RESUMO
Preparations of plasma-derived small extracellular vesicles (sEVs) were deployed as liquid biopsy to study cytochrome P450 (CYP) 3A4 (CYP3A4) induction following modafinil 400 mg once daily × 14 days (young healthy volunteers, N = 10 subjects). Induction was confirmed using the 4ß-hydroxycholesterol-to-cholesterol (4ßHC/C) ratio, a plasma CYP3A4/5 biomarker, with a mean 2.1-fold increase (Day 15 vs. Day 1; 90% confidence interval (CI) = 1.8-2.3; P value = 0.0004). Proteomic analysis revealed the induction (mean Day 15 vs. Day 1 fold-increase (90% CI)) of both liver (1.3 (1.1-1.5), P value = 0.014) and nonliver (1.9 (1.6-2.2), P value = 0.04) sEV CYP3A4 protein expression. In CYP3A5 nonexpresser subjects, the baseline (pre-dose) 4ßHC/C plasma ratio was more highly correlated with liver sEVs (r = 0.937, P value = 0.001) than nonliver sEVs (r = 0.619, P value = 0.101) CYP3A4 protein expression. When CYP3A5 expressers (CYP3A5*1/*3) were included, the correlation with liver sEVs (r = 0.761, P value = 0.011) and nonliver sEVs (r = 0.391, P value = 0.264) CYP3A4 protein was weaker. Although modafinil-induced changes in plasma 4ßHC/C ratio did not correlate with sEVs CYP3A4 protein expression, the individual subject sEVs proteomic data were used successfully to predict victim drug (midazolam, triazolam, dextromethorphan, 17α-ethinylestradiol, and abemaciclib) area under the plasma concentration-time curve (AUC) ratios (AUCRs) following modafinil. Based on the AUCR values, modafinil was classified as a weak to moderate CYP3A4 inducer (vs. rifampicin). For the first time, it was possible to deploy plasma-derived sEVs to study CYP3A4 induction beyond rifampicin, a more potent CYP3A4 inducer.
Assuntos
Indutores do Citocromo P-450 CYP3A/administração & dosagem , Citocromo P-450 CYP3A/biossíntese , Modafinila/administração & dosagem , Biomarcadores/sangue , Citocromo P-450 CYP3A/sangue , Citocromo P-450 CYP3A/genética , Indutores do Citocromo P-450 CYP3A/efeitos adversos , Esquema de Medicação , Interações Medicamentosas , Indução Enzimática , Vesículas Extracelulares/efeitos dos fármacos , Vesículas Extracelulares/enzimologia , Voluntários Saudáveis , Humanos , Hidroxicolesteróis/sangue , Biópsia Líquida , Fígado/enzimologia , Modafinila/efeitos adversos , Modelos Biológicos , Plasma/enzimologia , Proteômica , Rifampina/administração & dosagem , Rifampina/efeitos adversos , Fatores de TempoRESUMO
Intestinal cytochrome P450 3A (CYP3A) plays an important role in oral drug metabolism, but only endogenous metabolic markers for measuring hepatic CYP3A activity were identified. Our study evaluated whether hepatic CYP3A markers reflected intestinal CYP3A activity. An open-label, three-period, six-treatment, one-sequence clinical trial was performed in 16 healthy Korean males. In the control phase, all subjects received a single dose of intravenous (IV) and oral midazolam (1 mg and 5 mg, respectively). Clarithromycin (500 mg) was administered twice daily for 4 days to inhibit hepatic and intestinal CYP3A, and 500 mL of grapefruit juice was given to inhibit intestinal CYP3A. Clarithromycin significantly inhibited total CYP3A activity, and the clearance of IV and apparent clearance of oral midazolam decreased by 0.15- and 0.32-fold, respectively. Grapefruit juice only reduced the apparent clearance of oral midazolam by 0.84-fold, which indicates a slight inhibition of intestinal CYP3A activity. Urinary markers, including 6ß-OH-cortisol/cortisol and 6ß-OH-cortisone/cortisone, were significantly decreased 0.5-fold after clarithromycin administration but not after grapefruit juice. The fold changes in 6ß-OH-cortisol/cortisol and 6ß-OH-cortisone/cortisone did not correlate to changes in intestinal availability but did correlate to hepatic availability. In conclusion, endogenous metabolic markers are only useful to measure hepatic, but not intestinal, CYP3A activity.
