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1.
Int J Surg ; 79: 131-135, 2020 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-32413504

RESUMO

BACKGROUND: The impact of major liver resection (LR) on the detoxifying function of the remaining liver tissue as represented by CYP3A activity has yet to be assessed. Therefore, this study evaluates the changes in CYP3A activity between preoperative values and after liver resection. MATERIAL AND METHODS: To determine CYP3A activity, midazolam (MDZ) was used as a marker substance, 3 µg were applied intravenously one day before surgery and on the 3rd day after surgery. Subsequently blood was withdrawn at 0, 0.25, 0.5, 1.0, 1.5, 2.0, 2.5, 3, 4 and 6 h post application of the study drug. Plasma MDZ and 1-OH-MDZ concentration was assessed using a LC-MS/MS method. Volumetric analysis of the resected liver was done by syngo.CT liver analysis software (Siemens Healthineers) using preoperative multidetector computed tomography. RESULTS: N = 13 (8 male/5 female) patients were included in this study and received preoperative evaluation, 11 patients were studied also after liver resection. The mean age was 62 (±15.3) years with a mean BMI of 23.6 ± 4.8 kg/m2. No patient suffered from acute liver dysfunction postoperatively. None of the pharmacokinetic parameters assessed were significantly altered by liver resection. CYP3A activity over time was not significantly reduced by major liver resection. CONCLUSION: This study gives first time data on the impact of major liver resection on CYP3A activity. It was shown that MDZ clearance representing in vivo CYP3A activity is not altered by major liver resection. This suggests no dose adjustment of commonly applied drugs which are CYP3A substrates needs to be carried out.


Assuntos
Citocromo P-450 CYP3A/metabolismo , Hepatectomia , Adulto , Idoso , Estudos Controlados Antes e Depois , Feminino , Humanos , Masculino , Midazolam/sangue , Pessoa de Meia-Idade , Período Pós-Operatório , Estudos Prospectivos
2.
Eur J Pharm Sci ; 141: 105095, 2020 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-31626965

RESUMO

PURPOSE: The aim of the present study was to develop a population pharmacokinetic model of midazolam, and to evaluate the influence of maturation process and other variability factors in critically ill children with severe acute bronchiolitis, who received a long-term intravenous infusion of midazolam. METHODS: In the study were included 49 critically ill children of both genders (from 0 to 130 weeks of age) with severe acute bronchiolitis hospitalised in intensive care units. Nonlinear mixed effects modelling approach was applied for data analyses and simulations. RESULTS: The final model is a two-compartment model that includes the effects of body weight using allometric scaling with fixed exponents and maturation of clearance. For a typical subject, scaled to the adult body weight of 70 kg, population pharmacokinetic values were estimated at 8.52 L/h for clearance (when maturation function was 1), 25.5 L/h for intercompartmental clearance, and 5.71 L and 39.8 L for the volume of the central and peripheral compartment, respectively. Based on the final model, maturation reaches 50% of the adult clearance in 45.9 weeks of postmenstrual age. The influence of gender, ABCB1 genotype and biochemical parameters on midazolam clearance was not detected. Results of simulations indicate the need for reduced dosing in certain groups of patients in order to maintain plasma concentrations of midazolam within recommended values. CONCLUSIONS: The developed population pharmacokinetic model can contribute to the dosing optimisation of midazolam, especially in critically ill children as it includes the influence of size and maturation of clearance, which are important parameters for achieving the desired plasma concentrations of midazolam.


Assuntos
Hipnóticos e Sedativos/farmacocinética , Midazolam/farmacocinética , Modelos Biológicos , Subfamília B de Transportador de Cassetes de Ligação de ATP/genética , Bronquiolite/genética , Bronquiolite/metabolismo , Bronquiolite/terapia , Estado Terminal , Feminino , Humanos , Hipnóticos e Sedativos/administração & dosagem , Hipnóticos e Sedativos/sangue , Lactente , Recém-Nascido , Infusões Intravenosas , Masculino , Midazolam/administração & dosagem , Midazolam/sangue , Polimorfismo de Nucleotídeo Único , Respiração Artificial
3.
Sci Rep ; 9(1): 16001, 2019 11 05.
Artigo em Inglês | MEDLINE | ID: mdl-31690757

RESUMO

Genetic polymorphism can result in abnormal pharmacodynamics that subsequently leads to the individual variance in sedative effects and adverse reactions. The aim of this study was to elucidate the association between midazolam-related genetic polymorphism and sedative effects, including adverse reactions, under conscious sedation during upper gastrointestinal endoscopy. We prospectively enrolled 100 eligible patients undergoing upper gastrointestinal endoscopy. The efficacy of the sedation, adverse reactions, plasma concentration of midazolam and 1-hydroxymidazolam were investigated as well as the genetic polymorphism of MDR1 and CYP3A5. The correlation between genetic polymorphism and sedative effects was assessed. Regarding MDR1 gene, the plasma concentration of midazolam was greater in patients with CGC haplotype (P = 0.012), while it was lower in patients with CAC haplotype (P = 0.005) than in those with other haplotypes. However, genetic polymorphism of neither MDR1 nor CYP3A5 correlated with the plasma concentration of 1-hydroxymidazolam. CGT haplotype of MDR1 was significantly correlated with sedation grade after midazolam administration (P = 0.042). In contrast, genetic polymorphism of CYP3A5 was not correlated with sedation grade. There was no association between genetic polymorphism of MDR1 or CYP3A5 and selected adverse reactions related to midazolam. Genetic polymorphism of MDR1 influences the concentration of midazolam and the sedation grade. However, it is not associated with adverse reactions such as paradoxical response and retrograde amnesia.


