmacodynamics in human subjects.


Asunto(s)
Cafeína/sangre , Cromatografía Líquida de Alta Presión/métodos , Espectrometría de Masa por Ionización de Electrospray/métodos , Espectrometría de Masas en Tándem/métodos , Humanos
7.
Pharmacotherapy ; 36(12): e200-e205, 2016 12.
Artículo en Inglés | MEDLINE | ID: mdl-27885711

RESUMEN

Regardless of practice setting, it is imperative that pharmacists be able to either participate in generating new knowledge or use the ever-expanding body of literature to guide patient care. However, competing priorities in Pharm.D. curricula and residency training programs have resulted in limited emphasis on acquiring research and scholarly skills. Factors likely contributing to this reduced focus include the lack of curricular and postgraduate training standards emphasizing the development of research skills, time to commit to scholarly activity, and accessibility to experienced mentors. Strategies for increasing scholarly activity for pharmacy students and residents should therefore continue to be a focus of professional degree and residency training programs. Several resources are available for academic planners, program directors, and institutions to augment scholarly experience for pharmacy trainees and clinicians. This commentary highlights the importance of providing research opportunities for students and residents, describes the potential barriers to these activities, and provides recommendations on how to increase the instruction and mentoring of trainees to generate and use research.


Asunto(s)
Educación en Farmacia/métodos , Residencias en Farmacia/métodos , Investigación , Estudiantes de Farmacia , Competencia Clínica , Curriculum , Humanos , Mentores , Servicios Farmacéuticos/organización & administración , Farmacéuticos/organización & administración
8.
Am J Pharm Educ ; 80(1): 4, 2016 Feb 25.
Artículo en Inglés | MEDLINE | ID: mdl-26941430

RESUMEN

OBJECTIVE: To assess first-year (P1) pharmacy students' studying behaviors and perceptions after implementation of a new computerized "composite examination" (CE) testing procedure. METHODS: Student surveys were conducted to assess studying behavior and perceptions about the CE before and after its implementation. RESULTS: Surveys were completed by 149 P1 students (92% response rate). Significant changes between survey results before and after the CE included an increase in students' concerns about the limited number of questions per course on each examination and decreased concerns about the time allotted and the inability to write on the CEs. Significant changes in study habits included a decrease in cramming (studying shortly before the test) and an increase in priority studying (spending more time on one course than another). CONCLUSION: The CE positively changed assessment practice at the college. It helped overcome logistic challenges in computerized testing and drove positive changes in study habits.


Asunto(s)
Educación en Farmacia , Evaluación Educacional , Percepción/fisiología , Farmacéuticos/psicología , Estudiantes de Farmacia/psicología , Adulto , Curriculum , Femenino , Humanos , Masculino , Persona de Mediana Edad , Encuestas y Cuestionarios , Adulto Joven
9.
Clin Cancer Res ; 22(4): 827-36, 2016 Feb 15.
Artículo en Inglés | MEDLINE | ID: mdl-26446947

RESUMEN

PURPOSE: Study objectives included evaluating the safety, tolerability, pharmacokinetics (PK), pharmacodynamics (PD), and antitumor activity of VX15/2503 in advanced solid tumor patients. EXPERIMENTAL DESIGN: Weekly i.v. doses were administered on a 28-day cycle. Safety, immunogenicity, PK, efficacy, T-cell membrane-associated SEMA4D (cSEMA4D) expression and saturation, soluble SEMA4D (sSEMA4D) serum levels, and serum biomarker levels were evaluated. RESULTS: Forty-two patients were enrolled into seven sequential cohorts and an expansion cohort (20 mg/kg). VX15/2503 was well tolerated. Treatment-related adverse events were primarily grade 1 or 2 and included nausea (14.3%) and fatigue (11.9%); arthralgia, decreased appetite, infusion-related reaction, and pyrexia were each 7.3%. One pancreatic cancer patient (15 mg/kg) experienced a Grade 3 dose-limiting toxicity; elevated γ-glutamyl transferase. Complete cSEMA4D saturation was generally observed at serum antibody concentrations ≥ 0.3 µg/mL, resulting in decreased cSEMA4D expression. Soluble SEMA4D levels increased with dose and infusion number. Neutralizing anti-VX15/2503 antibodies led to treatment discontinuation for 1 patient. VX15/2503 Cmax and AUC generally increased with dose and dose number. One patient (20 mg/kg) experienced a partial response, 19 patients (45.2%) exhibited SD for ≥ 8 weeks, and 8 (19%) had SD for ≥ 16 weeks. Subjects with elevated B/T lymphocytes exhibited longer progression-free survival. CONCLUSIONS: VX15/2503 was well tolerated and produced expected PD effects. The correlation between immune cell levels at baseline and progression-free survival is consistent with an immune-mediated mechanism of action. Future investigations will be in combination with immunomodulatory agents.