Assuntos
Citrus paradisi/metabolismo , Claritromicina/urina , Citocromo P-450 CYP3A/urina , Mucosa Intestinal/metabolismo , Fígado/metabolismo , Midazolam/urina , Administração Intravenosa , Administração Oral , Adulto , Biomarcadores/sangue , Biomarcadores/urina , Claritromicina/administração & dosagem , Claritromicina/sangue , Citocromo P-450 CYP3A/sangue , Citocromo P-450 CYP3A/genética , Interações Alimento-Droga/fisiologia , Voluntários Saudáveis , Humanos , Mucosa Intestinal/efeitos dos fármacos , Fígado/efeitos dos fármacos , Masculino , Taxa de Depuração Metabólica/efeitos dos fármacos , Taxa de Depuração Metabólica/fisiologia , Midazolam/administração & dosagem , Midazolam/sangueRESUMO
PURPOSE: Fedratinib, an oral selective kinase inhibitor with activity against both wild type and mutationally activated Janus kinase 2, has been approved for the treatment of adult patients with intermediate-2 or high-risk myelofibrosis by the US Food and Drug Administration. In vitro studies indicated that fedratinib was an inhibitor of several cytochrome P450 (CYP) enzymes. The primary objective of this study was to evaluate the effects of repeated doses of fedratinib on the activity of CYP2D6, CYP2C19, and CYP3A4 in patients with solid tumors using a CYP probe cocktail. METHODS: An open-label, one-sequence, two-period, two-treatment crossover study was conducted. Patients were administered a single oral dose cocktail of metoprolol (100 mg), omeprazole (20 mg), and midazolam (2 mg) used as probe substrates for CYP2D6, CYP2C19, and CYP3A4 enzyme activities, respectively, without fedratinib on Day -1 or with fedratinib on Day 15. RESULTS: Coadministration of 500 mg once-daily doses of fedratinib for 15 days increased the mean area under the plasma concentration-time curve from time zero to infinity following a single-dose cocktail containing metoprolol (CYP2D6 substrate), omeprazole (CYP2C19 substrate), and midazolam (CYP3A4 substrate) by 1.77-fold (90% confidence interval [CI] 1.27-2.47) for metoprolol, 2.82-fold (90% CI 2.26-3.53) for omeprazole, and 3.84-fold (90% CI 2.62-5.63) for midazolam, respectively. The mean plasma Day 14/Day 1 ratio of 4ß-hydroxycholesterol, an endogenous biomarker of CYP3A4 activity, was 0.59 (90% CI 0.54-0.66), suggesting a net inhibition of CYP3A4 by fedratinib. CONCLUSION: Fedratinib is a weak inhibitor of CYP2D6, and a moderate inhibitor of CYP2C19 and CYP3A4. These results serve as the basis for dose modifications of these CYP substrate drugs when co-administered with fedratinib.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Inibidores das Enzimas do Citocromo P-450/farmacocinética , Neoplasias/tratamento farmacológico , Pirrolidinas/administração & dosagem , Sulfonamidas/administração & dosagem , Administração Oral , Idoso , Idoso de 80 Anos ou mais , Protocolos de Quimioterapia Combinada Antineoplásica/farmacocinética , Estudos Cross-Over , Citocromo P-450 CYP2C19/sangue , Citocromo P-450 CYP2D6/sangue , Citocromo P-450 CYP3A/sangue , Inibidores das Enzimas do Citocromo P-450/administração & dosagem , Interações Medicamentosas , Feminino , Humanos , Hidroxicolesteróis/sangue , Masculino , Metoprolol/administração & dosagem , Metoprolol/sangue , Midazolam/administração & dosagem , Midazolam/sangue , Pessoa de Meia-Idade , Omeprazol/administração & dosagem , Omeprazol/sangue , Inibidores de Proteínas Quinases/administração & dosagem , Inibidores de Proteínas Quinases/efeitos adversos , Inibidores de Proteínas Quinases/farmacocinética , Pirrolidinas/efeitos adversos , Pirrolidinas/farmacocinética , Sulfonamidas/efeitos adversos , Sulfonamidas/farmacocinéticaRESUMO
We analyzed the relationship between polymorphic loci of CYP3A genes (CYP3A4 (rs2740574), CYP3A5 (rs776746) and CYP3A7 (rs2257401)) with the development of chronic mercury intoxication. Of 170 men examined, 120 were workers chronically exposed to mercury vapors and 50 were carriers of GG-HSPA1B (+1267A/G) genotype associated with chronic mercury intoxication. Urinary content of 4-hydroxyantipyrine (4-HAP) generated in the reaction predominantly catalyzed by CYP3A4/CYP3A5 was studied in workers without chronic mercury intoxication (group 1, N=46) and patients in the delayed period of chronic mercury intoxication (group 2, N=74) depending on the genotypes of CYP3A4 and CYP3A5. For polymorphic loci CYP3A5 and CYP3A7, a tendency to an increase in the frequency of genotypes with rare alleles was found (p=0.071 and p=0.078) in the combined group (group 2 together with GGHSPA1B genotype carriers) relative to group 1. The high level of linkage disequilibrium was noted, especially for the pair rs776746 and rs2257401 (LD (r)=0.89). In group 2, a trend to 4-HAP decrease compared to group 1 (p=0.056 and p=0.065) was revealed for carriers of AA-CYP3A4 and GG-CYP3A5 genotypes. The involvement of CYP3A in the development of mercury neurotoxic effect remains unclear.
Assuntos
Citocromo P-450 CYP3A/genética , Intoxicação por Mercúrio/genética , Mercúrio/toxicidade , Doenças Profissionais/genética , Polimorfismo de Nucleotídeo Único , Alelos , Antipirina/análogos & derivados , Antipirina/urina , Estudos de Casos e Controles , Citocromo P-450 CYP3A/sangue , Expressão Gênica , Frequência do Gene , Genótipo , Humanos , Desequilíbrio de Ligação , Masculino , Intoxicação por Mercúrio/sangue , Intoxicação por Mercúrio/diagnóstico , Intoxicação por Mercúrio/patologia , Pessoa de Meia-Idade , Doenças Profissionais/sangue , Doenças Profissionais/diagnóstico , Doenças Profissionais/patologiaRESUMO