Assuntos
Citocromo P-450 CYP3A/genética , Hipnóticos e Sedativos/administração & dosagem , Midazolam/administração & dosagem , Polimorfismo Genético , Subfamília B de Transportador de Cassetes de Ligação de ATP/genética , Adolescente , Adulto , Idoso , Sedação Consciente , Endoscopia Gastrointestinal , Feminino , Humanos , Hipnóticos e Sedativos/efeitos adversos , Hipnóticos e Sedativos/sangue , Masculino , Midazolam/efeitos adversos , Midazolam/análogos & derivados , Midazolam/sangue , Pessoa de Meia-Idade , Estudos Prospectivos , República da Coreia , Adulto Jovem
4.
Bioanalysis ; 11(19): 1737-1754, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31617393

RESUMO

Aim: Collection and quantitative analysis in dry blood using volumetric absorptive microsampling (VAMS™) potentially offers significant advantages over conventional wet whole blood analysis. This manuscript explores their use for pediatric sampling and explores additional considerations for the validation of the bioanalytical method. Results: HPLC-MS/MS methods for the determination of midazolam and its major metabolite 1-OH midazolam in both whole wet blood, and dry blood collected on VAMS were developed, validated, and used to support an observational clinical study to compare pharmacokinetic parameters in pediatric patients. Conclusion: Validation data met internationally accepted guideline criteria. A strong correlation was observed in calculated concentrations between wet and dry test samples, indicating that VAMS is a suitable technique for use in pediatric clinical studies.


Assuntos
Coleta de Amostras Sanguíneas/métodos , Teste em Amostras de Sangue Seco/métodos , Hipnóticos e Sedativos/sangue , Midazolam/sangue , Adulto , Criança , Cromatografia Líquida de Alta Pressão/métodos , Humanos , Limite de Detecção , Espectrometria de Massas em Tandem/métodos
5.
Biol Pharm Bull ; 42(9): 1590-1595, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31474719

RESUMO

There are large inter- and intra-individual variations in CYP3A4 activity. Midazolam, which is predominantly metabolized to 1'-hydroxymidazolam and 4-hydroxymidazolam by CYP3A4, is considered an effective probe for CYP3A4. To determine the area under the curve (AUC) of midazolam or midazolam clearance for CYP3A4 activity, multiple plasma samples of midazolam are required. This study aimed to evaluate whether measurement of a single plasma concentration or urinary excretion of midazolam could be used to predict the AUC of midazolam in healthy volunteers. We conducted a retrospective analysis of two pharmacokinetic studies. Nineteen volunteers received intravenous (5, 15, and 30 µg/kg) and oral (15, 50, and 100 µg/kg) administration of midazolam on sequential days. The midazolam concentration in plasma and urine was determined by LC-MS/MS. Plasma midazolam concentrations showed a good correlation with the AUC at all blood sampling points after the administrations. The coefficient of determination was highest at 1-2 and 2-4 h after intravenous (>0.96) and oral administration (>0.94), respectively, among all the sampling times. The errors for bias and accuracy of prediction were the lowest at 1.5 and 4 h after intravenous and oral administration, respectively. In case of urinary excretion, a significant positive correlation between midazolam and the AUC was observed only after oral administration. Thus, the AUC of midazolam can be evaluated by blood sampling at 1.5 h after intravenous administration and at 4 h after oral administration.


Assuntos
Citocromo P-450 CYP3A/metabolismo , Voluntários Saudáveis , Midazolam/administração & dosagem , Midazolam/sangue , Midazolam/urina , Administração Oral , Área Sob a Curva , Estudos Cross-Over , Relação Dose-Resposta a Droga , Humanos , Injeções Intravenosas , Taxa de Depuração Metabólica , Valor Preditivo dos Testes , Estudos Retrospectivos , Fatores de Tempo
6.
J Vet Pharmacol Ther ; 42(6): 722-731, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31469454

RESUMO

Midazolam is a benzodiazepine with sedative, muscle relaxant, anxiolytic, and anticonvulsant effects. Twelve ball pythons (Python regius) were used in a parallel study evaluating the pharmacokinetics of 1 mg/kg midazolam following a single intracardiac (IC) or intramuscular (IM) administration. Blood was collected from a central venous catheter placed 7 days prior, or by cardiocentesis, at 15 time points starting just prior to and up to 72 hr after drug administration. Plasma concentrations of midazolam and 1-hydroxymidazolam were determined by the use of high-performance liquid chromatography tandem-mass spectrometry and pharmacokinetic parameters were estimated using noncompartmental analysis. The mean ± SD terminal half-lives of IC and IM midazolam were 12.04 ± 3.25 hr and 16.54 ± 7.10 hr, respectively. The area under the concentration-time curve extrapolated to infinity, clearance, and apparent volume of distribution in steady-state of IC midazolam were 19,112.3 ± 3,095.9 ng*hr/ml, 0.053 ± 0.008 L hr-1  kg-1 , and 0.865 ± 0.289 L/kg, respectively. The bioavailability of IM midazolam was estimated at 89%. Maximum plasma concentrations following an IM administration were reached 2.33 ± 0.98 hr and 24.00 ± 14.12 hr postinjection for midazolam and 1-hydroxymidazolam, respectively, and 22.33 ± 20.26 hr postinjection for 1-hydroxymidazolam following IC administration.