Asunto(s)
Anticuerpos Monoclonales Humanizados/uso terapéutico , Antineoplásicos/uso terapéutico , Neoplasias del Colon/tratamiento farmacológico , Adulto , Anciano , Anciano de 80 o más Años , Anticuerpos Monoclonales Humanizados/farmacocinética , Antineoplásicos/farmacocinética , Área Bajo la Curva , Supervivencia sin Enfermedad , Femenino , Humanos , Masculino , Persona de Mediana Edad , Resultado del Tratamiento
10.
Curr Med Res Opin ; 31(11): 2021-9, 2015 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-26390258

RESUMEN

OBJECTIVE: The objective of this study was to determine the association between warfarin discontinuation and stroke among patients with nonvalvular atrial fibrillation (NVAF). RESEARCH DESIGN AND METHODS: This was a retrospective, observational study of adult NVAF patients (≥ 18 years) who were on warfarin in the Truven MarketScan commercial claims and encounters and Medicare supplemental and coordination of benefits databases (1 January 2008 to 30 June 2012). Warfarin discontinuation was defined as a gap of ≥ 45 days in warfarin prescription within 1 year after initiation. Patients who did and did not discontinue warfarin were matched at a 1:1 ratio using a propensity score method. Matched patients were followed for up to 1 year to determine risks of ischemic stroke, transient ischemic attack (TIA), and hemorrhagic stroke. A multivariate Cox proportional hazards model was used to further adjust for the effects of potential confounders. RESULTS: A total of 27,000 patients were included. Patients who discontinued warfarin had higher rates of ischemic stroke compared to persistent patients (1.0 vs. 0.5 per 100 patient years, P < 0.01), but similar rates of TIA (1.2 vs. 0.9 per 100 patient years, respectively; P = 0.07) and hemorrhagic stroke (0.3 vs. 0.2 per 100 patient years, P = 0.31). After adjustment for potential confounders, warfarin discontinuation was significantly associated with increased risk of ischemic stroke (hazard ratio [HR]: 2.04; 95% confidence interval [CI]: 1.47-2.84), TIA (HR: 1.36; 95% CI: 1.04-1.78), and ischemic stroke or TIA (HR: 1.50; 95% CI: 1.20-1.87). CONCLUSIONS: Warfarin discontinuation is associated with increased risk of ischemic stroke and TIA. Health care providers may need to take a more active role in the management of warfarin discontinuation and clinical outcomes, e.g., by considering newer anticoagulants with favorable risk-benefit profiles. Key limitations of the study include unavailability of important clinical factors and measures in claims data.


Asunto(s)
Anticoagulantes/administración & dosificación , Fibrilación Atrial/complicaciones , Accidente Cerebrovascular/epidemiología , Warfarina/administración & dosificación , Anciano , Anciano de 80 o más Años , Anticoagulantes/uso terapéutico , Bases de Datos Factuales , Femenino , Humanos , Ataque Isquémico Transitorio/epidemiología , Masculino , Persona de Mediana Edad , Puntaje de Propensión , Modelos de Riesgos Proporcionales , Estudios Retrospectivos , Accidente Cerebrovascular/etiología , Warfarina/uso terapéutico
11.
J Manag Care Spec Pharm ; 21(7): 596-606, 2015 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-26108384