Alprazolam is used in the treatment of patients with anxiety disorders comorbid with alcohol use disorder. Some proportion of these patients does not respond adequately to treatment with alprazolam, while many of them experience dose-dependent adverse drug reactions. Results of the previous studies have shown that CYP3A is involved in the biotransformation of alprazolam, the activity of which is dependent, inter alia, on the polymorphism of the encoding gene. OBJECTIVE: The objective of our study was to investigate the effect of 99366316G>A polymorphism of the CYP3A4 gene on the concentration/dose indicator of alprazolam in patients with anxiety disorders comorbid with alcohol use disorder, using findings on enzymatic activity of CYP3A (as evaluated by the 6-beta-hydroxy-cortisol/cortisol ratio measurement) and on CYP3A4 expression level obtained by measuring the miR-27b plasma concentration levels in patients with anxiety disorders comorbid with alcoholism. MATERIAL AND METHODS: Our study enrolled 105 patients with anxiety disorders comorbid with alcohol use disorder (age - 37.8±14.6 years). Therapy included alprazolam in an average daily dose of 5.6±2.4 mg per day. Treatment efficacy was evaluated using the psychometric scales. Therapy safety was assessed using the UKU Side-Effect Rating Scale. For genotyping and estimation of the microRNA (miRNA) plasma levels, we performed the real-time polymerase chain reaction. The activity of CYP3A was evaluated using the HPLC-MS/MS method by the content of the endogenous substrate of the given isoenzyme and its metabolite in urine (6- beta-hydroxy-cortisol/cortisol). Therapeutic drug monitoring (TDM) has been performed using HPLC-MS/MS. RESULTS: Our study revealed the statistically significant results in terms of the treatment efficacy evaluation (HAMA scores at the end of the treatment course): (GG) 3.0 [2.0; 5.0] and (GA) 4.0 [4.0; 5.0], p = 0.007; at the same time, the statistical significance in the safety profile was not obtained (the UKU scores): (GG) 3.0 [2.0; 3.8] and (GA) 3.0 [1.5; 4.0], p = 0.650. We revealed a statistical significance for concentration/dose indicator of alprazolam in patients with different genotypes: (GG) 1.583 [0.941; 2.301] and (GA) 2.888 [2.305; 4.394], p = 0.001). Analysis of the results of the pharmacotranscriptomic part of the study didn't show the statistically significant difference in the miR-27b plasma levels in patients with different genotypes: (GG) 25.6 [20.4; 28.8], (GA) 25.7 [19.7; 33.1], p = 0.423. At the same time, correlation analysis revealed a statistically significant relationship between the alprazolam efficacy profile evaluated by changes in HAMA scale scores and the miR-27b plasma concentration: rs = 0.20, p = 0.042. Also, we didn't reveal the correlation between the miRNA concentration and safety profile: rs = 0.15, p = 0.127. In addition, we revealed the relationship between the CYP3A enzymatic activity (as evaluated by 6-beta-hydroxycortisol/ cortisol ratio measurement) and the miR-27b plasma concentration: rs = -0.27, p = 0.006. At the same time, correlation analysis revealed a statistically significant relationship between the alprazolam concentration and the miR-27b plasma concentration: rs = 0.28, p = 0.003. CONCLUSION: The effect of genetic polymorphism of the CYP3A4 gene on the efficacy and safety profiles of alprazolam was demonstrated in a group of 105 patients with anxiety disorders comorbid with alcohol use disorder. At the same time, miR-27b remains a promising biomarker for assessing the level of CYP3A4 expression, because it correlates with the encoded isoenzyme's activity.
Assuntos
Alcoolismo/tratamento farmacológico , Alprazolam/farmacocinética , Transtornos de Ansiedade/tratamento farmacológico , Citocromo P-450 CYP3A/genética , MicroRNAs/sangue , Polimorfismo Genético/genética , Adulto , Alprazolam/sangue , Biomarcadores/sangue , Biotransformação , Comorbidade , Citocromo P-450 CYP3A/sangue , Genótipo , Humanos , Isoenzimas , Masculino , MicroRNAs/genética , Pessoa de Meia-Idade , Farmacogenética , Medicina de Precisão , Resultado do Tratamento , Adulto JovemRESUMO
AIMS: To characterize the population pharmacokinetics (PK) of sildenafil and its active metabolite, N-desmethyl sildenafil (DMS), in premature infants. METHODS: We performed a multicentre, open-label trial to characterize the PK of sildenafil in infants ≤28 weeks gestation and < 365 postnatal days (cohort 1) or < 32 weeks gestation and 3-42 postnatal days (cohort 2). In cohort 1, we obtained PK samples from infants receiving sildenafil as ordered per the local standard of care (intravenous [IV] or enteral). In cohort 2, we administered a single IV dose of sildenafil and performed PK sampling. We performed a population PK analysis and dose-exposure simulations using the software NONMEM®. RESULTS: We enrolled 34 infants (cohort 1 n = 25; cohort 2 n = 9) and collected 109 plasma PK samples. Sildenafil was given enterally (0.42-2.09 mg/kg) in 24 infants in cohort 1 and via IV (0.125 or 0.25 mg/kg) in all infants in cohort 2. A 2-compartment PK model for sildenafil and 1-compartment model for DMS, with presystemic conversion of sildenafil to DMS, characterized the data well. Coadministration of fluconazole (n = 4), a CYP3A inhibitor, resulted in an estimated 59% decrease in sildenafil clearance. IV doses of 0.125, 0.5 and 1 mg/kg every 8 hours (in the absence of fluconazole) resulted in steady-state maximum sildenafil concentrations that were generally within the range of those reported to inhibit phosphodiesterase type 5 activity in vitro. CONCLUSIONS: We successfully characterized the PK of sildenafil and DMS in premature infants and applied the model to inform dosing for a follow-up, phase II study.