Assuntos
Boidae/sangue , Midazolam/análogos & derivados , Midazolam/farmacocinética , Animais , Área Sob a Curva , Cateteres Venosos Centrais/veterinária , Meia-Vida , Hipnóticos e Sedativos , Injeções Intramusculares , Midazolam/sangue , Midazolam/metabolismo
7.
J Ethnopharmacol ; 245: 112174, 2019 Dec 05.
Artigo em Inglês | MEDLINE | ID: mdl-31442620

RESUMO

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.


Assuntos
Cafeína/farmacocinética , Losartan/farmacocinética , Metoprolol/farmacocinética , Midazolam/farmacocinética , Omeprazol/farmacocinética , Própole , Terfenadina/análogos & derivados , Subfamília B de Transportador de Cassetes de Ligação de ATP/metabolismo , Adulto , Cafeína/sangue , Estudos Cross-Over , Sistema Enzimático do Citocromo P-450/genética , Sistema Enzimático do Citocromo P-450/metabolismo , Interações Medicamentosas , Feminino , Humanos , Losartan/sangue , Masculino , Metoprolol/sangue , Midazolam/sangue , Omeprazol/sangue , Terfenadina/sangue , Terfenadina/farmacocinética
8.
Neonatology ; 116(2): 154-162, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31256150

RESUMO

BACKGROUND: Phenobarbital and midazolam are commonly used drugs in (near-)term neonates treated with therapeutic hypothermia for hypoxic-ischaemic encephalopathy, for sedation, and/or as anti-epileptic drug. Phenobarbital is an inducer of cytochrome P450 (CYP) 3A, while midazolam is a CYP3A substrate. Therefore, co-treatment with phenobarbital might impact midazolam clearance. OBJECTIVES: To assess pharmacokinetics and clinical anti-epileptic effectiveness of phenobarbital and midazolam in asphyxiated neonates and to develop dosing guidelines. METHODS: Data were collected in the prospective multicentre PharmaCool study. In the present study, neonates treated with therapeutic hypothermia and receiving midazolam and/or phenobarbital were included. Plasma concentrations of phenobarbital and midazolam including its metabolites were determined in blood samples drawn on days 2-5 after birth. Pharmacokinetic analyses were performed using non-linear mixed effects modelling; clinical effectiveness was defined as no use of additional anti-epileptic drugs. RESULTS: Data were available from 113 (phenobarbital) and 118 (midazolam) neonates; 68 were treated with both medications. Only clearance of 1-hydroxy midazolam was influenced by hypothermia. Phenobarbital co-administration increased midazolam clearance by a factor 2.3 (95% CI 1.9-2.9, p < 0.05). Anticonvulsant effectiveness was 65.5% for phenobarbital and 37.1% for add-on midazolam. CONCLUSIONS: Therapeutic hypothermia does not influence clearance of phenobarbital or midazolam in (near-)term neonates with hypoxic-ischaemic encephalopathy. A phenobarbital dose of 30 mg/kg is advised to reach therapeutic concentrations. Phenobarbital co-administration significantly increased midazolam clearance. Should phenobarbital be substituted by non-CYP3A inducers as first-line anticonvulsant, a 50% lower midazolam maintenance dose might be appropriate to avoid excessive exposure during the first days after birth.


Assuntos
Anticonvulsivantes/farmacocinética , Asfixia Neonatal/terapia , Hipotermia Induzida , Hipóxia-Isquemia Encefálica/terapia , Midazolam/farmacocinética , Fenobarbital/farmacocinética , Anticonvulsivantes/administração & dosagem , Anticonvulsivantes/sangue , Interações Medicamentosas , Quimioterapia Combinada , Feminino , Humanos , Recém-Nascido , Masculino , Taxa de Depuração Metabólica , Midazolam/administração & dosagem , Midazolam/sangue , Fenobarbital/administração & dosagem , Fenobarbital/sangue , Guias de Prática Clínica como Assunto , Estudos Prospectivos
9.
Comp Med ; 69(4): 321-326, 2019 08 01.
Artigo em Inglês | MEDLINE | ID: mdl-31182185

RESUMO

Two healthy research cats involved in a randomized, blinded prospective pharmacodynamics study evaluating midazolam continuous-rate infusion as a means to decrease sevoflurane concentrations experienced unexpectedly prolonged recoveries. Midazolam loading doses, infusion rates, and the targeted plasma midazolam concentrations at steady-state were determined by pharmacokinetic modeling based on the results of a preliminary pharmacokinetic study using a single dose of midazolam. In the pharmacodynamics study, cats remained oversedated after recovery from anesthesia, and plasma concentrations of midazolam and its primary metabolite (1-hydroxymidazolam) remained elevated. The use of flumazenil was unsuccessful in timely treatment of oversedation. Administration of intravenous lipid emulsion was used in one of the cats to facilitate recovery and appeared to be effective in both reducing the depth of midazolam-induced oversedation and significantly reducing the plasma concentration of 1-hydroxymidazolam. The effects after the administration of both treatment modalities on clinical signs and plasma drug concentrations in cats are discussed. The observations suggest that cats may eliminate 1-hydroxymidazolam more slowly than expected; consequently dose adjustments may be required when continuous infusion of midazolam is intended. In addition, intravenous lipid emulsion may facilitate recovery from midazolam oversedation, particularly in cases unresponsive to traditional treatment modalities. However, further investigations are warranted to delineate the efficacy of this modality in the treatment of midazolam oversedation.