RESUMEN

BACKGROUND: Use of warfarin is standard of care for stroke prevention in patients with atrial fibrillation (AF). However, AF patients experience high rates of warfarin discontinuation/interruption, resulting in increased health risks and health care costs. As such, it is important to study the rates and predictors of warfarin discontinuation/interruption in this population. OBJECTIVES: To determine (a) rates of warfarin discontinuation and interruption and (b) demographic, clinical, and health care-related factors associated with discontinuation and interruption in patients with nonvalvular AF (NVAF) in the usual clinical practice settings in the United States. METHODS: This retrospective cohort study used the MarketScan Database and included patients (aged ≥ 18 years) with NVAF who were initiated on warfarin. The study period was January 1, 2008, to June 30, 2012. To be included, patients were required to have at least 2 claims with AF diagnosis separated by ≥ 30 days and ≤ 12 months and at least 1 outpatient claim. Warfarin initiation had to occur within 30 days of the AF diagnosis. Patients also had to have continuous enrollment in prescription drug plans from 6 months prior to warfarin use to at least 12 months after warfarin initiation. Patients were followed for 1 year after warfarin initiation. Persistence was defined as warfarin therapy without a gap ≥ 45 days between the end date of the former prescription and the start date of the current prescription or with international normalized ratio (INR) monitoring at least every 42 days. Interruption was defined as a gap in warfarin therapy ≥ 45 days and ≤ 90 days between the end date of the former prescription and the start date of the current prescription and without INR monitoring at least every 42 days. Discontinuation was defined as greater than 90 days without warfarin therapy between the end date of the former prescription and the start date of the current prescription and without INR monitoring at least every 42 days. Chi-square tests were used to analyze categorical variables, and independent samples t-tests were used for continuous variables. Cox proportional hazards regression model was performed to determine factors associated with warfarin discontinuation/interruption, including demographic (e.g., age, gender); clinical (e.g., comorbidities, CHADS2 score); and health care-related (e.g., hospitalizations or emergency room visits) characteristics. Sensitivity analyses were conducted by varying prescription gaps by 7, 14, and 30 days. RESULTS: A total of 58,593 patients with NVAF were included. The mean age was approximately 71 years (SD = 12.00) and mean CHADS2 score was 1.66 (SD = 1.23). The majority of patients were male (60%). During 12 months after warfarin initiation, 45% of patients were persistent with warfarin; 12% had interruption without discontinuation; and 43% had discontinuation. The risk of warfarin interruption or discontinuation was significantly greater in patients who were younger than 65 years (HR = 1.22; 95% CI = 1.19-1.25), lived in the West (HR = 1.07; 95% CI = 1.03-1.11), had history of anemia (HR = 1.10; 95% CI = 1.06-1.14), had history of bleeding (HR = 1.10; 95% CI = 1.06-1.14), or had history of hospitalization or emergency room visits (HR = 1.11; 95% CI = 1.08-1.13). The significant factors associated with interruption and discontinuation were similar. In the sensitivity analyses, the significant factors associated with discontinuation/interruption were similar across different prescription gaps. CONCLUSIONS: In the U.S. clinical practice setting, more than 50% of NVAF patients discontinued or interrupted warfarin within 1 year after initiation. Aged less than 65 years, history of anemia, and history of hospitalization/emergency room visits were associated with increased risk of discontinuation/interruption. Given the high prevalence of warfarin discontinuation/interruption, health care providers should take a more active role in understanding and addressing the reasons behind patient discontinuation/interruption.


Asunto(s)
Anticoagulantes/administración & dosificación , Fibrilación Atrial/tratamiento farmacológico , Accidente Cerebrovascular/prevención & control , Warfarina/administración & dosificación , Factores de Edad , Anciano , Anciano de 80 o más Años , Fibrilación Atrial/complicaciones , Estudios de Cohortes , Bases de Datos Factuales , Femenino , Hospitalización/estadística & datos numéricos , Humanos , Relación Normalizada Internacional , Masculino , Cumplimiento de la Medicación , Persona de Mediana Edad , Modelos de Riesgos Proporcionales , Estudios Retrospectivos , Factores de Riesgo , Accidente Cerebrovascular/etiología , Estados Unidos
12.
Clin Pharmacokinet ; 54(6): 627-38, 2015 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-25511794

