Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 122
Filtrar
1.
Br J Clin Pharmacol ; 2024 Aug 19.
Artigo em Inglês | MEDLINE | ID: mdl-39160000

RESUMO

AIM: We aimed to assess if dicloxacillin/flucloxacillin reduces the therapeutic efficacy of direct oral anticoagulants (DOACs) and the underlying molecular mechanism. METHODS: In a randomized, crossover study, we assessed whether dicloxacillin reduces oral absorption of drugs through P-glycoprotein (P-gp) during 10 and 28 days of treatment. To study the impact of dicloxacillin/flucloxacillin on intestinal and hepatic expression of P-gp in vitro, we usd LS174T cells and 3D spheroids of primary human hepatocytes. Finally, we used nationwide Danish health registries and the UK's Clinical Practice Research Datalink to estimate hazard ratios (HRs) for the risk of stroke and systemic embolism following dicloxacillin/flucloxacillin exposure among DOAC users, using phenoxymethylpenicillin and amoxicillin as active comparators. RESULTS: Dicloxacillin reduced the area under the curve of dabigatran to a geometric mean ratio 10 days of 0.67 (95% confidence interval [CI]: 0.42-1.1) and geometric mean ratio 28 days of 0.72 (95% CI: 0.39-1.4), suggesting reduced oral absorption via increased P-gp expression. In vitro, dicloxacillin raised P-gp expression in both intestinal and liver cells, while flucloxacillin only affected liver cells. In the pharmacoepidemiologic study, dicloxacillin and flucloxacillin were not associated with increased risk of stroke/systemic embolism (dicloxacillin vs. phenoxymethylpenicillin HR: 0.93, 95% CI: 0.72-1.2; flucloxacillin vs. amoxicillin HR: 0.89, 95% CI: 0.51-1.5). CONCLUSIONS: Dicloxacillin increases expression of intestinal P-gp, leading to reduced oral absorption of dabigatran. However, concomitant use of dicloxacillin/flucloxacillin was not associated with stroke and systemic embolism among DOAC users, suggesting no clinical impact from the drug-drug interaction between dicloxacillin/flucloxacillin and DOACs.

2.
Br J Clin Pharmacol ; 87(4): 1963-1969, 2021 04.
Artigo em Inglês | MEDLINE | ID: mdl-33118168

RESUMO

AIMS: Recently a limited sampling strategy (LSS) for determination of metformin' pharmacokinetics was developed. The LSS utilizes the plasma concentration of metformin 3 and 10 hours after oral intake of a single dose to estimate the area under the concentration-time curve up to 24 hours (AUC0-24h ). The main purpose of this study was to support the feasibility of this strategy in a large prospective trial. METHODS: Volunteers orally ingested two 500-mg tablets of metformin hydrochloride. A blood sample was drawn three and ten hours after the ingestion. Urine was collected for 0-10 and 10-24 hours and urine volumes recorded. The AUC0-24h was calculated using the equation AUC0-24h = 4.779 * C3 + 13.174 * C10 . Additionally, all participants were genotyped for the single-nucleotide polymorphism A270S in OCT2, g.-66 T > C in MATE1, R61C, G465R, G401S and the deletion M420del in OCT1. RESULTS: In total, 212 healthy volunteers participated. The median (25th - 75th interquartile range) AUC0 - 24h , CLrenal , C3 and C10 , were 10 600 (8470-12 500) ng* hr* mL-1 , 29 (24-34) L* hour-1 , 1460 (1180-1770) and 260 (200-330) ng* mL-1 , respectively, which is in agreement with our previous results. GFRi was correlated with metformin AUC and CLrenal (P < .001). As expected, we found a great pharmacokinetic interindividual variability among the volunteers and no effect of the OCT1 genotype on the AUC0 - 24h . We were unable to reproduce our previous finding of a gene-gene interaction (OCT2 and MATE1) effect on CLrenal in this cohort. CONCLUSION: This study further supports the use of the 2-point LSS algorithm in large pharmacokinetic trials.


Assuntos
Metformina , Área Sob a Curva , Genótipo , Voluntários Saudáveis , Humanos , Hipoglicemiantes , Estudos Prospectivos
3.
Cardiovasc Drugs Ther ; 35(3): 491-503, 2021 06.
Artigo em Inglês | MEDLINE | ID: mdl-32770520

RESUMO

PURPOSE: The glucose-lowering drug metformin has recently been shown to reduce myocardial oxygen consumption and increase myocardial efficiency in chronic heart failure (HF) patients without diabetes. However, it remains to be established whether these beneficial myocardial effects are associated with metformin-induced alterations in whole-body insulin sensitivity and substrate metabolism. METHODS: Eighteen HF patients with reduced ejection fraction and without diabetes (median age, 65 (interquartile range 55-68); ejection fraction 39 ± 6%; HbA1c 5.5 to 6.4%) were randomized to receive metformin (n = 10) or placebo (n = 8) for 3 months. We studied the effects of metformin on whole-body insulin sensitivity using a two-step hyperinsulinemic euglycemic clamp incorporating isotope-labeled tracers of glucose, palmitate, and urea. Substrate metabolism and skeletal muscle mitochondrial respiratory capacity were determined by indirect calorimetry and high-resolution respirometry, and body composition was assessed by bioelectrical impedance analysis. The primary outcome measure was change in insulin sensitivity. RESULTS: Compared with placebo, metformin treatment lowered mean glycated hemoglobin levels (absolute mean difference, - 0.2%; 95% CI - 0.3 to 0.0; p = 0.03), reduced body weight (- 2.8 kg; 95% CI - 5.0 to - 0.6; p = 0.02), and increased fasting glucagon levels (3.2 pmol L-1; 95% CI 0.4 to 6.0; p = 0.03). No changes were observed in whole-body insulin sensitivity, endogenous glucose production, and peripheral glucose disposal or oxidation with metformin. Equally, resting energy expenditure, lipid and urea turnover, and skeletal muscle mitochondrial respiratory capacity remained unaltered. CONCLUSION: Increased myocardial efficiency during metformin treatment is not mediated through improvements in insulin action in HF patients without diabetes. CLINICAL TRIAL REGISTRATION: URL: https://clinicaltrials.gov . Unique identifier: NCT02810132. Date of registration: June 22, 2016.