Assuntos
Gatos , Hipnóticos e Sedativos/administração & dosagem , Midazolam/administração & dosagem , Animais , Relação Dose-Resposta a Droga , Hipnóticos e Sedativos/sangue , Hipnóticos e Sedativos/farmacocinética , Infusões Intravenosas , Midazolam/sangue , Midazolam/farmacocinética
10.
Drug Test Anal ; 11(9): 1460-1464, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31242346

RESUMO

The stability of compounds in formalin solution is an important factor for drug analysis in a toxicological investigation. In this article, the authors report a complex medico-legal case involving midazolam and oxycodone. The complexity of this case comes from the fact that the body was embalmed with formalin solution before the autopsy. This technique, called thanatopraxy, allows the preservation of corpses from decomposition, the destruction of a maximal number of micro-organisms, and the presentation of the body with a natural appearance to the family. Unfortunately, when thanatopraxy is performed before the collection of biological specimens, the toxicological results are not representative of the time of the death. In addition, the interpretation of the results is difficult, because formalin can cause oxidation of xenobiotics present in the body at the time of the death, alter the pH of the tissues and dilute the compounds. To document the chemical stability of midazolam and oxycodone in formalin solution and interpret the results, a stability study was conducted for 21 days. Blood containing midazolam and oxycodone was spiked with formalin, kept at 4°C and regularly tested for both drugs. This study showed a rapid degradation of midazolam and oxycodone (85% during the first 24 hours for oxycodone). In the peripheral blood of the victim, methanol (1.31 g/L), midazolam (74ng/mL) and oxycodone (152 ng/mL) were identified. According to the stability study, the measured concentrations in formalin fixed-tissues are to be interpreted very carefully, knowing that significant degradation has occurred.


Assuntos
Hipnóticos e Sedativos/sangue , Midazolam/sangue , Entorpecentes/sangue , Oxicodona/sangue , Adulto , Autopsia/métodos , Cromatografia Líquida de Alta Pressão , Diagnóstico , Monitoramento de Medicamentos , Overdose de Drogas/sangue , Overdose de Drogas/diagnóstico , Toxicologia Forense , Formaldeído/química , Humanos , Hipnóticos e Sedativos/toxicidade , Masculino , Midazolam/toxicidade , Entorpecentes/toxicidade , Oxicodona/toxicidade , Espectrometria de Massas em Tandem
11.
Biomed Chromatogr ; 33(9): e4564, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31041812

RESUMO

Midazolam (MDZ) is the first choice in palliative sedation, and commonly used in sleep induction in anesthesia, with rapid onset of action. However, monitoring of the level of sedation in patients is not accurate. We developed and validated a bioanalytical method to detect MDZ in plasma using high-performance liquid chromatography (HPLC) coupled to a photodiode array detector (PDA) for future monitoring of sedation. MDZ was extracted by solid-phase extraction (SPE). Analyses were performed on a C18 column, using 0.05% triethylamine and acetonitrile as mobile phase, analyzing at 220 nm. Recovery was evaluated by comparing extracted and nonextracted solutions. Precision, accuracy, linearity, limits of detection (LD) and quantification (LQ), specificity and selectivity were determined. The mean recovery obtained by SPE was 101.03%. The method was linear in the range 1.0-50.0 µg/mL. The LD and LQ were, respectively, 0.43 and 1.43 µg/mL. The specificity of the MDZ peak was adequate. The method was able to detect MDZ among other drugs. Plasma anticoagulants showed no interference with the drug detection. The bioanalytical method using HPLC-PDA and SPE was successfully validated and showed linearity, precision, accuracy, specificity and high sensitivity for detection of MDZ in human plasma.


Assuntos
Cromatografia Líquida de Alta Pressão/métodos , Midazolam/sangue , Extração em Fase Sólida/métodos , Humanos , Limite de Detecção , Modelos Lineares , Reprodutibilidade dos Testes
12.
Eur J Clin Pharmacol ; 75(9): 1211-1218, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31123759

RESUMO

PURPOSE: Cytochrome P450 (CYP) 3A plays an important role in the metabolism of many clinically used drugs and exhibits substantial between-subject variability (BSV) in activity. Current methods to assess variability in CYP3A activity have limitations and there remains a need for a minimally invasive clinically translatable strategy to define CYP3A activity. The purpose of this study was to evaluate the potential for a caffeine metabolic ratio to describe variability in CYP3A activity. METHODS: The metabolic ratio 1,3,7-trimethyluric acid (TMU) to caffeine was evaluated as a biomarker to describe variability in CYP3A activity in a cohort (n = 28) of healthy 21 to 35-year-old males. Midazolam, caffeine, and TMU concentrations were assessed at baseline and following dosing of rifampicin (300 mg daily) for 7 days. RESULTS: At baseline, correlation coefficients for the relationship between apparent oral midazolam clearance (CL/F) with caffeine/TMU ratio measured at 3, 4, and 6 h post dose were 0.82, 0.79, and 0.65, respectively. The strength of correlations was retained post rifampicin dosing; 0.72, 0.87, and 0.82 for the ratios at 3, 4, and 6 h, respectively. Weaker correlations were observed between the change in midazolam CL/F and change in caffeine/TMU ratio post/pre-rifampicin dosing. CONCLUSION: BSV in CYP3A activity was well described by caffeine/TMU ratios pre- and post-induction. The caffeine/TMU ratio may be a convenient tool to assess BSV in CYP3A activity, but assessment of caffeine/TMU ratio alone is unlikely to account for all sources of variability in CYP3A activity.