RESUMEN

BACKGROUND AND OBJECTIVE: Human carboxylesterase-1 (CES1) and human carboxylesterase-2 (CES2) play an important role in metabolizing many medications. Alcohol is a known inhibitor of these enzymes but the relative effect on CES1 and CES2 is unknown. The aim of this study was to determine the impact of alcohol on the metabolism of specific probes for CES1 (oseltamivir) and CES2 (aspirin). METHODS: The effect of alcohol on CES1- and CES2-mediated probe drug hydrolysis was determined in vitro using recombinant human carboxylesterase. To characterize the in vivo effects of alcohol, healthy volunteers received each probe drug alone and in combination with alcohol followed by blood sample collection and determination of oseltamivir, aspirin, and respective metabolite pharmacokinetics. RESULTS: Alcohol significantly inhibited oseltamivir hydrolysis by CES1 in vitro but did not affect aspirin metabolism by CES2. Alcohol increased the oseltamivir area under the plasma concentration-time curve (AUC) from 0 to 6 h (AUC0 → 6 h) by 27% (range 11-46%, p = 0.011) and decreased the metabolite/oseltamivir AUC0 → 6 h ratio by 34% (range 25-41%, p < 0.001). Aspirin pharmacokinetics were not affected by alcohol. CONCLUSIONS: Alcohol significantly inhibited the hydrolysis of oseltamivir by CES1 both in vitro and in humans, but did not affect the hydrolysis of aspirin to salicylic acid by CES2. These results suggest that alcohol's inhibition of CES1 could potentially result in clinically significant drug interactions with other CES1-substrate drugs, but it is unlikely to significantly affect CES2-substrate drug hydrolysis.


Asunto(s)
Antivirales/farmacocinética , Carboxilesterasa/metabolismo , Hidrolasas de Éster Carboxílico/metabolismo , Etanol/farmacología , Oseltamivir/farmacocinética , Adulto , Antiinflamatorios no Esteroideos/administración & dosificación , Antiinflamatorios no Esteroideos/sangre , Antiinflamatorios no Esteroideos/farmacocinética , Antivirales/administración & dosificación , Antivirales/sangre , Aspirina/administración & dosificación , Aspirina/sangre , Aspirina/farmacocinética , Carboxilesterasa/antagonistas & inhibidores , Hidrolasas de Éster Carboxílico/antagonistas & inhibidores , Estudios Cruzados , Inhibidores Enzimáticos/sangre , Inhibidores Enzimáticos/farmacología , Etanol/sangre , Femenino , Humanos , Hidrólisis/efectos de los fármacos , Masculino , Persona de Mediana Edad , Oseltamivir/administración & dosificación , Oseltamivir/sangre
13.
Clin Pharmacokinet ; 53(9): 825-36, 2014 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-25103325

RESUMEN

BACKGROUND AND OBJECTIVE: Human carboxylesterase-1 (CES1) is an enzyme that is primarily expressed in the liver, where it plays an important role in the metabolism of many commonly used medications. Ethanol (alcohol)-mediated inhibition of CES1 and loss-of-function polymorphisms in the CES1 gene can markedly reduce this enzyme's function. Such alterations in CES1 activity may have important effects on the disposition of substrate drugs. The aim of this study is to develop a physiologically based pharmacokinetic (PBPK) model to predict changes in CES1 substrate drug exposure in humans with CES1 activity impaired by ethanol or loss-of-function CES1 genetic polymorphisms. METHODS: The antiviral drug oseltamivir, an ethyl ester prodrug that is rapidly converted in vivo to the active metabolite oseltamivir carboxylate (OSC) by CES1 was used as a probe drug for CES1 activity. Oseltamivir PBPK models integrating in vitro and in vivo data were developed and refined. Then the changes in oseltamivir and OSC exposure in humans with CES1 impaired by ethanol or polymorphisms were simulated using a PBPK model incorporating in vitro inhibition and enzyme kinetic data. Model assumptions were verified by comparison of simulations with observed and published data. A sensitivity analysis was performed to gain a mechanistic understanding of the exposure changes of oseltamivir and OSC. RESULTS: The simulated changes in oseltamivir and OSC exposures in humans with CES1 impaired by ethanol or polymorphism were similar to the observed data. The observed exposures to oseltamivir were increased by 46 and 37 % for the area under the plasma concentration-time curve from time zero to 6 h (AUC6) and from time zero to 24 h (AUC24), respectively, with co-administration of ethanol 0.6 g/kg. In contrast, only a slight change was observed in OSC exposure. The simulated data show the same trend as evidenced by greater change in exposures to oseltamivir (27 and 26 % for AUC(6) and AUC(24), [corrected] respectively) than OSC (≤6 %). CONCLUSIONS: The PBPK model of impaired CES1 activity correctly predicts observed human data. This model can be extended to predict the effects of drug interactions and other factors affecting the pharmacokinetics of other CES1 substrate drugs.