Assuntos
Peso Corporal/efeitos dos fármacos , Insuficiência Cardíaca/tratamento farmacológico , Insuficiência Cardíaca/fisiopatologia , Resistência à Insulina/fisiologia , Metformina/farmacologia , Idoso , Composição Corporal , Calorimetria Indireta , Método Duplo-Cego , Feminino , Glucagon/efeitos dos fármacos , Hemoglobinas Glicadas/efeitos dos fármacos , Humanos , Masculino , Pessoa de Meia-Idade , Mitocôndrias/efeitos dos fármacos , Músculo Esquelético/efeitos dos fármacos , Consumo de Oxigênio/efeitos dos fármacos , Volume Sistólico/efeitos dos fármacos
4.
Diabetologia ; 62(7): 1251-1256, 2019 07.
Artigo em Inglês | MEDLINE | ID: mdl-30976851

RESUMO

AIMS/HYPOTHESIS: Metformin is the endorsed first-line glucose-lowering drug for treating patients with type 2 diabetes but despite more than 50 years of use, no consensus has been reached on its mechanisms of action. In this study, we investigated the glucose-lowering effects of metformin in individuals with type 2 diabetes and non-diabetic individuals. METHODS: We performed a randomised, placebo-controlled trial in 24 individuals with recent-onset type 2 diabetes (diabetes duration 50 [48] months) who had good glycaemic control (HbA1c 48 mmol/mmol [6.5%]). The studies were conducted at Aarhus University Hospital between 2013 and 2016. Participants were randomised to receive either metformin (2000 mg/day, n = 12, MET group) or placebo (n = 12, PLA group) for 90 days, using block randomisation set up by an unblinded pharmacist. Two participants withdrew from the study prior to completion and were replaced with two new participants receiving the same treatment. In addition, we recruited a group of non-diabetic individuals with similar age and BMI (n = 12, CONT group), who were all treated with 2000 mg metformin daily. Before and after treatment all individuals underwent studies of whole-body glucose metabolism by non-steady-state [3-3H]glucose kinetics, hyperinsulinaemic-euglycaemic clamping, indirect calorimetry, metabolomics, dual x-ray absorptiometry and muscle biopsies. The primary study endpoint was the effect of metformin treatment on lipid kinetics as well as glucose rate of disappearance (Rd) and endogenous glucose production (EGP). RESULTS: One participant from the CONT group withdrew due to intolerable gastrointestinal side-effects and was excluded from analysis. As expected, metformin treatment lowered fasting plasma glucose (FPG) in the MET group (~1.5 mmol/l, p < 0.01), whereas no effect was observed in the PLA and CONT groups. Body weight and composition did not change in any of the groups. In both of the metformin-treated groups (MET and CONT), basal glucose Rd, EGP and glucagon levels increased by ~30% (p < 0.05) whereas this was not the case in the PLA group. CONCLUSIONS/INTERPRETATION: Ninety days of metformin treatment resulted in similar increases in EGP and glucose Rd in individuals with recent-onset type 2 diabetes and in non-diabetic control individuals. These results challenge the existing paradigm that metformin primarily acts in the liver by inhibiting EGP, at least in individuals with type 2 diabetes of short duration and who have discretely affected glycaemic status. Whether metformin increases basal glucose Rd by facilitating glucose uptake in other tissues such as the intestines remains to be further clarified. TRIAL REGISTRATION: ClinicalTrials.gov NCT01729156 FUNDING: This study was supported by grants from The Danish Council for Independent Research | Medical Sciences, Aase Danielsen Fund, the Novo Nordisk Foundation, the Danish Diabetes Association and the Danish Diabetes Academy supported by the Novo Nordisk Foundation.


Assuntos
Diabetes Mellitus Tipo 2/sangue , Diabetes Mellitus Tipo 2/tratamento farmacológico , Glucose/metabolismo , Hipoglicemiantes/uso terapêutico , Metformina/uso terapêutico , Glicemia/efeitos dos fármacos , Peso Corporal/efeitos dos fármacos , Humanos , Efeito Placebo
5.
Br J Clin Pharmacol ; 85(8): 1761-1770, 2019 08.
Artigo em Inglês | MEDLINE | ID: mdl-30973968

RESUMO

AIMS: Metformin is first-line treatment of type 2 diabetes mellitus and reduces cardiovascular events in patients with insulin resistance and type 2 diabetes. Target tissue for metformin action is thought to be the liver, where metformin distribution depends on facilitated transport by polyspecific transmembrane organic cation transporters (OCTs). Non-alcoholic fatty liver disease (NAFLD) is the most common liver disease in the western world with strong associations to insulin resistance and the metabolic syndrome, but whether NAFLD affects metformin biodistribution to the liver is not known. In this study, the primary aim was to investigate in vivo hepatic uptake of metformin dynamically in humans with variable degrees of liver affection. As a secondary aim, we wished to correlate hepatic metformin distribution with OCT gene transcription determined in diagnostic liver biopsies. METHODS: Eighteen patients with biopsy-proven NAFLD were investigated using 11C-metformin PET/CT technique. Gene transcripts of OCTs were determined by real-time polymerase chain reaction (PCR). RESULTS: We observed similar hepatic volume of distribution of metformin between patients with simple steatosis and non-alcoholic steatohepatitis (NASH) (Vd 2.38 ± 0.56 vs. 2.10 ± 0.39, P = 0.3). There was no association between hepatic exposure to metformin and the degree of inflammation or fibrosis, and no clear correlation between metformin distribution and OCT gene transcription. CONCLUSION: Metformin is distributed to the liver in patients with NAFLD and the distribution is not impaired by inflammation or fibrosis. The findings imply that metformin action in liver in patients with NAFLD may be preserved.