Assuntos
Cafeína/sangue , Citocromo P-450 CYP3A/metabolismo , Ácido Úrico/análogos & derivados , Adulto , Biomarcadores/sangue , Cafeína/farmacocinética , Grupos de Populações Continentais/genética , Citocromo P-450 CYP3A/genética , Indutores do Citocromo P-450 CYP3A/sangue , Indutores do Citocromo P-450 CYP3A/farmacocinética , Dieta , Genótipo , Humanos , Masculino , Midazolam/sangue , Midazolam/farmacocinética , Fenótipo , Rifampina/sangue , Rifampina/farmacocinética , Ácido Úrico/sangue , Adulto Jovem
13.
Drug Metab Dispos ; 47(7): 724-731, 2019 07.
Artigo em Inglês | MEDLINE | ID: mdl-31028057

RESUMO

Midazolam is a widely used index substrate for assessing effects of xenobiotics on CYP3A activity. A previous study involving human hepatocytes showed the primary route of midazolam metabolism, 1'-hydroxylation, shifted to N-glucuronidation in the presence of the CYP3A inhibitor ketoconazole, which may lead to an overprediction of the magnitude of a xenobiotic-midazolam interaction. Because ketoconazole is no longer recommended as a clinical CYP3A inhibitor, indinavir was selected as an alternate CYP3A inhibitor to evaluate the contribution of the N-glucuronidation pathway to midazolam metabolism. The effects of indinavir on midazolam 1'-hydroxylation and N-glucuronidation were first characterized in human-derived in vitro systems. Compared with vehicle, indinavir (10 µM) inhibited midazolam 1'-hydroxylation by recombinant CYP3A4, human liver microsomes, and high-CYP3A activity cryopreserved human hepatocytes by ≥70%; the IC50 obtained with hepatocytes (2.7 µM) was within reported human unbound indinavir Cmax (≤5 µM). Midazolam N-glucuronidation in hepatocytes increased in the presence of indinavir in both a concentration-dependent (1-33 µM) and time-dependent (0-4 hours) manner (by up to 2.5-fold), prompting assessment in human volunteers (n = 8). As predicted by these in vitro data, indinavir was a strong inhibitor of the 1'-hydroxylation pathway, decreasing the 1'-hydroxymidazolam/midazolam area under the plasma concentration versus time curve (AUC)0-12h ratio by 80%. Although not statistically significant, the midazolam N-glucuronide/midazolam AUC0-12h ratio increased by 40%, suggesting a shift to the N-glucuronidation pathway. The amount of midazolam N-glucuronide recovered in urine increased 4-fold but remained <10% of the oral midazolam dose (2.5 mg). A powered clinical study would clarify whether N-glucuronidation should be considered when assessing the magnitude of a xenobiotic-midazolam interaction.


Assuntos
Inibidores do Citocromo P-450 CYP3A/farmacologia , Glucuronídeos/metabolismo , Inibidores da Protease de HIV/farmacologia , Indinavir/farmacologia , Midazolam/farmacocinética , Estudos Cross-Over , Interações Medicamentosas , Feminino , Hepatócitos/metabolismo , Humanos , Hidroxilação , Técnicas In Vitro , Masculino , Midazolam/sangue , Midazolam/urina , Estudos Prospectivos
14.
Palliat Med ; 33(7): 850-855, 2019 07.
Artigo em Inglês | MEDLINE | ID: mdl-31023150

RESUMO

BACKGROUND: Cytochrome P450 3A is the most relevant drug-metabolizing enzyme in humans as it is involved in the elimination of 50% of marketed drugs. Nothing is known about the activity of cytochrome P450 3A in palliative care patients who have complicated symptoms often associated with a terminal illness. AIM: In order to improve drug dosing in end-of-life care and to avoid drug interactions, cytochrome P450 3A activity was determined in patients of a palliative care unit under real-life clinical conditions. DESIGN: As midazolam is an established marker substance for cytochrome P450 3A activity, this single-arm prospective trial was designed to obtain a 4-h pharmacokinetic profile of midazolam after oral administration of a 10-µg dose from each enrolled patient. Plasma concentrations of midazolam and its primary metabolite 1'-hydroxy-midazolam were quantified by mass spectrometry techniques. Cytochrome P450 3A activity was calculated as partial metabolic clearance from a limited sampling area under the curve. All other drugs taken by the participating patients were considered, as well as recent blood test results and patients' diagnoses. The trial was registered at German Clinical Trials Register ( www.drks.de ): DRKS00011753. SETTING/PARTICIPANTS: The trial was carried out at a university palliative care unit under real-life clinical conditions. Every patient admitted to the ward was screened for possible participation, independent of the individual performance status. RESULTS: Partial metabolic clearance of midazolam in palliative care patients was 31.7 ± 32.1 L/h. This was a highly significant 40% reduction (p < 0.0001) in comparison with the cytochrome P450 3A activity of healthy subjects. CONCLUSION: Dosing of cytochrome P450 3A substrate drugs (e.g. macrolide antibiotics, benzodiazepines, calcium channel blockers) needs to be adjusted in palliative care patients; otherwise, escalation of debilitating symptoms due to drug interactions might occur.