Asunto(s)
Antivirales/farmacocinética , Hidrolasas de Éster Carboxílico/metabolismo , Modelos Biológicos , Oseltamivir/farmacocinética , Adulto , Antivirales/sangre , Hidrolasas de Éster Carboxílico/genética , Simulación por Computador , Humanos , Masculino , Oseltamivir/análogos & derivados , Oseltamivir/sangre , Polimorfismo Genético
14.
Rapid Commun Mass Spectrom ; 28(11): 1285-92, 2014 Jun 15.
Artículo en Inglés | MEDLINE | ID: mdl-24760569

RESUMEN

RATIONALE: Clopidogrel (CLO) is a prodrug used to prevent ischemic events in patients undergoing percutaneous coronary intervention or with myocardial infarction. A previous study found ethyl clopidogrel (ECLO) is formed by transesterification of CLO when incubated with alcohol in human liver microsomes. We hypothesize that ECLO will be subject to further metabolism and developed an assay to identify its metabolites. METHODS: A liquid chromatography/triple quadrupole mass spectrometry (LC/MS/MS) method was developed to identify metabolites of ECLO. According to the predicted metabolic pathway of ECLO, precursor-product ion pairs were used to screen the possible metabolites of ECLO in human liver S9 fractions. Subsequently, the detected metabolites were characterized by the results of product ion scan. RESULTS: In the presence of alcohol, CLO was tranesterified to ECLO, which was further oxidized to form ethylated 2-oxo-clopidogrel and several ethylated thiol metabolites including the ethylated form of the H4 active metabolite. CONCLUSIONS: The ECLO formed by transesterification with alcohol is subject to metabolism by CYP450 enzymes producing ethylated forms of 2-oxo-clopidogrel and the active H4 thiol metabolite.


Asunto(s)
Alcoholes/metabolismo , Cromatografía Líquida de Alta Presión/métodos , Espectrometría de Masas/métodos , Ticlopidina/análogos & derivados , Alcoholes/análisis , Clopidogrel , Esterificación , Humanos , Microsomas Hepáticos/química , Microsomas Hepáticos/metabolismo , Estructura Molecular , Ticlopidina/química , Ticlopidina/metabolismo
15.
Drug Metab Dispos ; 42(2): 201-6, 2014 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-24212379

RESUMEN

Dabigatran etexilate (DABE) is an oral prodrug that is rapidly converted to the active thrombin inhibitor, dabigatran (DAB), by serine esterases. The aims of the present study were to investigate the in vitro kinetics and pathway of DABE hydrolysis by human carboxylesterase enzymes, and the effect of alcohol on these transformations. The kinetics of DABE hydrolysis in two human recombinant carboxylesterase enzymes (CES1 and CES2) and in human intestinal microsomes and human liver S9 fractions were determined. The effects of alcohol (a known CES1 inhibitor) on the formation of DABE metabolites in carboxylesterase enzymes and human liver S9 fractions were also examined. The inhibitory effect of bis(4-nitrophenyl) phosphate on the carboxylesterase-mediated metabolism of DABE and the effect of alcohol on the hydrolysis of a classic carboxylesterase substrate (cocaine) were studied to validate the in vitro model. The ethyl ester of DABE was hydrolyzed exclusively by CES1 to M1 (Km 24.9 ± 2.9 µM, Vmax 676 ± 26 pmol/min per milligram protein) and the carbamate ester of DABE was exclusively hydrolyzed by CES2 to M2 (Km 5.5 ± 0.8 µM; Vmax 71.1 ± 2.4 pmol/min per milligram protein). Sequential hydrolysis of DABE in human intestinal microsomes followed by hydrolysis in human liver S9 fractions resulted in complete conversion to DAB. These results suggest that after oral administration of DABE to humans, DABE is hydrolyzed by intestinal CES2 to the intermediate M2 metabolite followed by hydrolysis of M2 to DAB in the liver by CES1. Carboxylesterase-mediated hydrolysis of DABE was not inhibited by alcohol.


Asunto(s)
Antitrombinas/metabolismo , Bencimidazoles/metabolismo , Carboxilesterasa/metabolismo , Intestinos/enzimología , Hígado/enzimología , Profármacos/metabolismo , Piridinas/metabolismo , Administración Oral , Antitrombinas/administración & dosificación , Bencimidazoles/administración & dosificación , Biotransformación , Carboxilesterasa/antagonistas & inhibidores , Hidrolasas de Éster Carboxílico/antagonistas & inhibidores , Hidrolasas de Éster Carboxílico/metabolismo , Cocaína/metabolismo , Dabigatrán , Inhibidores Enzimáticos/farmacología , Humanos , Hidrólisis , Intestinos/efectos de los fármacos , Cinética , Hígado/efectos de los fármacos , Microsomas Hepáticos/enzimología , Profármacos/administración & dosificación , Piridinas/administración & dosificación , Proteínas Recombinantes/metabolismo , Especificidad por Sustrato
17.
Pharmacotherapy ; 33(12): e337-46, 2013 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-24114730

RESUMEN

Developing clinical pharmacists' research skills and their ability to compete for extramural funding is an important component of the American College of Clinical Pharmacy's (ACCP) vision for pharmacists to play a prominent role in generating the new knowledge used to guide patient pharmacotherapy. Given the recent emphasis on clinical/translational research at the National Institutes of Health (NIH) and the key role of drug therapy in the management of many diseases, there is an unprecedented opportunity for the profession to contribute to this enterprise. A crucial question facing the profession is whether we can generate enough appropriately trained scientists to take advantage of these opportunities to generate the new knowledge to advance drug therapy. Since the 2009 publication of the ACCP Research Affairs Committee editorial recommending the Ph.D. degree (as opposed to fellowship training) as the optimal method for preparing pharmacists as clinical/translational scientists, significant changes have occurred in the economic, professional, political, and research environments. As a result, the 2012 ACCP Research Affairs Committee was charged with reexamining the college's position on training clinical pharmacy scientists in the context of these substantial environmental changes. In this commentary, the potential impact of these changes on opportunities for pharmacists in clinical/translational research are discussed as are strategies for ACCP, colleges of pharmacy, and the profession to increase the number and impact of clinical pharmacy scientists. Failure of our profession to take advantage of these opportunities risks our ability to contribute substantively to the biomedical research enterprise and ultimately improve the pharmacotherapy of our patients.


Asunto(s)
Investigación Biomédica/educación , Farmacéuticos/organización & administración , Investigación en Medicina Traslacional/educación , Investigación Biomédica/organización & administración , Selección de Profesión , Quimioterapia , Educación en Farmacia/métodos , Humanos , Competencia Profesional , Rol Profesional , Investigadores/educación , Investigadores/organización & administración , Sociedades Farmacéuticas , Investigación en Medicina Traslacional/organización & administración , Estados Unidos , Recursos Humanos
18.
J Mass Spectrom ; 48(8): 945-50, 2013 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-23893642

RESUMEN

A hydrophilic interaction chromatography/mass spectrometry (HILIC-MS)-based assay for imipenem (IMP) and cilastatin (CIL) was recently reported. This orthogonal electrospray ion source-based (ORS) assay utilized nonvolatile salt (unremovable) to stabilize IMI in plasma. Unfortunately, this method was not applicable to conventional MS with off-axis spray (OAS-MS) because MS sensitivity was rapidly deteriorated by the nonvolatile salt. Therefore, we aimed to find a nonvolatile salt- and ion suppression-free approach to stabilize and measure the analytes in plasma using OAS-MS. Acetonitrile and methanol were tested to stabilize the analytes in the plasma samples. The recoveries, matrix effects and stabilities of the analytes in the stabilizer-treated samples were studied. The variations in MS signal intensities were used as the indicator of the assay ruggedness. The results show that a mixture of methanol and acetonitrile (1:1) is best for the storage and measurement of IMP and CIL in human plasma. Utilization of this precipitant not only blocked the hydrolysis of the analytes in plasma but also resulted in an ion suppression-free, fast (120 s per sample) and sensitive detection. The sensitivity obtained using the less sensitive OAS-MS (API3000, 4 pg on column) is much greater than that of the published ORS-MS-based assay (API4000, 77 pg on column). The ruggedness of the assay was demonstrated by its constant MS signal intensity. In conclusion, an improved HILIC/MS-based assay for IMP and CIL was established. The approach presented here provides a simple solution to the challenge of analyzing hydrolytically unstable ß-lactam antibiotics in biological samples.


Asunto(s)
Cromatografía Liquida/métodos , Cilastatina/sangre , Imipenem/sangre , Espectrometría de Masa por Ionización de Electrospray/métodos , Acetonitrilos/química , Cilastatina/química , Humanos , Interacciones Hidrofóbicas e Hidrofílicas , Imipenem/química , Modelos Lineales , Metanol , Oseltamivir/análogos & derivados , Oseltamivir/sangre , Oseltamivir/química , Reproducibilidad de los Resultados , Sensibilidad y Especificidad
19.
Pharmacotherapy ; 33(2): 210-22, 2013 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-23386599

RESUMEN

Carboxylesterases are a multigene family of mammalian enzymes widely distributed throughout the body that catalyze the hydrolysis of esters, amides, thioesters, and carbamates. In humans, two carboxylesterases, hCE1 and hCE2, are important mediators of drug metabolism. Both are expressed in the liver, but hCE1 greatly exceeds hCE2. In the intestine, only hCE2 is present and highly expressed. The most common drug substrates of these enzymes are ester prodrugs specifically designed to enhance oral bioavailability by hydrolysis to the active carboxylic acid after absorption from the gastrointestinal tract. Carboxylesterases also play an important role in the hydrolysis of some drugs to inactive metabolites. It has been widely believed that drugs undergoing hydrolysis by hCE1 and hCE2 are not subject to clinically significant alterations in their disposition, but evidence exists that genetic polymorphisms, drug-drug interactions, drug-disease interactions and other factors are important determinants of the variability in the therapeutic response to carboxylesterase-substrate drugs. The implications for drug therapy are far-reaching, as substrate drugs include numerous examples from widely prescribed therapeutic classes. Representative drugs include angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, antiplatelet drugs, statins, antivirals, and central nervous system agents. As research interest increases in the carboxylesterases, evidence is accumulating of their important role in drug metabolism and, therefore, the outcomes of pharmacotherapy.


Asunto(s)
Hidrolasas de Éster Carboxílico/fisiología , Preparaciones Farmacéuticas/metabolismo , Inhibidores de la Enzima Convertidora de Angiotensina/química , Inhibidores de la Enzima Convertidora de Angiotensina/metabolismo , Animales , Antivirales/química , Antivirales/metabolismo , Hidrolasas de Éster Carboxílico/metabolismo , Humanos , Redes y Vías Metabólicas/fisiología , Preparaciones Farmacéuticas/química , Inhibidores de Agregación Plaquetaria/química , Inhibidores de Agregación Plaquetaria/metabolismo , Profármacos/química , Profármacos/metabolismo
20.
J Pharm Biomed Anal ; 72: 245-50, 2013 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-23000242

RESUMEN

Although liquid chromatography/electrospray ionization tandem mass spectrometry-based assays have been reported for the measurement of the antiviral oseltamivir (OS) in human samples, these assays either involve complicated sample pretreatment or lack sensitivity. Here we introduce a straightforward approach to improve the assay performance for OS and its metabolite oseltamivir carboxylate (OSC) in human plasma. A very low concentration of mobile phase modifier can improve the ionization efficiency of both analytes, thus enabling a high sensitivity without any matrix effect. The fast LC gradient further increases the sensitivity by narrowing the peak width (6-9s) and eluting the analytes at higher organic content. The increased ionization efficiency and minimized matrix effects enabled us to introduce a one-step protein precipitation for sample clean-up without compromising the sensitivity. The lower limit of quantification was 0.34 ng/mL for both analytes, which was at least 3 times more sensitive than published assays that involve complicated sample pretreatment. The assay involves measurement of analytes and their stable-isotope internal standards in small-volume (30-µL) plasma. Sodium fluoride was utilized to prevent the hydrolysis of OS during and after sampling. The calibration curve was linear over the range of 0.34-1000 ng/mL. Accuracy was 95-110% and the precision was 2.2-11.0%. This method was applied successfully to the human pharmacokinetic study of OS, and can estimate the relevant pharmacokinetic parameters of OS with more accuracy. The approach utilized in the optimization of assay performance can be extended to the measurement of other drugs in biomatrices.


Asunto(s)
Oseltamivir/análogos & derivados , Oseltamivir/sangre , Oseltamivir/química , Cromatografía Líquida de Alta Presión/métodos , Humanos , Oseltamivir/metabolismo , Espectrometría de Masa por Ionización de Electrospray/métodos , Espectrometría de Masas en Tándem/métodos
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