Assuntos
Diabetes Mellitus Tipo 2/tratamento farmacológico , Hipoglicemiantes/farmacocinética , Fígado/metabolismo , Metformina/farmacocinética , Hepatopatia Gordurosa não Alcoólica/metabolismo , Adulto , Idoso , Biópsia , Radioisótopos de Carbono , Diabetes Mellitus Tipo 2/etiologia , Feminino , Perfilação da Expressão Gênica , Humanos , Hipoglicemiantes/administração & dosagem , Fígado/patologia , Masculino , Metformina/administração & dosagem , Pessoa de Meia-Idade , Hepatopatia Gordurosa não Alcoólica/complicações , Hepatopatia Gordurosa não Alcoólica/diagnóstico , Hepatopatia Gordurosa não Alcoólica/patologia , Proteínas de Transporte de Cátions Orgânicos/genética , Proteínas de Transporte de Cátions Orgânicos/metabolismo , Tomografia por Emissão de Pósitrons combinada à Tomografia Computadorizada , Distribuição Tecidual
6.
Diabetes Obes Metab ; 20(7): 1593-1601, 2018 07.
Artigo em Inglês | MEDLINE | ID: mdl-29457876

RESUMO

AIMS: To assess potential causes of metformin intolerance, including altered metformin uptake from the intestine, increased anaerobic glucose utilization and subsequent lactate production, altered serotonin uptake, and altered bile acid pool. METHODS: For this pharmacokinetic study, we recruited 10 severely intolerant and 10 tolerant individuals, matched for age, sex and body mass index. A single 500-mg dose of metformin was administered, with blood sampling at 12 time points over 24 hours. Blood samples were analysed for metformin, lactate, serotonin and bile acid concentrations, and compared across the phenotypes. RESULTS: The intolerant individuals were severely intolerant to 500 mg metformin. No significant difference was identified between tolerant and intolerant cohorts in metformin pharmacokinetics: median (interquartile range [IQR]) peak concentration 2.1 (1.7-2.3) mg/L and 2.0 (1.8-2.2) mg/L, respectively (P = .76); time to peak concentration 2.5 hours; median (IQR) area under the curve (AUC)0-24 16.9 (13.9-18.6) and 13.9 (12.9-16.8) mg/L*h, respectively (P = .72). Lactate concentration peaked at 3.5 hours, with mean peak concentration of 2.4 mmol/L in both cohorts (95% CI 2.0-2.8 and 1.8-3.0 mmol/L, respectively), and similar incremental AUC0-24 in each cohort: tolerant cohort 6.98 (95% CI 3.03-10.93) and intolerant cohort 4.47 (95% CI -3.12-12.06) mmol/L*h (P = .55). Neither serotonin nor bile acid concentrations were significantly different. CONCLUSIONS: Despite evidence of severe intolerance in our cohort, there was no significant difference in metformin pharmacokinetics or systemic measures of lactate, serotonin or bile acids. This suggests that metformin intolerance may be attributable to local factors within the lumen or enterocyte.


Assuntos
Diabetes Mellitus Tipo 2/tratamento farmacológico , Gastroenteropatias/induzido quimicamente , Hipoglicemiantes/farmacocinética , Metformina/farmacocinética , Dor Abdominal/etiologia , Idoso , Ácidos e Sais Biliares/sangue , Índice de Massa Corporal , Estudos de Coortes , Diabetes Mellitus Tipo 2/complicações , Diarreia/etiologia , Feminino , Gastroenteropatias/sangue , Gastroenteropatias/metabolismo , Gastroenteropatias/fisiopatologia , Meia-Vida , Humanos , Hipoglicemiantes/efeitos adversos , Hipoglicemiantes/sangue , Hipoglicemiantes/uso terapêutico , Ácido Láctico/sangue , Masculino , Taxa de Depuração Metabólica , Metformina/efeitos adversos , Metformina/sangue , Pessoa de Meia-Idade , Sobrepeso/complicações , Serotonina/sangue , Índice de Gravidade de Doença
7.
Br J Clin Pharmacol ; 84(3): 510-519, 2018 03.
Artigo em Inglês | MEDLINE | ID: mdl-29105855