Assuntos
Citocromo P-450 CYP3A/administração & dosagem , Citocromo P-450 CYP3A/metabolismo , Cuidados Paliativos , Assistência Terminal , Adulto , Idoso , Idoso de 80 Anos ou mais , Interações Medicamentosas , Feminino , Humanos , Fígado/enzimologia , Masculino , Midazolam/administração & dosagem , Midazolam/sangue , Midazolam/farmacocinética , Pessoa de Meia-Idade , Estudos Prospectivos , Adulto Jovem
15.
Xenobiotica ; 49(12): 1470-1477, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-30714842

RESUMO

1. 5-Fluorouracil (5-FU) is a pyrimidine derivative widely used for the treatment of cancer. In this study, we investigated the effects of 5-FU on the protein expression of hepatic CYP3A and their enzyme activity for metabolizing midazolam (MDZ), a typical substrate of CYP3A, in rat liver microsomes. We also examined the pharmacokinetic behavior of intravenously administered MDZ in rats treated with 5-FU (120 mg/kg, ip). 2. 5-FU was shown to induce hepatic CYP3A2 protein 2 days after administration without changing the expression of CYP3A1/3A23. However, affinity of 5-FU-inducible CYP3A protein to MDZ for its 4- and 1'-hydroxylation was decreased. Furthermore, the susceptibility of MDZ hydroxylation activity to a CYP3A inhibitor differed between the control and 5-FU groups. 3. Pharmacokinetic analysis of the MDZ disposition demonstrated no significant differences in the total clearance (CLtot) and elimination rate constant (ke) between the control and 5-FU-treated rats. Lack of alteration in the metabolic clearance of MDZ may be attributable to the induction of CYP3A protein with reduced affinity for the substrate of CYP3A enzymes. 4. Our findings provide novel information regarding the manifestation of inductive and interfering actions of 5-FU toward hepatic CYP3A to help in assessing the pharmacokinetics of CYP3A substrate drugs.


Assuntos
Citocromo P-450 CYP3A/metabolismo , Fluoruracila/farmacocinética , Fígado/metabolismo , Midazolam/farmacocinética , Administração Intravenosa , Animais , Peso Corporal/efeitos dos fármacos , Inibidores do Citocromo P-450 CYP3A/farmacologia , Hidroxilação/efeitos dos fármacos , Inativação Metabólica , Cinética , Fígado/efeitos dos fármacos , Masculino , Microssomos Hepáticos/efeitos dos fármacos , Microssomos Hepáticos/metabolismo , Midazolam/administração & dosagem , Midazolam/sangue , Tamanho do Órgão/efeitos dos fármacos , Ratos Sprague-Dawley
16.
Biopharm Drug Dispos ; 40(2): 81-93, 2019 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-30724384

RESUMO

CYP3A probe drugs such as midazolam and endogenous markers, and plasma 4ß-hydroxycholesterol (4ß-OHC) and urinary 6ß-hydroxycortisol-to-cortisol ratios (6ß-OHC/C) have been used as markers of CYP3A induction in cynomolgus monkeys, as with humans. However, there is limited information on their sensitivity and ability to detect CYP3A induction, as most studies were evaluated only at a high dose of the inducer, rifampicin (RIF; 20 mg/kg). In the present study, the CYP3A induction by RIF over a range doses of 0.2, 2 and 20 mg/kg (n = 4) was examined using CYP3A probe drugs (midazolam, triazolam and alprazolam) and the plasma and urinary endogenous CYP3A markers (4ß-OHC and 6ß-OHC/C). The sensitivity and relationship for detecting CYP3A induction was compared among the markers. Four days repeated oral administration of rifampicin to cynomolgus monkeys reduced the area under the plasma concentration-time curve of all CYP3A probe drugs in a rifampicin dose-dependent manner. Although the endogenous CYP3A markers (4ß-OHC and 6ß-OHC/C) were also changed for the middle (2 mg/kg) and high (20 mg/kg) doses of rifampicin, the fold-changes were relatively small, and CYP3A induction could not be detected at the lowest dose of rifampicin (0.2 mg/kg). In conclusion, CYP3A probe drugs are more sensitive for detecting CYP3A induction than endogenous CYP3A markers in cynomolgus monkeys, even for a short experimental period.