Assuntos
Recém-Nascido Prematuro/sangue , Modelos Biológicos , Inibidores da Fosfodiesterase 5/farmacocinética , Citrato de Sildenafila/farmacocinética , Administração Oral , Estudos de Coortes , Citocromo P-450 CYP3A/sangue , Citocromo P-450 CYP3A/genética , Fluconazol/administração & dosagem , Fluconazol/farmacocinética , Idade Gestacional , Humanos , Hipertensão Pulmonar/sangue , Hipertensão Pulmonar/tratamento farmacológico , Lactente , Recém-Nascido , Doenças do Prematuro/sangue , Doenças do Prematuro/tratamento farmacológico , Injeções Intravenosas , Inibidores da Fosfodiesterase 5/administração & dosagem , Inibidores da Fosfodiesterase 5/sangue , Inibidores da Fosfodiesterase 5/uso terapêutico , Citrato de Sildenafila/administração & dosagem , Citrato de Sildenafila/sangue , Citrato de Sildenafila/uso terapêuticoRESUMO
OBJECTIVE: This study aimed to evaluate the relationship between endogenous CYP3A markers and plasma amlodipine (AML) exposure and metabolism parameters in early postpartum and non-peripartum women. METHODS: Twenty-four AML-treated early postpartum women with hypertensive disorders of pregnancy and 30 non-peripartum women with essential hypertension were enrolled. Blood samples for determination of CYP3A markers including total cholesterol-adjusted 4ß-hydroxycholesterol (4ß-OHC/TC), 25-hydroxyvitamin D (25-OHD), and AML and its metabolites in plasma were collected at 24â¯h after the AML treatment. RESULTS: The plasma 4ß-OHC/TC in postpartum women was higher than that in non-peripartum women, while the plasma 25-OHD was lower. The postpartum women had a lower plasma AML concentration and its metabolic ratio was higher. The plasma 4ß-OHC/TC decreased as the number of days post-delivery increased. The plasma AML concentration increased as the number of days post-delivery increased, while the metabolic ratio of AML declined slightly. Tendency toward negative correlations between the plasma 4ß-OHC/TC but not 25-OHD, and AML concentration were observed in both postpartum and non-peripartum women. In both groups, the plasma 4ß-OHC/TC was correlated with the metabolic ratio of AML. CONCLUSIONS: The early postpartum women had higher plasma 4ß-OHC and AML metabolism. The plasma 4ß-OHC had positive relationships with amlodipine metabolism in both women groups. AML metabolism and plasma 4ß-OHC may be useful as CYP3A markers in early postpartum and non-peripartum women.
Assuntos
Anlodipino/uso terapêutico , Anti-Hipertensivos/uso terapêutico , Citocromo P-450 CYP3A/sangue , Hipertensão/tratamento farmacológico , Pré-Eclâmpsia/tratamento farmacológico , Complicações Cardiovasculares na Gravidez/tratamento farmacológico , Administração Oral , Adulto , Idoso , Idoso de 80 Anos ou mais , Anlodipino/administração & dosagem , Anti-Hipertensivos/administração & dosagem , Biomarcadores/sangue , Estudos de Casos e Controles , Feminino , Humanos , Hipertensão/sangue , Pessoa de Meia-Idade , Período Periparto , Pré-Eclâmpsia/sangue , Gravidez , Complicações Cardiovasculares na Gravidez/sangue , Cuidado Pré-Natal , Adulto JovemRESUMO
BACKGROUND: This study aimed to evaluate the relationships between concomitant biologic disease-modifying anti-rheumatic drugs (DMARDs) and prednisolone administration and blood tacrolimus exposure or serum CYP3A4/5-related markers in rheumatoid arthritis (RA) patients without severe disease activity. METHODS: Forty-six RA patients treated with oral tacrolimus once daily for maintenance of clinical remission to moderate disease activity were enrolled. The blood concentrations of tacrolimus and its major metabolite were determined at 12â¯h after the evening dosing. Blood samples for determination of serum markers including 4ß-hydroxycholesterol (4ß-OHC), 25-hydroxyvitamin D (25-OHD) and interleukin-6 (IL-6), and CYP3A5 genotype were collected. RESULTS: Most enrolled patients had RA with clinical remission to mild disease activity. Concomitant tocilizumab or low-dose prednisolone administration did not alter the blood tacrolimus exposure. Serum 4ß-OHC level was lower in tocilizumab co-treated patients than in the biologic DMARD non-treated patients. The blood tacrolimus concentration was inversely correlated with the serum level of 25-OHD, but not 4ß-OHC and IL-6. The serum level of 4ß-OHC was positively associated with that of 25-OHD. No correlations were observed between the serum levels of CYP3A4/5 activity markers and IL-6. The patients with the homozygous CYP3A5*3 had the higher blood tacrolimus concentration, while CYP3A5*3 allele was not associated with the serum levels of 4ß-OHC and 25-OHD. CONCLUSIONS: Concomitant use of tocilizumab or low-dose prednisolone had no effect on the pharmacokinetics of tacrolimus, while tocilizumab lowered serum 4ß-OHC. Blood tacrolimus exposure was negatively associated with serum 25-OHD in RA patients with clinical remission to moderate disease activity.
Assuntos
Antirreumáticos/uso terapêutico , Artrite Reumatoide/sangue , Artrite Reumatoide/tratamento farmacológico , Citocromo P-450 CYP3A/sangue , Imunossupressores/uso terapêutico , Prednisolona/uso terapêutico , Tacrolimo/uso terapêutico , Idoso , Antirreumáticos/administração & dosagem , Artrite Reumatoide/enzimologia , Biomarcadores/sangue , Feminino , Humanos , Hidroxicolesteróis/sangue , Imunossupressores/sangue , Limite de Detecção , Masculino , Pessoa de Meia-Idade , Prednisolona/administração & dosagem , Tacrolimo/administração & dosagem , Vitamina D/análogos & derivados , Vitamina D/sangueRESUMO
Physiologically-based pharmacokinetic (PBPK) modeling allows assessment of the covariates contributing to the large pharmacokinetic (PK) variability of tacrolimus; these include multiple physiological and biochemical differences among patients. A PBPK model of tacrolimus was developed, including a virtual population with physiological parameter distributions reflecting renal transplant patients. The ratios of predicted to observed dose-normalized maximum plasma concentration (Cmax ), 0-12-hour area under the concentration-time curve (AUC0-12 hour ), and trough plasma concentration (Ctrough ) ranged from 0.92-fold to 1.15-fold, indicating good predictive performance. The model quantitatively indicated the impact of cytochrome P450 (CYP)3A4 abundance, hematocrit, and serum albumin levels, in addition to CYP3A5 genotype status, on tacrolimus PK and associated variability. Age-dependent change in tacrolimus trough concentration in pediatric patients was mainly attributed to the CYP3A ontogeny profile. This study demonstrates the utility of PBPK modeling as a tool for mechanistic and quantitative assessment of the impact of patient physiological differences on observed large PK variability.
Assuntos
Imunossupressores/farmacocinética , Biologia de Sistemas/métodos , Tacrolimo/farmacocinética , Área Sob a Curva , Citocromo P-450 CYP3A/sangue , Citocromo P-450 CYP3A/genética , Humanos , Imunossupressores/administração & dosagem , Taxa de Depuração Metabólica , Modelos Teóricos , Polimorfismo de Nucleotídeo Único , Albumina Sérica/análise , Tacrolimo/administração & dosagemRESUMO
A number of cytochrome P450 (CYP)3A phenotyping probes have been used to characterize the drug interaction potential of new molecular entities; of these, midazolam has emerged as the gold standard. Recently, plasma 4ß-hydroxycholesterol (4ß-OHC), the metabolite of CYP3A-mediated cholesterol metabolism, has been championed as an endogenous biomarker for CYP3A, particularly during chronic conditions where CYP3A activity is altered by disease and in long-term treatment studies where midazolam administration is not optimal. Multiple studies in humans have shown that 4ß-OHC can qualitatively differentiate among weak, moderate, and potent CYP3A induction when an inducer, typically rifampin, is administered for up to 2 weeks. Conversely, longer durations of CYP3A inhibitor administration (≥1 month) appear to be necessary to differentiate among weak, moderate, and potent CYP3A inhibitors. A number of studies have reported statistically significant linear relationships between 4ß-OHC plasma concentrations (and 4ß-OHC:cholesterol ratios) and midazolam clearance. However, sufficiently powered studies assessing the ability of 4ß-OHC or 4ß-OHC:cholesterol ratios to measure CYP3A activity (ie, predictive performance) have not been conducted to date. Additional limitations associated with 4ß-OHC phenotyping include inability to detect acute changes in CYP3A activity, uncertainty with regard to its intestinal formation, ambiguity surrounding the role of CYP3A5 in its metabolism, and lack of clarity regarding the role of transporters in its disposition. As such, the data do not support the use of 4ß-OHC or 4ß-OHC:cholesterol ratios as an endogenous biomarker for CYP3A activity.
Assuntos
Citocromo P-450 CYP3A/metabolismo , Hidroxicolesteróis/sangue , Animais , Biomarcadores/sangue , Citocromo P-450 CYP3A/sangue , Indutores do Citocromo P-450 CYP3A/farmacologia , Inibidores do Citocromo P-450 CYP3A/farmacologia , Humanos , Taxa de Depuração Metabólica/efeitos dos fármacosRESUMO
Morbid obesity and bariatric surgery induce anatomical, physiological and metabolic alterations that may alter the body's disposition of drugs. Current literature on this topic is limited and sometimes inconsistent. Cytochrome P450 (CYP) is a superfamily of enzymes that metabolize around 75% of all marketed drugs. The purpose of this study was to evaluate the impact of body mass index and bariatric surgery on CYP activities. Firstly, we evaluated the in vivo activity of 4 major CYP isoenzymes (CYP2D6, CYP3A4, CYP2C9, and CYP1A2) in normal weight, overweight, and morbidly obese individuals. Secondly, we assessed the short- (1 month) and medium-term (6 month) effects of the most commonly employed bariatric surgery techniques (laparoscopic sleeve gastrectomy and Roux-en-Y gastric bypass) on the activity of these enzymes. CYP3A4 activity was lower in morbidly obese individuals, compared to normal-weight controls. Interestingly, bariatric surgery normalized CYP3A4 activity. In comparison with normal-weight controls, morbidly obese individuals had higher CYP2D6 activity, which was only observed in individuals with two functional alleles for this isoenzyme. Neither body mass index nor surgery had significant effects on CYP2C9 and CYP1A2 activities. Overall, no relevant differences in CYP activities were found between surgical techniques. In conclusion, further studies should evaluate whether the observed alterations in CYP3A4 activity will require dose adjustments for CYP3A4 substrates especially in morbidly obese individuals before and after bariatric surgery.
Assuntos
Cirurgia Bariátrica , Citocromo P-450 CYP1A2/sangue , Citocromo P-450 CYP2C9/sangue , Citocromo P-450 CYP2D6/sangue , Citocromo P-450 CYP3A/sangue , Obesidade Mórbida/cirurgia , Adulto , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Obesidade Mórbida/sangue , Resultado do Tratamento , Adulto JovemRESUMO
AIM: To develop an LC-MS/MS assay to quantitate well-tolerated substrates; midazolam (CYP3A), omeprazole (CYP2C19), dextromethorphan (CYP2D6), losartan (CYP2C9) and their respective metabolites' concentrations in plasma samples. PATIENTS & METHODS: A solid-phase extraction method was optimized to extract analytes of interest simultaneously from human plasma samples. The assay analyzed plasma samples collected from patients who received equal or lower than therapeutic doses of CYP substrates. RESULTS: This assay was validated based on the European Medicines Agency guideline for bioanalytical method validation and was sensitive, linear, accurate and precise with acceptable recovery and matrix effects. CONCLUSION: Small sample volume and dose of cytochrome P450 substrates, short-run time, using stable isotope internal standards and being cost effective are the major advantages of the assay.
Assuntos
Cromatografia Líquida/métodos , Sistema Enzimático do Citocromo P-450/metabolismo , Ensaios Enzimáticos/métodos , Espectrometria de Massas em Tandem/métodos , Citocromo P-450 CYP2C19/sangue , Citocromo P-450 CYP2C19/metabolismo , Citocromo P-450 CYP2C9/sangue , Citocromo P-450 CYP2C9/metabolismo , Citocromo P-450 CYP2D6/sangue , Citocromo P-450 CYP2D6/metabolismo , Citocromo P-450 CYP3A/sangue , Citocromo P-450 CYP3A/metabolismo , Sistema Enzimático do Citocromo P-450/sangue , HumanosAssuntos
Síndrome Coronariana Aguda/genética , Citocromo P-450 CYP2C19/genética , Citocromo P-450 CYP3A/genética , Família 4 do Citocromo P450/genética , Polimorfismo Genético/genética , Subfamília B de Transportador de Cassetes de Ligação de ATP/sangue , Subfamília B de Transportador de Cassetes de Ligação de ATP/genética , Síndrome Coronariana Aguda/sangue , Síndrome Coronariana Aguda/tratamento farmacológico , Plaquetas/efeitos dos fármacos , Plaquetas/metabolismo , Clopidogrel/química , Clopidogrel/metabolismo , Clopidogrel/farmacocinética , Citocromo P-450 CYP2C19/sangue , Citocromo P-450 CYP3A/sangue , Família 4 do Citocromo P450/sangue , Relação Dose-Resposta a Droga , Feminino , Genótipo , Humanos , Masculino , Pessoa de Meia-Idade , Inibidores da Agregação Plaquetária/administração & dosagem , Inibidores da Agregação Plaquetária/farmacologiaRESUMO
Systemic inflammation has been linked to suppressed CYP3A4 activity. The aim of this study was to examine associations between levels of a broad selection of cytokines and CYP3A4 phenotype in patients with rheumatoid arthritis (RA). The study included 31 RA patients treated with tumor necrosis factor (TNF)-α inhibitors. CYP3A4 phenotype was measured as serum concentration of 4ß-hydroxycholesterol (4ßOHC) by ultra-performance liquid chromatography-tandem mass spectrometry in samples collected prior to and 3 months after initiation of treatment with TNF-α inhibitors. Serum levels of the following 21 cytokines were determined in the same samples using a bead-based multiplex immunoassay (Luminex technology): CCL2, CCL3, CXCL8, granulocyte colony-stimulating factor, granulocyte-macrophage colony-stimulating factor, interferon γ, interleukin (IL)-1ß, IL-1 receptor antagonist (ra), IL-2, IL-4, IL-5, IL-6, IL-7, IL-10, IL-12, IL-13, IL-15, IL-17A, IL-18, IL-23, and TNF-α Correlations between levels of cytokines and 4ßOHC were assessed by Spearman's rank correlation tests. Among the investigated cytokines, three were negatively correlated with CYP3A4 phenotype during treatment with TNF-α inhibitors: i.e., IL-1ra (r = -0.408, P = 0.023), IL-6 (r = -0.410, P = 0.022) and CXCL8 (r = -0.403, P = 0.025) (P ≥ 0.3 for all other cytokines). None of the analyzed cytokines were correlated with CYP3A4 phenotype prior to TNF-α inhibitor treatment (P > 0.1 for all cytokines). These findings suggest that immune responses associated with increased levels of IL-1ra, IL-6, and CXCL8 may suppress CYP3A4 metabolism. Further studies are required to evaluate these preliminary findings in different patient populations and also examine the possible molecular mechanisms behind our observations.
Assuntos
Artrite Reumatoide/sangue , Citocromo P-450 CYP3A/sangue , Citocromo P-450 CYP3A/genética , Citocinas/metabolismo , Adulto , Idoso , Anti-Inflamatórios/farmacologia , Anti-Inflamatórios/uso terapêutico , Artrite Reumatoide/tratamento farmacológico , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Fator de Necrose Tumoral alfa/antagonistas & inibidores , Adulto JovemRESUMO
OBJECTIVE: Drug-metabolizing enzymes (DMEs), such as cytochrome P450 (CYP) enzymes, and transporters have emerged as major determinants of variability in drug metabolism and response. This study investigated the association between CYP and P-glycoprotein activities and plasma antidepressant concentration in an outpatient clinical setting. Secondary outcomes were antidepressant efficacy and tolerance. We also describe phenotypes in patients treated with antidepressants and evaluate the tolerance of a minimally invasive phenotyping approach. METHODS: From January 2015 to August 2015, 64 patients on a stable antidepressant regimen underwent a simultaneous assessment of steady-state antidepressant concentration and DME (CYP1A2, CYP2B6, CYP2C9, CYP2C19, CYP2D6, CYP3A) and P-glycoprotein transporter activity using a cocktail phenotyping approach. Psychiatric diagnoses were in accordance with DSM-5. RESULTS: We observed a high proportion of subjects (> 20%) with reduced activity of CYP2C19, CYP2D6, CYP3A4, and P-glycoprotein. As expected, higher CYP activity for major metabolic pathways was associated with lower concentration of the parent compound (CYP2C19 and escitalopram, P = .025; CYP2D6 and fluoxetine, P < .001; CYP2C19 and sertraline, P = .001), higher concentration of the metabolite (CYP2D6 and O-desmethylvenlafaxine, P = .007), and higher metabolite-to-parent drug ratio (CYP2C19 and escitalopram, P = .03; CYP2D6 and fluoxetine, P < .001; CYP2C19 and sertraline, P = .048; CYP2B6 and sertraline, P = .006). Phenotyping also highlighted the relevance of a minor metabolic pathway for venlafaxine (CYP3A4). Insufficient response and adverse reactions to antidepressants were not significantly associated with plasma antidepressant concentration, DME, or P-glycoprotein activity. Tolerance of the phenotypic test in ambulatory settings was found to be excellent. CONCLUSIONS: The phenotypic assessment of DMEs and a transporter is a valuable, well-tolerated method to explore the interindividual variability in drug disposition in clinical settings. The method is able to account for the inhibitory activity of antidepressants themselves and for polymedication, which is frequent in this population of refractory depressed patients. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT02438072.
Assuntos
Membro 1 da Subfamília B de Cassetes de Ligação de ATP/sangue , Antidepressivos de Segunda Geração/sangue , Citalopram/sangue , Citocromo P-450 CYP2C19/sangue , Citocromo P-450 CYP2D6/sangue , Citocromo P-450 CYP3A/sangue , Transtorno Depressivo/sangue , Transtorno Depressivo/tratamento farmacológico , Fluoxetina/sangue , Redes e Vias Metabólicas , Sertralina/sangue , Adulto , Idoso , Transtorno Bipolar/sangue , Transtorno Bipolar/tratamento farmacológico , Estudos Transversais , Humanos , Pessoa de Meia-Idade , Adulto JovemRESUMO
PURPOSE: Plasma paclitaxel (PTX) concentration 24 h or later after PTX administration may predict myelosuppression. Here, we explored predictive markers for neutropenia induced by intravenous administration of PTX in an outpatient clinic. METHODS: Thirty women suffering from uterine, ovarian or cervical cancer were enrolled in this study. PTX (mean dose: 167 mg/m2) was intravenously infused and followed by carboplatin. Plasma samples were obtained 4 h after PTX administration. Genotyping was carried out for CYP3A5*3, ABCB1 1236 C>T, 2677 G>T/A, and 3435 C>T. RESULTS: There was no significant relationship between genotype and reduced neutrophil count. Neutrophil reduction rate correlated with the patient's height, neutrophil count on the day of administration, and plasma PTX concentration. Multiple regression analysis with those three indices explained 47.7% of the interindividual variability of the neutrophil reduction rate. The model with plasma PTX concentration, patient's height, and plasma 6-α-hydroxy-paclitaxel /PTX concentration ratio also explained 30.0% of the interindividual variability for the neutrophil nadir count after PTX administration. CONCLUSIONS: These results indicate that neutrophil reduction after PTX administration can be partially predicted by multiple regression analysis involving plasma concentration data collected at outpatient clinics.
Assuntos
Antineoplásicos Fitogênicos/sangue , Neutropenia/induzido quimicamente , Neutrófilos , Neoplasias Ovarianas/tratamento farmacológico , Paclitaxel/sangue , Neoplasias do Colo do Útero/tratamento farmacológico , Neoplasias Uterinas/tratamento farmacológico , Subfamília B de Transportador de Cassetes de Ligação de ATP/sangue , Adulto , Idoso , Idoso de 80 Anos ou mais , Instituições de Assistência Ambulatorial , Antineoplásicos/uso terapêutico , Antineoplásicos Fitogênicos/farmacocinética , Antineoplásicos Fitogênicos/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica , Carboplatina/uso terapêutico , Citocromo P-450 CYP3A/sangue , Feminino , Humanos , Contagem de Leucócitos , Pessoa de Meia-Idade , Pacientes Ambulatoriais , Neoplasias Ovarianas/genética , Paclitaxel/farmacocinética , Paclitaxel/uso terapêutico , Neoplasias do Colo do Útero/genética , Neoplasias Uterinas/genéticaRESUMO
BACKGROUND: Rivaroxaban is metabolized in the liver via CYP3A4, the cytochrome involved in the metabolism of nearly 50% of all medications. Thus, its effective concentration depends on multiple pharmacologic parameters. METHODS: The primary goal of our research was to study the correlation between the CYP3A family activity and the safety and efficacy of anticoagulant therapy with rivaroxaban in patients with deep vein thrombosis (DVT). Thirty one patients with DVT aged 21-83 years, 18 men and 13 women, received rivaroxaban (Xarelto) 30 mg/day for 21 days after diagnosis and 20 mg/day for the follow-up period of 6 months. During the study period, Doppler ultrasound was performed weekly to assess the clot dynamics and recanalization time. RESULTS: We found a direct statistically reliable correlation between CYP3A4 activity and both peak and trough rivaroxaban levels. A correlation was also found between the initial clot length and the time to full recanalization r = 0.764 (0.554-0.883), p < 0.0001. No significant link was found between either the glomerular filtration rate and peak rivaroxaban concentrations or between CYP3A4 activity and the treatment effectiveness parameters. No connection between renal function and rivaroxaban concentration was established in our study, which agrees with the clinical trials data that allow unlimited rivaroxaban use in patients with glomerular filtration rate >30 mL/min. CONCLUSIONS: The direct link between the initial clot length and time to full recanalization that has been found means that patients with more advanced stages of thrombosis need more time to reach recanalization than their counterparts with a less severe condition.
Assuntos
Citocromo P-450 CYP3A/metabolismo , Rivaroxabana/sangue , Trombose Venosa/tratamento farmacológico , Adulto , Idoso , Idoso de 80 Anos ou mais , Anticoagulantes/administração & dosagem , Anticoagulantes/farmacocinética , Citocromo P-450 CYP3A/sangue , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Rivaroxabana/administração & dosagem , Rivaroxabana/farmacocinética , Federação Russa , Trombose Venosa/sangue , Trombose Venosa/enzimologiaRESUMO
Oxcarbazepine is a cytochrome P450 (CYP) 3A4 inducer, which is structurally similar to carbamazepine. Although lacking Food and Drug Administration approval, oxcarbazepine is sometimes prescribed to treat aggressive behavior in youth with autism spectrum disorder (ASD). These youths may also be taking second-generation antipsychotics, some of which are substrates of the CYP3A4 metabolic pathway. The combination of these medications may result in decreased serum antipsychotic concentrations, potentially reducing effectiveness. A limited number of reports are available which discuss reduced atypical antipsychotic concentrations secondary to oxcarbazepine CYP3A4 induction. We report a young boy taking oxcarbazepine (1200 mg/d) who presented with an unexpectedly low serum aripiprazole concentration. Utilizing therapeutic drug monitoring, pharmacogenetic testing, and a tool to evaluate drug-drug interactions, we estimate that oxcarbazepine possibly reduced his serum aripiprazole concentration by 68%. Our report is important, as it is the first to describe a drug-drug interaction between oxcarbazepine and aripiprazole. This report should encourage the completion of in vitro and clinical studies and the publication of case reports describing the possible inductive effects of oxcarbazepine on atypical antipsychotics (including cariprazine, lurasidone, quetiapine, aripiprazole, brexpiprazole, iloperidone, and risperidone) mediated by induction of the CYP3A4 metabolic pathway.
Assuntos
Anticonvulsivantes/sangue , Antipsicóticos/sangue , Aripiprazol/sangue , Transtorno do Espectro Autista/sangue , Carbamazepina/análogos & derivados , Interações Medicamentosas/fisiologia , Anticonvulsivantes/administração & dosagem , Antipsicóticos/administração & dosagem , Aripiprazol/administração & dosagem , Transtorno do Espectro Autista/tratamento farmacológico , Carbamazepina/administração & dosagem , Carbamazepina/sangue , Criança , Citocromo P-450 CYP1A2/sangue , Citocromo P-450 CYP3A/sangue , Humanos , Masculino , Oxcarbazepina , Resultado do TratamentoRESUMO
OBJECTIVES: We investigated the relationship between 4,4'-methylene-bis(2-chloroaniline) (MBOCA) exposure and micronucleus (MN) frequency, and how this association was affected by genetic polymorphism of the cytochrome P450 enzyme (CYP3A4). METHODS: We divided the study population into an exposed group (n=44 with total urine MBOCA ≥20â µg/g creatinine) and a control group (n=47 with total urine MBOCA <20â µg/g creatinine). Lymphocyte MN frequency (MNF) and micronucleated cell (MNC) frequency were measured by the cytokinesis-block MN assay method. MNF reported as the number of micronuclei in binucleated cells per 1000 cells, and MNC reported as the number of binucleated cells with the presence of MN per 1000 cells. CYP3A4 alleles were measured by PCR-based restriction fragment length polymorphism (PCR-RFLP). RESULTS: The mean MNF (6.11 vs 4.46â MN/1000 cells, p<0.001) and MNC (5.75 vs 4.15â MN/1000 cells, p<0.001) in the exposed workers was significantly higher than that in the controls. The CYP3A4 polymorphism A/A+A/G influenced the difference in the mean MNF (5.97 vs 4.38â MN/1000 cells, p<0.001) and MNC (5.60 vs 4.15â MN/1000 cells, p<0.001) between the MBOCA-exposed and control groups. After adjusting risk factors, the MNF level in the MBOCA-exposed workers was 0.520â MN cells/1000 cells (p<0.001) higher than the control group among the CYP3A4 A/A+A/G genotype. Similarly, the MNC level in the MBOCA-exposed workers was 0.593â MN/1000 cells (p<0.001) higher than the control group among the CYP3A4 A/A+A/G genotype. However, the difference in adjusted MNF and MNC between the exposed and control groups was not significant for the CYP3A4 polymorphism with the G/G genotype. CONCLUSIONS: We recommend that lymphocytes MNF and MNC are good indicators to evaluate MBOCA genotoxicity. Individuals with the CYP3A4 polymorphism A/A and A/G genotypes appear to be more susceptible to MBOCA genotoxicity.
Assuntos
Compostos de Anilina/efeitos adversos , Citocromo P-450 CYP3A/genética , Metilenobis (cloroanilina)/efeitos adversos , Exposição Ocupacional/efeitos adversos , Polimorfismo Genético , Adulto , Consumo de Bebidas Alcoólicas/epidemiologia , Análise de Variância , Compostos de Anilina/urina , Índice de Massa Corporal , Citocromo P-450 CYP3A/sangue , Citocromo P-450 CYP3A/urina , Sistema Enzimático do Citocromo P-450 , Feminino , Genótipo , Humanos , Linfócitos/química , Masculino , Metilenobis (cloroanilina)/análise , Pessoa de Meia-Idade , Testes de Mutagenicidade , Reação em Cadeia da Polimerase , Fatores de Risco , Fumar/epidemiologia , Taiwan/epidemiologiaRESUMO
BACKGROUND: Rilpivirine pharmacokinetics is defined by its absorption, distribution, metabolism, and excretion. Pregnancy can affect these factors by changes in cardiac output, protein binding, volume of distribution, and cytochrome P450 (CYP) 3A4 activity. Rilpivirine is metabolized by CYP3A4. The impact of pregnancy on rilpivirine pharmacokinetics is largely unknown. METHODS: International Maternal Pediatric Adolescent AIDS Clinical Trials P1026s is a multicenter, nonblinded, prospective study evaluating antiretroviral pharmacokinetics in HIV-infected pregnant women that included a cohort receiving rilpivirine 25 mg once daily as part of their combination antiretrovirals for clinical care. Thirty-two women were enrolled in this study. Intensive pharmacokinetic sampling was performed at steady state during the second trimester, the third trimester, and postpartum. Maternal and umbilical cord blood samples were obtained at delivery. Plasma rilpivirine concentration was measured using liquid chromatography-mass spectrometry; lower limit of quantitation was 10 ng/mL. RESULTS: Median (range) AUC0-24 were 1969 (867-4987, n = 15), 1669 (556-4312, n = 28), and 2387 (188-6736, n = 28) ng·h/mL in the second trimester, the third trimester, and postpartum, respectively (P < 0.05 for either trimester vs postpartum). Median (range) C24 were 63 (37-225, n = 17), 56 (<10-181, n = 30), and 81 (<10-299, n = 28) ng/mL (P < 0.05 for either trimester vs postpartum). High variability in pharmacokinetic parameters was observed between subjects. Median (range) cord blood/maternal concentration ratio was 0.55 (0.3-0.8, n = 21). Delivery HIV-1 RNA was ≤50 copies per milliliter in 70% and ≤400 copies per milliliter in 90% of women. Cmin were significantly lower at 15 visits with detectable HIV-1 RNA compared with 61 visits with undetectable HIV-1 RNA, 29 (<10-93) vs 63 (15-200) ng/mL (P = 0.0001). Cmin was below the protein binding-adjusted EC90 concentration (12.2 ng/mL) at 4 visits in 3 of 31 women (10%). CONCLUSIONS: Rilpivirine exposure is lower during pregnancy compared with postpartum and highly variable. Ninety percent of women had minimum concentrations above the protein binding-adjusted EC90 for rilpivirine.