RESUMO

AIM: The aim of this study was to study potential cytochrome P450 (CYP) induction by dicloxacillin. METHODS: We performed an open-label, randomized, two-phase, five-drug clinical pharmacokinetic cocktail crossover study in 12 healthy men with and without pretreatment with 1 g dicloxacillin three times daily for 10 days. Plasma and urine were collected over 24 h and the concentration of all five drugs and their primary metabolites was determined using a liquid chromatography coupled to triple quadrupole mass spectrometry method. Cryopreserved primary human hepatocytes were exposed to dicloxacillin for 48 h and changes in gene expression and the activity of CYP3A4, CYP2C9, CYP2B6 and CYP1A2 were investigated. The activation of nuclear receptors by dicloxacillin was assessed using luciferase assays. RESULTS: A total of 10 days of treatment with dicloxacillin resulted in a clinically and statistically significant reduction in the area under the plasma concentration-time curve from 0 to 24 h for omeprazole (CYP2C19) {geometric mean ratio [GMR] [95% confidence interval (CI)]: 0.33 [0.24, 0.45]}, tolbutamide (CYP2C9) [GMR (95% CI): 0.73 (0.65, 0.81)] and midazolam (CYP3A4) [GMR (95% CI): 0.54 (0.41, 0.72)]. Additionally, other relevant pharmacokinetic parameters were affected, indicating the induction of CYP2C- and CYP3A4-mediated metabolism by dicloxacillin. Investigations in primary hepatocytes showed a statistically significant dose-dependent increase in CYP expression and activity by dicloxacillin, caused by activation of the pregnane X receptor. CONCLUSIONS: Dicloxacillin is an inducer of CYP2C- and CYP3A-mediated drug metabolism, and we recommend caution when prescribing dicloxacillin to users of drugs with a narrow therapeutic window.


Assuntos
Citocromo P-450 CYP2C19/efeitos dos fármacos , Citocromo P-450 CYP2C9/efeitos dos fármacos , Citocromo P-450 CYP3A/efeitos dos fármacos , Dicloxacilina/farmacologia , Adulto , Antibacterianos/farmacologia , Área Sob a Curva , Cromatografia Líquida , Estudos Cross-Over , Citocromo P-450 CYP2C19/biossíntese , Citocromo P-450 CYP2C9/biossíntese , Citocromo P-450 CYP3A/biossíntese , Sistema Enzimático do Citocromo P-450/biossíntese , Sistema Enzimático do Citocromo P-450/efeitos dos fármacos , Interações Medicamentosas , Indução Enzimática/efeitos dos fármacos , Feminino , Hepatócitos/efeitos dos fármacos , Hepatócitos/enzimologia , Humanos , Masculino , Espectrometria de Massas , Adulto Jovem
8.
Br J Clin Pharmacol ; 82(4): 1002-10, 2016 10.
Artigo em Inglês | MEDLINE | ID: mdl-27324407

RESUMO

AIM: The aim was to develop and validate limited sampling strategy (LSS) models to predict the area under the plasma concentration-time curve (AUC) for metformin. METHODS: Metformin plasma concentrations (n = 627) at 0-24 h after a single 500 mg dose were used for LSS development, based on all subsets linear regression analysis. The LSS-derived AUC(0,24 h) was compared with the parameter 'best estimate' obtained by non-compartmental analysis using all plasma concentration data points. Correlation between the LSS-derived and the best estimated AUC(0,24 h) (r(2) ), bias and precision of the LSS estimates were quantified. The LSS models were validated in independent cohorts. RESULTS: A two-point (3 h and 10 h) regression equation with no intercept estimated accurately the individual AUC(0,24 h) in the development cohort: r(2)  = 0.927, bias (mean, 95% CI) -0.5, -2.7-1.8% and precision 6.3, 4.9-7.7%. The accuracy of the two point LSS model was verified in study cohorts of individuals receiving single 500 or 1000 mg (r(2)  = -0.933-0.934) or seven 1000 mg daily doses (r(2)  = 0.918), as well as using data from 16 published studies covering a wide range of metformin doses, demographics, clinical and experimental conditions (r(2)  = 0.976). The LSS model reproduced previously reported results for effects of polymorphisms in OCT2 and MATE1 genes on AUC(0,24 h) and renal clearance of metformin. CONCLUSIONS: The two point LSS algorithm may be used to assess the systemic exposure to metformin under diverse conditions, with reduced costs of sampling and analysis, and saving time for both subjects and investigators.


Assuntos
Área Sob a Curva , Monitoramento de Medicamentos/métodos , Metformina/farmacocinética , Feminino , Voluntários Saudáveis , Humanos , Imunossupressores/sangue , Imunossupressores/farmacocinética , Masculino , Metformina/sangue , Modelos Estatísticos
9.
Br J Clin Pharmacol ; 81(2): 313-5, 2016 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-26446447

RESUMO

AIM: The aim of the present case report was to describe a novel pharmacokinetic drug­drug interaction between the antiplatelet agent clopidogrel and the antineoplastic agent paclitaxel. METHODS: The patient was identified in a previously described cohort of 93 patients with ovarian carcinoma treated with paclitaxel. The effect of clopidogrel acyl-ß-D-glucuronide on the metabolism of paclitaxel was assessed in human liver microsomes. The analysis of clopidogrel in plasma and the quantification of paclitaxel and 6-hydroxypaclitaxel in in vitro samples were performed by liquid chromatography tandem mass spectrometry. RESULTS: The patient was a 60-year-old female treated with an unknown dose of clopidogrel at the time of paclitaxel therapy. Clopidogrel was present in all three of the plasma samples obtained during paclitaxel dosing. Estimated unbound paclitaxel clearance was 238 l h−1, which was only 62% of the cohort geometric mean (385 l h−1; range 176­726). She was hospitalized three times, developed severe neuropathy and paclitaxel treatment was subsequently discontinued. In vitro, 30-min preincubation with 100 µM clopidogrel acyl-ß-D-glucuronide inhibited the depletion rate of 0.5 µM paclitaxel by 51% and the formation rate of 6-hydroxypaclitaxel by 77%. CONCLUSION: This is the first report of a clopidogrel­paclitaxel interaction, suggesting that clinically used doses of clopidogrel can reduce the cytochrome P450 2C8 (CYP2C8)-mediated systemic clearance of paclitaxel, leading to an increased risk of paclitaxel toxicity. Caution should be exercised whenever the simultaneous use of paclitaxel and clopidogrel cannot be avoided.