Assuntos
Alprazolam/farmacologia , Indutores do Citocromo P-450 CYP3A/farmacologia , Citocromo P-450 CYP3A/biossíntese , Midazolam/farmacologia , Rifampina/farmacologia , Triazolam/farmacologia , Alprazolam/sangue , Animais , Área Sob a Curva , Biomarcadores/sangue , Biomarcadores/urina , Indutores do Citocromo P-450 CYP3A/metabolismo , Relação Dose-Resposta a Droga , Interações Medicamentosas , Hidrocortisona/análogos & derivados , Hidrocortisona/urina , Hidroxicolesteróis/sangue , Macaca fascicularis , Masculino , Midazolam/sangue , Rifampina/sangue , Triazolam/sangue
17.
Clin Pharmacokinet ; 58(6): 805-814, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-30574672

RESUMO

OBJECTIVE: The objective of this study was to characterize the effects of risankizumab on the in vivo activity of cytochrome P450 (CYP) 1A2, CYP2C9, CYP2C19, CYP2D6, and CYP3A in psoriasis patients using a cocktail approach. METHODS: Patients with moderate to severe chronic plaque psoriasis (n = 21) received single oral doses of sensitive probe substrates for CYP1A2 (caffeine 100 mg), CYP2C9 (warfarin 10 mg), CYP2C19 (omeprazole 20 mg), CYP2D6 (metoprolol 50 mg), and CYP3A (midazolam 2 mg) on day 1, followed by 12 weeks of subcutaneous risankizumab treatment of 150 mg once every 4 weeks from day 8 to day 92, and again the same cocktail of substrates on day 98. Serial blood samples were collected for determination of the CYP probe drugs and metabolites with and without risankizumab. Trough samples were collected for risankizumab. RESULTS: The 90% confidence intervals (CIs) for the area under the plasma concentration-time curve (AUC) from time zero to infinity (AUC∞) ratios for the CYP probe substrates administered with risankizumab versus without risankizumab were within the default 0.8-1.25 equivalence bounds. Similar results were observed for maximum plasma concentration (Cmax), except for omeprazole, for which the lower bound of the 90% CI for Cmax (0.73) extended slightly below the default equivalence limit. No differences were observed in metabolite-to-parent drug Cmax or AUC ratios with risankizumab versus without risankizumab. Risankizumab trough plasma concentrations significantly exceeded those of the phase III regimen of risankizumab in psoriasis (150 mg subcutaneously at weeks 0 and 4 and every 12 weeks thereafter). CONCLUSIONS: Risankizumab did not affect the in vivo activity of CYP1A2, CYP2C9, CYP2C19, CYP2D6, or CYP3A enzymes in patients with moderate or severe plaque psoriasis and therefore has no potential for drug interactions through these enzymes. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT02772601.


Assuntos
Anticorpos Monoclonais/sangue , Cafeína/sangue , Sistema Enzimático do Citocromo P-450/metabolismo , Midazolam/sangue , Omeprazol/sangue , Psoríase/sangue , Varfarina/sangue , Anticorpos Monoclonais/administração & dosagem , Anticorpos Monoclonais/uso terapêutico , Área Sob a Curva , Doença Crônica , Relação Dose-Resposta a Droga , Interações Medicamentosas , Feminino , Humanos , Injeções Subcutâneas , Masculino , Psoríase/tratamento farmacológico , Psoríase/enzimologia , Índice de Gravidade de Doença , Especificidade por Substrato
18.
J Pharm Biomed Anal ; 163: 204-210, 2019 Jan 30.
Artigo em Inglês | MEDLINE | ID: mdl-30317077

RESUMO

Drug-drug interactions (DDIs) are thought to be associated with the inhibition of cytochrome P450 activities. The cocktail method with analysis of the metabolism of two or more probe drugs is used to determine CYP450 activities. In this study, we established a UHPLC-MS/MS method for simultaneous quantitation of four CYP450 probe drugs (phenacetin, omeprazole, metoprolol and midazolam) and their metabolites (acetaminophen, 5'-hydroxy omeprazole, α-hydroxy metoprolol and 1'-hydroxy midazolam) in rat plasma. Sample preparation by plasma protein precipitation was combined with a liquid-liquid extraction method. The separation was carried out on a ZORBAX Eclipse Plus C18 Rapid Resolution High Definition column with a gradient elution, using water containing 0.1% formic acid (A) and acetonitrile (B) in a run time of only 3.0 min. Detection was conducted with a 6420 series triple-quadrupole tandem mass spectrometer, using ESI in positive ion mode with multiple reaction monitoring (MRM). The calibration curves were linear over the concentration range 10-5000 ng/mL for phenacetin, omeprazole, metoprolol and midazolam, and 1-500 ng/mL for their metabolites. Intra- and inter-day precisions were within 15%, and the accuracies were in the range of 87-112%. The method was successfully applied to the pharmacokinetic study of probe drugs/metabolites and DDIs with 3-n-butylphthalide (NBP) after administration of a single oral dose of phenacetin, omeprazole, metoprolol and midazolam in rats.


Assuntos
Benzofuranos/farmacologia , Sistema Enzimático do Citocromo P-450/metabolismo , Interações Medicamentosas , Extração Líquido-Líquido/métodos , Administração Oral , Animais , Cromatografia Líquida de Alta Pressão/instrumentação , Cromatografia Líquida de Alta Pressão/métodos , Extração Líquido-Líquido/instrumentação , Masculino , Metoprolol/sangue , Metoprolol/metabolismo , Metoprolol/farmacologia , Midazolam/sangue , Midazolam/metabolismo , Midazolam/farmacologia , Omeprazol/sangue , Omeprazol/metabolismo , Omeprazol/farmacologia , Fenacetina/sangue , Fenacetina/metabolismo , Fenacetina/farmacologia , Ratos , Ratos Sprague-Dawley , Reprodutibilidade dos Testes , Espectrometria de Massas em Tandem/instrumentação , Espectrometria de Massas em Tandem/métodos
19.
Clin Pharmacol Drug Dev ; 7(8): 844-859, 2018 11.
Artigo em Inglês | MEDLINE | ID: mdl-30044899