Assuntos
Antineoplásicos Fitogênicos/efeitos adversos , Inibidores do Citocromo P-450 CYP2C8/sangue , Síndromes Neurotóxicas/etiologia , Neoplasias Ovarianas/tratamento farmacológico , Paclitaxel/efeitos adversos , Ticlopidina/análogos & derivados , Antineoplásicos Fitogênicos/administração & dosagem , Antineoplásicos Fitogênicos/sangue , Antineoplásicos Fitogênicos/uso terapêutico , Hidrocarboneto de Aril Hidroxilases/metabolismo , Clopidogrel , Citocromo P-450 CYP2C8/metabolismo , Inibidores do Citocromo P-450 CYP2C8/administração & dosagem , Inibidores do Citocromo P-450 CYP2C8/uso terapêutico , Interações Medicamentosas , Feminino , Humanos , Pessoa de Meia-Idade , Síndromes Neurotóxicas/sangue , Neoplasias Ovarianas/sangue , Paclitaxel/administração & dosagem , Paclitaxel/sangue , Paclitaxel/uso terapêutico , Ticlopidina/administração & dosagem , Ticlopidina/sangue , Ticlopidina/uso terapêutico
10.
Diabetologia ; 58(11): 2494-502, 2015 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-26271344

RESUMO

AIMS/HYPOTHESIS: Metformin is believed to reduce glucose levels primarily by inhibiting hepatic glucose production. Recent data indicate that metformin antagonises glucagon-dependent glucose output, suggesting that compensatory mechanisms protect against hypoglycaemia. Here, we examined the effect of metformin on glucose metabolism in humans after a glycogen-depleting fast and the role of reduced-function alleles in OCT1 (also known as SLC22A1). METHODS: In a randomised, crossover trial, healthy individuals with or without reduced-function alleles in OCT1 were fasted for 42 h twice, either with or without prior treatment with 1 g metformin twice daily. Participants were recruited from the Pharmacogenomics Biobank of the University of Southern Denmark. Treatment allocation was generated by the Good Clinical Practice Unit, Odense University Hospital, Denmark. Variables of whole-body glucose metabolism were assessed using [3-(3)H]glucose, indirect calorimetry and measurement of substrates and counter-regulatory hormones. The primary outcome was endogenous glucose production (EGP). RESULTS: Thirty-seven individuals were randomised. Thirty-four completed the study (12 had none, 13 had one and nine had two reduced-function alleles in OCT1). Three were excluded from the analysis because of early dropout. Metformin significantly stimulated glucose disposal rates and non-oxidative glucose metabolism with no effect on glucose oxidation. This increase in glucose utilisation was explained by a concomitant increase in glycolytic flux and accompanied by increased EGP, most likely mediated by increased plasma lactate, glucagon and cortisol levels. There was no effect of reduced-function OCT1 alleles on any of these measures. All individuals completed the glycogen-depleting fast without hypoglycaemia. CONCLUSIONS/INTERPRETATION: Metformin stimulates glycolytic glucose utilisation and lactate production in the glycogen-depleted state. This may trigger a rise in glucose counter-regulatory hormones and subsequently an increase in EGP, which protects against hypoglycaemia. TRIAL REGISTRATION: ClinicalTrials.gov NCT01400191 FUNDING: Danish Research Council for Health and Disease (0602-02695B) and Odense University Hospital Free Research Fund, 2012.


Assuntos
Gluconeogênese/efeitos dos fármacos , Glucose/metabolismo , Hipoglicemiantes/farmacologia , Metformina/farmacologia , Transportador 1 de Cátions Orgânicos/genética , Adulto , Glicemia/metabolismo , Calorimetria Indireta , Estudos Cross-Over , Jejum/sangue , Feminino , Glucagon/metabolismo , Haplótipos , Humanos , Masculino , Adulto Jovem
11.
Pharmacogenet Genomics ; 25(5): 259-62, 2015 May.
Artigo em Inglês | MEDLINE | ID: mdl-25738371

RESUMO

OBJECTIVE: The aim of this study was to determine the intrapair similarity in trough steady-state plasma concentrations of metformin in monozygotic and dizygotic twin pairs. METHODS: We included 16 twin pairs (eight monozygotic and eight dizygotic twin pairs) for this study after contacting 524 twin pairs. They were dosed with metformin to steady state (1 g twice daily) for 6 days and on day 7, the trough concentration of metformin was determined 12 h after the last dose. RESULTS: There was no strong intrapair similarity in trough steady-state plasma concentrations of metformin in either dizygotic or monozygotic twin pairs. CONCLUSION: The trough steady-state plasma concentration of metformin does not appear to be tightly genetically regulated. The interpretation of this finding is limited by the small sample size.


Assuntos
Diabetes Mellitus/sangue , Diabetes Mellitus/genética , Metformina/sangue , Adolescente , Adulto , Diabetes Mellitus/tratamento farmacológico , Feminino , Humanos , Masculino , Metformina/farmacocinética , Gêmeos Dizigóticos , Gêmeos Monozigóticos
12.
Br J Clin Pharmacol ; 79(2): 298-306, 2015 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-25223504

RESUMO

AIMS: Our objective was to investigate the steady-state pharmacokinetic and pharmacodynamic interaction between the antidepressive herbal medicine St John's wort and the antidiabetic drug metformin. METHODS: We performed an open cross-over study in 20 healthy male subjects, who received 1 g of metformin twice daily for 1 week with and without 21 days of preceding and concomitant treatment with St John's wort. The pharmacokinetics of metformin was determined, and a 2 h oral glucose tolerance test was performed. RESULTS: St John's wort decreased the renal clearance of metformin but did not affect any other metformin pharmacokinetic parameter. The addition of St John's wort decreased the area under the glucose concentration-time curve [702 (95% confidence interval, 643-761) vs. 629 min*mmol/L (95% confidence interval, 568-690), P = 0.003], and this effect was caused by a statistically significant increase in the acute insulin response. CONCLUSIONS: St John's wort improves glucose tolerance by enhancing insulin secretion independently of insulin sensitivity in healthy male subjects taking metformin.


Assuntos
Hypericum/química , Hipoglicemiantes/farmacocinética , Metformina/farmacocinética , Extratos Vegetais/farmacologia , Adulto , Antidepressivos/farmacologia , Glicemia/efeitos dos fármacos , Estudos Cross-Over , Interações Medicamentosas , Teste de Tolerância a Glucose , Humanos , Hipoglicemiantes/farmacologia , Insulina/metabolismo , Secreção de Insulina , Masculino , Metformina/farmacologia , Adulto Jovem
13.
Eur J Clin Pharmacol ; 71(6): 691-697, 2015 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-25939711

RESUMO

PURPOSE: The aim of the study was to determine the steady-state pharmacokinetics of metformin in healthy volunteers with different numbers of reduced-function alleles in the organic cation transporter 1 gene (OCT1). METHODS: The study was conducted as part of a randomized cross-over trial. Thirty-four healthy volunteers with known OCT1 genotypes (12 with two wild-type alleles, 13 with one and 9 with two reduced-function alleles) were included. In one of the study periods, they were titrated to steady-state with 1 g metformin twice daily. RESULTS: Neither AUC(0-12), C(max) nor Cl(renal) were statistically significantly affected by the number of reduced-function alleles (0, 1 or 2) in OCT1: (AUC(0-12): 0, 1, 2: 14, 13 and 14 h ng/L (P = 0.61)); (C(max): 0, 1, 2: 2192, 1934 and 2233 ng/mL, (P = 0.26)) and (Cl(renal): 0, 1, 2: 31, 28 and 30 L/h (P = 0.57)) CONCLUSIONS: In a cohort of healthy volunteers, we found no impact of different OCT1 genotypes on metformin steady-state pharmacokinetics.


Assuntos
Hipoglicemiantes/farmacocinética , Transportador 1 de Cátions Orgânicos/genética , Adulto , Alelos , Estudos Cross-Over , Feminino , Genótipo , Voluntários Saudáveis , Humanos , Masculino , Metformina/farmacocinética , Polimorfismo Genético/genética , Adulto Jovem
14.
Forensic Sci Med Pathol ; 11(2): 193-201, 2015 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-25801127

RESUMO

PURPOSE: Deaths among drug addicts are frequently caused by intoxication with methadone and/or morphine. These drugs are often used in combination with other drugs, such as buprenorphine. In addition, methadone is generally used as a mixture of R- and S-enantiomers. To date, a method for separation and quantitation of these specific drugs has not been developed. The aim of this study was to develop a sensitive enantioselective method for quantitation of morphine, its active metabolite morphine 6-glucuronide, buprenorphine, and R- and S-methadone, in a single analytical run. METHODS: Whole blood samples were diluted with 0.5 mol/L ammonium carbonate buffer and extracted on a Bond Elut C18 solid-phase extraction column with an automatic solid-phase extraction system. Chromatographic separation was performed on a chiral alpha-1-acid glycoprotein column with an acetonitrile/ammonium acetate buffer (10 mmol/L, pH 7.0, 22:78 v/v) mobile phase. The whole blood concentrations of the drugs were quantified by mass spectrometry using their stable isotope-labeled compounds as internal standards. RESULTS: The method was validated with respect to specificity, linearity, precision, limits of detection, and quantification and matrix effects. The precision (coefficient of variation) was below 15%, and the accuracy was between 90 and 115%. CONCLUSIONS: This method will be useful for routine analyses in forensic laboratories where blood samples are frequently analyzed for drugs of abuse. In some cases, sudden death from methadone overdose is caused by the enantiomeric form of the methadone, which makes the enantiomer separation capability of this method important.


Assuntos
Buprenorfina/sangue , Metadona/sangue , Derivados da Morfina/sangue , Morfina/sangue , Entorpecentes/sangue , Buprenorfina/química , Cromatografia Líquida , Toxicologia Forense , Humanos , Espectrometria de Massas , Metadona/química , Estrutura Molecular , Morfina/química , Derivados da Morfina/química , Entorpecentes/química , Extração em Fase Sólida , Estereoisomerismo , Transtornos Relacionados ao Uso de Substâncias/sangue
15.
Ther Drug Monit ; 36(2): 211-7, 2014 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-24097013

RESUMO

We describe an analytical method for the quantification of the widely used antihyperglycemic agent, metformin, in human plasma and urine. The separation was performed using isocratic hydrophilic interaction liquid chromatography on a Luna hydrophilic interaction liquid chromatography column (125 × 4.6 mm, 3 µm). The sample preparation was accomplished by solid-phase extraction. Validation of the method was performed in the range 10-2000 ng/mL for plasma and 5-30 mcg/mL for urine. The methods were linear within the investigated range (r(2) > 0.988). Within-day repeatability ranged from 3.1% to 7.5% in plasma and 1.6% to 6.2% in urine. Between-day reproducibility ranged from 2.9% to 5.3% in plasma and 0.6% to 1.8% in urine. The inaccuracy expressed as bias ranged from -3.1% to 1.9% in plasma and from -7.2% to 0.7% in urine. The lower limit of quantification for metformin in plasma was 5 ng/mL and in urine was 40 ng/mL. The method was therefore considered to be precise, accurate, reproducible, and sensitive enough to be appropriate for pharmacokinetic studies of metformin. The applicability of the method for human pharmacokinetic studies was demonstrated by dosing a healthy male volunteer with 500-mg metformin hydrochloride as a single oral dose; plasma and urine concentrations were measured for 24 hours.