RESUMO

Amenamevir (formerly ASP2151) is a helicase-primase inhibitor being developed for the treatment of herpesvirus infection. Amenamevir is both a substrate and inducer of cytochrome P450 (CYP) 3A4. Three studies were done in healthy volunteers to investigate potential CYP3A pharmacokinetic interactions with the following drugs: (1) Midazolam (probe substrate for CYP3A): After 10 days' pretreatment with amenamevir 400 mg daily, geometric mean maximum concentration of drug in blood plasma (Cmax ) and area under the plasma drug concentration-time curve from time zero to infinity (AUC0-∞ ) of midazolam 7.5 mg were about 68% and 51%, respectively, of those after midazolam alone. (2) Cyclosporine (substrate and inhibitor of CYP3A): After 5 days' pretreatment with cyclosporine 100 mg twice daily, geometric mean Cmax of amenamevir after 400-mg and 1200-mg single doses was, respectively, about 66% and 69%, and AUC0-∞ about 82% and 79%, of those after amenamevir alone. (3) Ritonavir (inhibitor of CYP3A): When given with single doses of ritonavir 600 mg, geometric mean Cmax of amenamevir after 400-mg and 1200-mg single doses was, respectively, about 1.4 and 1.6 times higher, and geometric mean AUC0-∞ about 2.6 and 3.3 times higher, than after amenamevir alone. Amenamevir has the potential to be involved in CYP3A-mediated pharmacokinetic interactions in clinical practice.


Assuntos
Ciclosporina/farmacocinética , Citocromo P-450 CYP3A/metabolismo , Midazolam/farmacocinética , Oxidiazóis/farmacocinética , Ritonavir/farmacocinética , Adolescente , Adulto , Ciclosporina/sangue , Ciclosporina/farmacologia , Indutores do Citocromo P-450 CYP3A/sangue , Indutores do Citocromo P-450 CYP3A/farmacocinética , Indutores do Citocromo P-450 CYP3A/farmacologia , Inibidores do Citocromo P-450 CYP3A/sangue , Inibidores do Citocromo P-450 CYP3A/farmacocinética , Inibidores do Citocromo P-450 CYP3A/farmacologia , Interações Medicamentosas , Voluntários Saudáveis , Humanos , Masculino , Midazolam/sangue , Midazolam/farmacologia , Pessoa de Meia-Idade , Oxidiazóis/sangue , Oxidiazóis/farmacologia , Ritonavir/sangue , Ritonavir/farmacologia , Adulto Jovem
20.
J Cardiothorac Surg ; 13(1): 64, 2018 Jun 08.
Artigo em Inglês | MEDLINE | ID: mdl-29884189

RESUMO

BACKGROUND: Use of donor blood in congenital cardiac surgery increases the risk for post-operative morbidity and mortality. To reduce the need for allogenic blood transfusion a technique for peri-operative mechanical red cell salvage is applied. Blood from the operation site is collected in a reservoir, processed, passed through a lipophilic filter and returned to the patient. Influence of this cellsaver system on coagulation, fibrinolysis and inflammatory markers is known. To our knowledge no studies have been performed on the effects of autotransfusion on drug concentrations. A clinically relevant drug dose could potentially be returned to the patient through the auto-transfused blood, leading to unwanted drug reactions post-operatively. We aimed to measure drug concentrations in blood salvaged from the operation site and in the auto-transfused blood to determine if a clinically relevant drug dose is returned to the patient. METHODS: The study was performed at the Department of Cardiothoracic Surgery of a tertiary university hospital. Blood samples were taken from the reservoir, after processing before the lipophilic filter, the auto-transfused blood, and the waste fluid. Samples were stored at - 80 C and drug concentration for sufentanil, propofol, midazolam and cefazolin were measured using liquid chromatography-tandem mass spectrometry (LC-MS/MS). Drug concentrations measured in the reservoir and the auto-transfused blood were compared and the relative reduction was calculated for each patient. RESULTS: Blood samples were taken from 18 cellsaver runs in 18 patients, age 0-13 years. Drug concentrations in the reservoir were comparable to concomitant concentrations in the patient. For sufentanil 34% (median, IQR 27-50) of drug concentration was retained from the reservoir in the auto-transfused blood, for midazolam 6% (median, IQR 4-10), for cefazolin 5% (median, IQR 2-6) and for propofol 0% (median, IQR 0-0) respectively. CONCLUSION: Depending on the drug, up to 34% of the drug concentration salvaged from the operation site is returned to the patient through autotransfusion, potentially causing unwanted drug reactions post-operatively. Additionally, influence of a cellsaver system should be considered in pharmacological research during and after congenital cardiac surgery and could result in dose adjustments in the postoperative phase. TRIAL REGISTRATION: Registration at the Dutch Trial Registry ( NTR3579 ) at August 14 2012.


Assuntos
Anestésicos Intravenosos/sangue , Antibacterianos/sangue , Transfusão de Sangue Autóloga , Cardiopatias Congênitas/cirurgia , Recuperação de Sangue Operatório , Adolescente , Procedimentos Cirúrgicos Cardíacos , Cefazolina/sangue , Criança , Pré-Escolar , Feminino , Humanos , Lactente , Masculino , Midazolam/sangue , Propofol/sangue , Sufentanil/sangue
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