Assuntos
Cromatografia Líquida/métodos , Hipoglicemiantes/análise , Hipoglicemiantes/farmacocinética , Metformina/análise , Metformina/farmacocinética , Plasma/química , Urina/química , Voluntários Saudáveis , Humanos , Interações Hidrofóbicas e Hidrofílicas , Hipoglicemiantes/sangue , Hipoglicemiantes/urina , Limite de Detecção , Masculino , Metformina/sangue , Metformina/urina , Reprodutibilidade dos Testes , Sensibilidade e Especificidade
16.
Clin Exp Pharmacol Physiol ; 41(11): 870-8, 2014 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-25115434

RESUMO

The aim of the present study was to determine the impact of CYP2C19*17 on the pharmacokinetics and pharmacodynamics of the active metabolite of clopidogrel and the pharmacokinetics of proguanil. Thus, we conducted an open-label two-phase cross-over study in 31 healthy male volunteers (11 CYP2C19*1/*1, 11 CYP2C19*1/*17 and nine CYP2C19*17/*17). In Phase A, the pharmacokinetics of the derivatized active metabolite of clopidogrel (CAMD) and platelet function were determined after administration of a single oral dose of 600 mg clopidogrel (Plavix; Sanofi-Avensis, Horsholm, Denmark). In Phase B, the pharmacokinetics of proguanil and its metabolites cycloguanil and 4-chlorphenylbiguanide (4-CPB) were determined in 29 of 31 subjects after a single oral dose of 200 mg proguanil given as the combination drug Malarone (GlaxoSmithKline Pharma, Brondby, Denmark). Significant correlations were found between the area under the time-concentration curve (AUC0-∞ ) of CAMD and both the absolute ADP-induced P2Y12 receptor-activated platelet aggregation (r = -0.60, P = 0.0007) and the percentage inhibition of aggregation (r = 0.59, P = 0.0009). In addition, the CYP2C19*17/*17 and CYP2C19*1/*17 genotype groups had significantly higher percentage inhibition of platelet aggregation compared with the CYP2C19*1/*1 subjects (geometric mean percentage inhibition of 84%, 73% and 63%, respectively; P = 0.014). Neither the absolute ADP-induced P2Y12 receptor-activated platelet aggregation, exposure to CAMD nor the pharmacokinetic parameters of proguanil, cycloguanil and 4-CPB exhibited any significant differences among the genotype groups. In conclusion, carriers of CYP2C19*17 exhibit higher percentage inhibition of platelet aggregation, but do not have significantly lower absolute P2Y12 receptor-activated platelet aggregation or higher exposure to the active metabolite after a single oral administration of 600 mg clopidogrel.


Assuntos
Citocromo P-450 CYP2C19/genética , Agregação Plaquetária/efeitos dos fármacos , Polimorfismo de Nucleotídeo Único , Proguanil/farmacocinética , Antagonistas do Receptor Purinérgico P2Y/farmacocinética , Ticlopidina/análogos & derivados , Área Sob a Curva , Clopidogrel , Estudos Cross-Over , Relação Dose-Resposta a Droga , Voluntários Saudáveis , Humanos , Masculino , Agregação Plaquetária/genética , Estudos Prospectivos , Antagonistas do Receptor Purinérgico P2Y/metabolismo , Antagonistas do Receptor Purinérgico P2Y/farmacologia , Especificidade por Substrato , Ticlopidina/metabolismo , Ticlopidina/farmacocinética , Ticlopidina/farmacologia , Fatores de Tempo
17.
Pharmacogenet Genomics ; 23(4): 219-27, 2013 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-23426382

RESUMO

OBJECTIVE: The aim of this study was to examine the effect of single nucleotide polymorphisms in CYP2C8, LPIN1, PPARGC1A and PPARγ on rosiglitazone's (i) trough steady-state plasma concentration (C(ss,min)), (ii) on glycosylated haemoglobin A1c (HbA1c) and (iii) the risk of developing adverse events, mainly oedema, in patients with type 2 diabetes mellitus (T2D). METHODS: The data used in this study were obtained from the South Danish Diabetes Study including 371 T2D patients with a focus on the 187 patients who were treated with rosiglitazone. The study was a placebo-controlled, partly blinded and multicentre clinical trial. The C(ss,min) of rosiglitazone and HbA1c was determined and the genotype of the patients was identified. RESULTS: The mean C(ss,min) of rosiglitazone was 21.3 ng/ml (95% confidence interval 18.8; 24.2 ng/ml), with observations ranging from 1 to 296 ng/ml. Carriers of CYP2C8*3 (n=32) (rs10509681 and rs11572080) had a statistically significantly lower mean C(ss,min) than wild types (n=106), and they also had a statistically significantly lower mean absolute difference in HbA1c during rosiglitazone treatment. Finally, the carriers of CYP2C8*3 had a lower odds ratio of developing oedema. CONCLUSION: We showed that CYP2C8*3 was associated with lower plasma levels of rosiglitazone and hence a reduced therapeutic response but also a lower risk of developing oedema during treatment with rosiglitazone. Individualized treatment with rosiglitazone on the basis of the CYP2C8 genotype may therefore be possible.


Assuntos
Hidrocarboneto de Aril Hidroxilases/genética , Diabetes Mellitus Tipo 2/genética , Proteínas de Choque Térmico/genética , PPAR gama/genética , Fosfatidato Fosfatase/genética , Fatores de Transcrição/genética , Idoso , Biomarcadores Farmacológicos , Citocromo P-450 CYP2C8 , Diabetes Mellitus Tipo 2/sangue , Diabetes Mellitus Tipo 2/complicações , Diabetes Mellitus Tipo 2/tratamento farmacológico , Edema/sangue , Edema/induzido quimicamente , Edema/complicações , Edema/genética , Feminino , Estudos de Associação Genética , Hemoglobinas Glicadas/genética , Hemoglobinas Glicadas/metabolismo , Humanos , Masculino , Pessoa de Meia-Idade , Coativador 1-alfa do Receptor gama Ativado por Proliferador de Peroxissomo , Polimorfismo de Nucleotídeo Único , Rosiglitazona , Tiazolidinedionas/administração & dosagem , Tiazolidinedionas/efeitos adversos
18.
Pharmacogenet Genomics ; 23(10): 526-34, 2013 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-23873119

RESUMO

OBJECTIVE: The aim of this study was to determine the association between the renal clearance (CL(renal)) of metformin in healthy Caucasian volunteers and the single-nucleotide polymorphism (SNP) c.808G>T (rs316019) in OCT2 as well as the relevance of the gene-gene interactions between this SNP and (a) the promoter SNP g.-66T>C (rs2252281) in MATE1 and (b) the OCT1 reduced-function diplotypes. METHODS: Fifty healthy volunteers genotyped for the c.808G>T were enrolled in the study. The distribution was 25 GG, 20 GT, and 5 TT volunteers. The pharmacokinetics of a 500 mg single oral dose of metformin was studied. RESULTS: When analyzed alone, the c.808 (G>T) affected neither the CL(renal) nor the secretory clearance (CL(sec)) of metformin. However, both CL(renal) and CL(sec) were increased for the volunteers with minor alleles in c.808 (G>T) who were also homozygous for the reference variant g.-66T>C: CL(renal): GG, GT, and TT: 28.1, 34.5, and 44.8 l/h (P = 0.004), respectively and CL(sec): GG, GT, and TT: 21.4, 27.8, and 37.6 l/h (P = 0.005), respectively. In the volunteers with minor alleles in c.808 (G>T) who were also heterozygous for g.-66T>C, both CL(renal) and CL(sec) were found to be reduced (P < 0.028) when compared with volunteers with minor alleles in c.808 (G>T) carrying the g.-66T>C reference genotype. CONCLUSION: We report counteracting effects of the c.808 (G>T) and g.-66T>C on the renal elimination of metformin. When adjusted for the genetic variation g.-66T>C, our results suggest that c.808 (G>T) could have a dominant genotype to phenotype correlation.


Assuntos
Hipoglicemiantes/farmacocinética , Rim/metabolismo , Metformina/farmacocinética , Proteínas de Transporte de Cátions Orgânicos/genética , Estudos de Coortes , Feminino , Variação Genética , Genótipo , Voluntários Saudáveis , Humanos , Hipoglicemiantes/administração & dosagem , Hipoglicemiantes/urina , Rim/efeitos dos fármacos , Desequilíbrio de Ligação , Masculino , Metformina/administração & dosagem , Metformina/urina , Transportador 2 de Cátion Orgânico , Polimorfismo de Nucleotídeo Único , População Branca/genética
20.
Eur J Clin Pharmacol ; 69(12): 1997-9, 2013 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-23917460

RESUMO

BACKGROUND: A four-drug cytochrome P450 (CYP) phenotyping cocktail was developed to rapidly and safely determine CYP2D6, CYP2C19, CYP2C9 and CYP1A2 enzyme activity and phenotype. METHODS: The cocktail consisted of the single CYP phenotyping probes of 50 mg tramadol (CYP2D6), 20 mg omeprazole (CYP2C19), 25 mg losartan (CYP2C9) and 200 mg caffeine (CYP1A2) and was administered as a single oral dose. For enzyme activity measurements, urine was collected as 8 h post-administration and blood was sampled at 4 h. The enzyme activity was determined by metabolic ratios of molar concentrations of the drugs and their enzyme catalyzed metabolites and was correlated to the relevant genotypes. RESULTS: In a pilot study in 12 healthy male volunteers the CYP genotype-phenotype correlation and robustness of the cocktail was successfully determined without detection of any adverse drug reactions. In the subsequent population study, four female volunteers experienced unexpected and unacceptable moderate and severe adverse reactions (ARs) of headache, dizziness, nausea, vomiting, blue fingers, nails and lips and difficulties in urinating, which led to the study being prematurely terminated after inclusion of only 22 subjects (15 males, 7 females) [corrected]. CONCLUSION: Attention must be paid to adverse reactions when designing new combinations of phenotype cocktails regardless of the doses and drugs involved. We specifically warn against the combination of tramadol, omeprazole, losartan and caffeine.


Assuntos
Cafeína/efeitos adversos , Losartan/efeitos adversos , Omeprazol/efeitos adversos , Tramadol/efeitos adversos , Adulto , Cafeína/farmacocinética , Estudos Cross-Over , Sistema Enzimático do Citocromo P-450/genética , Sistema Enzimático do Citocromo P-450/metabolismo , Combinação de Medicamentos , Feminino , Genótipo , Voluntários Saudáveis , Humanos , Losartan/farmacocinética , Masculino , Pessoa de Meia-Idade , Omeprazol/farmacocinética , Fenótipo , Tramadol/farmacocinética , Adulto Jovem
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA