RESUMO
In a genome-wide association study of atorvastatin pharmacokinetics in 158 healthy volunteers, the SLCO1B1 c.521T>C (rs4149056) variant associated with increased area under the plasma concentration-time curve from time zero to infinity (AUC0-∞) of atorvastatin (P = 1.2 × 10-10), 2-hydroxy atorvastatin (P = 4.0 × 10-8), and 4-hydroxy atorvastatin (P = 2.9 × 10-8). An intronic LPP variant, rs1975991, associated with reduced atorvastatin lactone AUC0-∞ (P = 3.8 × 10-8). Three UGT1A variants linked with UGT1A3*2 associated with increased 2-hydroxy atorvastatin lactone AUC0-∞ (P = 3.9 × 10-8). Furthermore, a candidate gene analysis including 243 participants suggested that increased function SLCO1B1 variants and decreased activity CYP3A4 variants affect atorvastatin pharmacokinetics. Compared with individuals with normal function SLCO1B1 genotype, atorvastatin AUC0-∞ was 145% (90% confidence interval: 98-203%; P = 5.6 × 10-11) larger in individuals with poor function, 24% (9-41%; P = 0.0053) larger in those with decreased function, and 41% (16-59%; P = 0.016) smaller in those with highly increased function SLCO1B1 genotype. Individuals with intermediate metabolizer CYP3A4 genotype (CYP3A4*2 or CYP3A4*22 heterozygotes) had 33% (14-55%; P = 0.022) larger atorvastatin AUC0-∞ than those with normal metabolizer genotype. UGT1A3*2 heterozygotes had 16% (5-25%; P = 0.017) smaller and LPP rs1975991 homozygotes had 34% (22-44%; P = 4.8 × 10-5) smaller atorvastatin AUC0-∞ than noncarriers. These data demonstrate that genetic variation in SLCO1B1, UGT1A3, LPP, and CYP3A4 affects atorvastatin pharmacokinetics. This is the first study to suggest that LPP rs1975991 may reduce atorvastatin exposure. [Correction added on 6 April, after first online publication: An incomplete sentence ("= 0.017) smaller in heterozygotes for UGT1A3*2 and 34% (22%, 44%; P × 10-5) smaller in homozygotes for LPP noncarriers.") has been corrected in this version.].
Assuntos
Área Sob a Curva , Atorvastatina , Citocromo P-450 CYP3A , Estudo de Associação Genômica Ampla , Glucuronosiltransferase , Transportador 1 de Ânion Orgânico Específico do Fígado , Polimorfismo de Nucleotídeo Único , Adulto , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Adulto Jovem , Atorvastatina/farmacocinética , Atorvastatina/sangue , Citocromo P-450 CYP3A/genética , Citocromo P-450 CYP3A/metabolismo , Genótipo , Glucuronosiltransferase/genética , Voluntários Saudáveis , Inibidores de Hidroximetilglutaril-CoA Redutases/farmacocinética , Inibidores de Hidroximetilglutaril-CoA Redutases/sangue , Transportador 1 de Ânion Orgânico Específico do Fígado/genética , Variantes Farmacogenômicos , Proteínas com Domínio LIM/genética , Proteínas do Citoesqueleto/genéticaRESUMO
AIMS: Objective methods to determine statin adherence are requested to improve lipid management. We have recently established a method to detect reduced adherence to atorvastatin therapy with cut-off values based on the sum of atorvastatin and its major metabolites in the blood. We aimed to validate this method in patients with and without cardiovascular disease, and optimize previous cut-off values. METHODS AND RESULTS: The pharmacokinetic study included 60 participants treated with atorvastatin 20 mg (N = 20), 40 mg (N = 20), and 80 mg (N = 20). Atorvastatin was then stopped and blood samples collected from day zero to day four. Quantification of the parent drug and its metabolites in blood plasma was performed with a liquid chromatography-tandem mass spectrometry assay. The cut-off values for reduced adherence were validated and optimized by calculating diagnostic sensitivity and specificity. Our candidate cut-off value of dose-normalized six-component sum of atorvastatin plus metabolites <0.10 nM/mg provided a sensitivity of 97% and a specificity of 93% for detecting ≥2 omitted doses. An optimized cut-off <0.062 nM/mg provided a sensitivity of 90% and a specificity of 100%. An alternative simplified two-component metabolite sum with a cut-off value <0.05 nM/mg provided a sensitivity of 98% and a specificity of 76%. An optimized cut-off <0.02 nM/mg provided a sensitivity of 97% and a specificity of 98%. CONCLUSION: This validation study confirms that our direct method discriminates reduced adherence from adherence to atorvastatin therapy with high diagnostic accuracy. The method may improve lipid management in clinical practice and serve as a useful tool in future studies.
Assuntos
Atorvastatina , Inibidores de Hidroximetilglutaril-CoA Redutases , Adesão à Medicação , Atorvastatina/farmacocinética , Atorvastatina/uso terapêutico , Atorvastatina/sangue , Humanos , Masculino , Feminino , Pessoa de Meia-Idade , Inibidores de Hidroximetilglutaril-CoA Redutases/farmacocinética , Inibidores de Hidroximetilglutaril-CoA Redutases/uso terapêutico , Inibidores de Hidroximetilglutaril-CoA Redutases/sangue , Inibidores de Hidroximetilglutaril-CoA Redutases/administração & dosagem , Idoso , Ácidos Heptanoicos/farmacocinética , Ácidos Heptanoicos/administração & dosagem , Ácidos Heptanoicos/sangue , Ácidos Heptanoicos/uso terapêutico , Pirróis/farmacocinética , Pirróis/sangue , Pirróis/administração & dosagem , Espectrometria de Massas em Tandem , Cromatografia Líquida , Doenças Cardiovasculares/tratamento farmacológico , Doenças Cardiovasculares/diagnóstico , Doenças Cardiovasculares/sangue , Doenças Cardiovasculares/prevenção & controle , Reprodutibilidade dos Testes , Relação Dose-Resposta a DrogaRESUMO
BACKGROUND AND OBJECTIVES: Gegenqinlian decoction (GQD), a classic traditional Chinese medicine (TCM), was described in Shanghan Lun. GQD is often combined with antihyperlipidemic drugs (mainly atrovastatin calcium) in TCM clinics. However, the herb-drug interaction between GQD and atrovastatin calcium (AC) is still unknown. To determine whether the combination is safe, we evaluated the effects of GQD on the activities of cytochrome P450 (CYP) 3A2 enzyme and investigated the impact of GQD on the pharmacokinetics and pharmacodynamics of AC in rats. METHODS: The pharmacokinetics of AC (10 mg/kg) with or without pretreatment with GQD (freeze-dried powder, 1.35 g/kg) were investigated using HPLC. The influence of GQD on pharmacodynamics of AC were determined by detecting the levels of serum total cholesterol (TC), triglycerides (TG), low density lipoprotein cholesterol (LDL-C), high density lipoprotein cholesterol (HDL-C), aspartate aminotransferase (AST) and alanine aminotransferase (ALT). Moreover, the probe drug method was used to explore the effect of GQD on CYP3A2 activity. RESULTS: The pharmacokinetic parameters of AC combined with GQD were significantly affected (P < 0.05) in hyperlipidemic rats. The serum TC, TG and LDL-C levels of the combination were significantly reduced (P < 0.05), and the serum HDL-C level was significantly increased (P < 0.05) compared with AC/GQD alone. AST and ALT activities treated with both GQD and AC+GQD group were significantly reduced (P < 0.05) compared with AC group. There was a significant difference in the pharmacokinetic parameters of midazolam between control and GQD groups (P < 0.05). Maximum concentration (Cmax), area under the concentration-time curve (AUC) from time 0 to the last quantifiable concentration (AUC0-t) and AUC from time 0 to infinity (AUC0-∞) increased significantly in GQD group. CONCLUSIONS: The result suggested that GQD combined with AC can improve the lipid-lowering effect of AC and reduce the damage of AC to the liver simultaneously. However, GQD can inhibit the activity of CYP3A2 in hyperlipidemic rats and increase the blood concentration of AC. Therefore, the clinical dose of AC should be adjusted when they are combined. Since the study was conducted in rats, further research should be carried out to assess the uniformity of the pharmacokinetics and pharmacodynamics between rats and humans.
Assuntos
Atorvastatina/farmacocinética , Medicamentos de Ervas Chinesas/farmacologia , Inibidores de Hidroximetilglutaril-CoA Redutases/farmacocinética , Animais , Área Sob a Curva , Atorvastatina/sangue , Modelos Animais de Doenças , Interações Ervas-Drogas , Inibidores de Hidroximetilglutaril-CoA Redutases/sangue , Hiperlipidemias/tratamento farmacológico , Masculino , Distribuição Aleatória , Ratos , Ratos Sprague-DawleyRESUMO
The inadequate adherence of patients whose hyperlipidemia is treated with atorvastatin (ATR) to medical instructions presents a serious health risk. Our aim was to develop a flexible approach based on therapeutic drug monitoring (TDM), nonparametric population pharmacokinetic modeling, and Monte Carlo simulation to differentiate adherent patients from partially and nonadherent individuals in a nonrandomized, unicentric, observational study. Sixty-five subjects were enrolled. Nonparametric, mixed-effect population pharmacokinetic models of the sums of atorvastatin and atorvastatin lactone concentrations (ATR+ATRL) and of the concentrations of the acid and lactone forms of ATR and its 2- and 4-hydroxylated pharmacologically active metabolites (ATR+MET) were elaborated by including the TDM results obtained in 128 samples collected from thirty-nine subjects. Monte Carlo simulation was performed based on the elaborated models to establish the probabilities of attaining a specific ATR+ATRL or ATR+MET concentration in the range of 0.002-10 nmol (mg dose)-1 L-1 at 1-24 h postdose by adherent, partially adherent, and nonadherent patients. The results of the simulations were processed to allow the estimation of the adherence of further 26 subjects who were phlebotomized at sampling times of 2-20 h postdose by calculating the probabilities of attaining the ATR+ATRL and ATR+MET concentrations measured in these subjects in adherent, partially adherent, and nonadherent individuals. The best predictive values of the estimates of adherence could be obtained with sampling at early sampling times. 61.54% and 38.46% of subjects in the adherence testing set were estimated to be fully and partially adherent, respectively, while in all cases the probability of nonadherence was extremely low. The evaluation of patient adherence to ATR therapy based on pharmacokinetic modeling and Monte Carlo simulation has important advantages over the collection of trough samples and the use of therapeutic ranges.
Assuntos
Atorvastatina/farmacocinética , Inibidores de Hidroximetilglutaril-CoA Redutases/farmacocinética , Hipercolesterolemia/tratamento farmacológico , Adesão à Medicação/estatística & dados numéricos , Adulto , Idoso , Idoso de 80 Anos ou mais , Atorvastatina/sangue , LDL-Colesterol/sangue , Monitoramento de Medicamentos , Feminino , Humanos , Inibidores de Hidroximetilglutaril-CoA Redutases/sangue , Hipercolesterolemia/sangue , Masculino , Pessoa de Meia-Idade , Método de Monte CarloRESUMO
BACKGROUND: Pantoprazole and atorvastatin are often used jointly in the clinic. The drug-drug interaction of pantoprazole and atorvastatin is worthy of being investigated. OBJECTIVE: A highly rapid, sensitive, and selective LC-MS/MS method was developed for simultaneous quantification of pantoprazole and atorvastatin in rat plasma. METHODS: Omeprazole and atorvastatin-d5 were used as the internal standards (ISs) of pantoprazole and atorvastatin, respectively. Simple protein precipitation was used to extract analytes from 50.0 µL plasma samples. RESULTS: The chromatographic separation was achieved on a C18 column and the total chromatographic run time was 3.2 min. Acquisition of mass spectrometric data was performed on a triple-quadrupole mass spectrometer in multiple- reaction-monitoring (MRM) mode with an ESI source using the transition m/z 384â 200 for pantoprazole and m/z 559.4â 440.2 for atorvastatin, respectively. The method was validated over the concentration range of 20.0 â¼ 5000 ng/mL for pantoprazole and 1.00 â¼ 250 ng/mL for atorvastatin. All the validation results, including linearity, specificity, precision, accuracy, extraction recovery, matrix effect, and stability, met the acceptance criteria as per FDA guidelines. CONCLUSION: This method was successfully applied to a pharmacokinetic interaction study in Wistar rats. The results revealed significant evidence for the drug-drug interaction between pantoprazole and atorvastatin.
Assuntos
Atorvastatina/sangue , Cromatografia Líquida/métodos , Pantoprazol/sangue , Espectrometria de Massas em Tandem/métodos , Animais , Atorvastatina/farmacologia , Interações Medicamentosas , Ensaios de Triagem em Larga Escala/métodos , Pantoprazol/farmacologia , Ratos , Ratos WistarRESUMO
Atorvastatin (ATV) is a poorly water-soluble drug that exhibits poor oral bioavailability. Therefore, present research was designed to develop ATV solid dispersions (SDs) to enhance the solubility, drug release, and oral bioavailability. Various SDs of ATV were formulated by conventional and microwave-induced melting methods using Gelucire®48/16 as a carrier. The formulated SDs were characterized for different physicochemical characterizations, drug release, and oral bioavailability studies. The results obtained from the different physicochemical characterization indicate the molecular dispersion of ATV within various SDs. The drug polymer interaction results showed no interaction between ATV and used carrier. There was marked enhancement in the solubility (1.95-9.32 folds) was observed for ATV in prepared SDs as compare to pure ATV. The drug content was found to be in the range of 96.19% ± 2.14% to 98.34% ± 1.32%. The drug release results revealed significant enhancement in ATV release from prepared SDs compared to the pure drug and the marketed tablets. The formulation F8 showed high dissolution performance (% DE30 value of 80.65 ± 3.05) among the other formulations. Optimized Gelucire®48/16-based SDs formulation suggested improved oral absorption of atorvastatin as evidenced with improved pharmacokinetic parameters (Cmax 2864.33 ± 573.86 ng/ml; AUC0-t 5594.95 ± 623.3 ng/h ml) as compared to ATV suspension (Cmax 317.82 ± 63.56 ng/ml; AUC0-t 573.94 ± 398.9 ng/h ml) and marketed tablets (Cmax 852.72 ± 42.63 ng/ml; 4837.4 ± 174.7 ng/h ml). Conclusively, solid dispersion-based oral formulation of atorvastatin could be a promising approach for enhanced drug solubilization, dissolution, and subsequently improved absorption.
Assuntos
Atorvastatina/farmacocinética , Inibidores de Hidroximetilglutaril-CoA Redutases/farmacocinética , Administração Oral , Animais , Atorvastatina/sangue , Atorvastatina/química , Disponibilidade Biológica , Portadores de Fármacos/química , Liberação Controlada de Fármacos , Inibidores de Hidroximetilglutaril-CoA Redutases/sangue , Inibidores de Hidroximetilglutaril-CoA Redutases/química , Técnicas In Vitro , Ratos , Solubilidade , ComprimidosRESUMO
The antihyerlipidemic drug atorvastatin (ATR) is used worldwide as part of the strategy to prevent cardiovascular events. The high prevalence of patient nonadherence remains an important challenge which could be addressed efficiently by precision pharmacotherapy based on therapeutic drug monitoring (TDM). ATR is metabolized to pharmacologically active metabolites, and evidence shows that the sums of ATR acid and lactone form concentrations (ATR + ATRL), or of ATR and hydroxylated metabolites (ATR + MET) should be assayed. A method is presented for the analysis of these substances in serum. Method validation included the estimation of the quantitative relationship between the concentrations and the standard deviations (SD), which supports the optimal incorporation of TDM results into nonparametric pharmacokinetic models. The concentrations of the analytes were evaluated in human subjects receiving ATR. The method's performance improved by taking the sums of acid and lactone concentrations into account. The concentration-SD relationship was linear, and we recommend applying Theil's regression for estimating the assay error. All analytes could be detected by 2 h post dose in the samples of human subjects. The changes in metabolite/parent drug concentration ratios in time depended on the dose. The method is suitable for the TDM of ATR with a focus on precision pharmacotherapy.
Assuntos
Atorvastatina/sangue , Cromatografia Líquida/métodos , Monitoramento de Medicamentos/métodos , Ácidos Heptanoicos/sangue , Lactonas/sangue , Medicina de Precisão , Espectrometria de Massas em Tandem/métodos , HumanosRESUMO
Herbals that are widely consumed as therapeutic alternatives to conventional drugs for cardiovascular diseases, may lead to herb-drug interactions (HDIs). Atorvastatin (ATR) is drug of choice for hyperlipidemia and is extensively metabolized through CYP3A4 enzyme. Thus, we postulate that concomitant administration of ATR with piperine (PIP, potent inhibitor of CYP3A4 enzyme)/ridayarishta (RID, cardiotonic herbal formulations containing PIP) may lead to potential HDI. A simple, accurate, sensitive high-performance liquid chromatography-photodiode array detection method using Kromasil-100 C18 column, mobile phase acetonitrile: 30 mM phosphate buffer (55:45 v/v) pH 4.5 with flow rate gradient programming was developed to study the potential HDI in rats. Method was found to be linear (2-100 ng/mL) with Lower Limit of Detection (LLOD) 2 ng/mL. The precision (%CV < 15%), accuracy (-1.0 to -10% R.E) with recoveries above 90% from rat plasma of ATR and IS were obtained. The pharmacokinetic (PK) interactions studies on co-administration of ATR (8.4 mg/kg, p.o.) with PIP (35 mg/kg, p.o.), demonstrated a threefold increase in Cmax of ATR (P < 0.01) with significant increase in AUC0-t/AUC0-∞ compared to ATR alone indicating potential PK-HDI. However co-administration of RID (4.2 mL/kg, p.o.) showed less significant changes (P > 0.05) indicating low HDI. The pharmacodynamic effects/interactions study (TritonX-100 induced hyperlipidemic model in rats) suggested no significant alterations in the lipid profile on co-administration of PIP/RID with ATR, indicating that there may be no significant pharmacodynamic interactions.
Assuntos
Alcaloides , Atorvastatina , Benzodioxóis , Cromatografia Líquida de Alta Pressão/métodos , Piperidinas , Alcamidas Poli-Insaturadas , Alcaloides/sangue , Alcaloides/química , Alcaloides/farmacocinética , Animais , Atorvastatina/sangue , Atorvastatina/química , Atorvastatina/farmacocinética , Benzodioxóis/sangue , Benzodioxóis/química , Benzodioxóis/farmacocinética , Interações Ervas-Drogas , Limite de Detecção , Modelos Lineares , Piperidinas/sangue , Piperidinas/química , Piperidinas/farmacocinética , Extratos Vegetais/sangue , Extratos Vegetais/química , Extratos Vegetais/farmacocinética , Alcamidas Poli-Insaturadas/sangue , Alcamidas Poli-Insaturadas/química , Alcamidas Poli-Insaturadas/farmacocinética , Ratos , Ratos Wistar , Reprodutibilidade dos TestesRESUMO
In the present work, nickel-1,4-benzenedioxyacetic acid was synthesized as a rod-like metal organic material and then modified with alumina nanoparticles to synthesize nickel metal organic modified-Al2 O3 nanoparticles. The material was found as an efficient sorbent for the enrichment of atorvastatin in human blood plasma. After the extraction of the sample of plasma by ultrasound-assisted dispersive solid phase extraction, high performance liquid chromatography-ultraviolet was used to determine the quantitatively pre-concentrated interest analyte. The conditions for optimum extraction were achieved by the optimization of the volume of eluent, dosage of the sorbent, and time of sonication. Solution pH of 7.0, 250 µL of ethanol, 45 mg of the sorbent, and 10 min of sonication time were the conditions for extracting the atorvastatin maximum recovery of higher than 97.0%. By using desirability function for the optimization of the process, the present method showed a response that was linear ranging from 0.2 to 800 ng/mL with regression coefficient of 0.999 in the plasma of human blood with a satisfactory detection limit of 0.05 ng/mL, while the precision of interday for the current method was found to be <5%. It can be concluded that dispersive solid phase extraction method is effective for the extraction of atorvastatin from human plasma samples (97.4-102%) due to its easy operation, simplicity, repeatability, and reliability.
Assuntos
Óxido de Alumínio/química , Atorvastatina/sangue , Estruturas Metalorgânicas/química , Nanopartículas/química , Extração em Fase Sólida , Ondas Ultrassônicas , Ácido Acético/química , Cromatografia Líquida de Alta Pressão , Humanos , Estruturas Metalorgânicas/síntese química , Níquel/química , Tamanho da PartículaRESUMO
Atorvastatin (ATV) is a blood cholesterol-lowering drug used to prevent cardiovascular events, the leading cause of death worldwide. As pharmacokinetics, metabolism and response vary among individuals, we wanted to determine the most reliable metabolic ATV phenotypes and identify novel and preponderant genetic markers that affect ATV plasma levels. A controlled, randomized, crossover, single-blind, three-treatment, three-period, and six-sequence clinical study of ATV (single 80-mg oral dose) was conducted among 60 healthy Mexican men. ATV plasma levels were measured using high-performance liquid chromatography mass spectrometry. Genotyping was performed by real-time PCR with TaqMan probes. Four ATV metabolizer phenotypes were found: slow, intermediate, normal and fast. Six gene polymorphisms, SLCO1B1-rs4149056, ABCB1-rs1045642, CYP2D6-rs1135840, CYP2B6-rs3745274, NAT2-rs1208, and COMT- rs4680, had a significant effect on ATV pharmacokinetics (P < 0.05). The polymorphisms in SLCO1B1 and ABCB1 seemed to have a greater effect and were especially important for the shift from an intermediate to a normal metabolizer. This is the first study that demonstrates how the interaction of genetic variants affect metabolic phenotyping and improves understanding of how SLCO1B1 and ABCB1 variants that affect statin metabolism may partially explain the variability in drug response. Notwithstanding, the influence of other genetic and non-genetic factors is not ruled out.
Assuntos
Atorvastatina/administração & dosagem , Atorvastatina/sangue , Transportador 1 de Ânion Orgânico Específico do Fígado/genética , Variantes Farmacogenômicos , Subfamília B de Transportador de Cassetes de Ligação de ATP/genética , Adulto , Arilamina N-Acetiltransferase/genética , Atorvastatina/farmacocinética , Catecol O-Metiltransferase/genética , Cromatografia Líquida , Estudos Cross-Over , Citocromo P-450 CYP2D6/genética , Técnicas de Genotipagem , Voluntários Saudáveis , Humanos , Masculino , Espectrometria de Massas , México , Polimorfismo de Nucleotídeo Único , Método Simples-Cego , Adulto JovemRESUMO
PURPOSE: A fixed-dose combination (FDC) of fimasartan and atorvastatin is used to treat hypertension and dyslipidemia. The peak plasma concentration (Cmax) of fimasartan and atorvastatin has a large intra-subject variability with a maximum coefficient of variation of 65% and 48%, respectively. Therefore, both drugs are classified as highly variable drugs. The purpose of this study was to compare the pharmacokinetics (PK) between a FDC of fimasartan 120 mg and atorvastatin 40 mg versus separate tablets in healthy male Korean subjects. SUBJECTS AND METHODS: A randomized, single-dose, two-treatment, three-sequence, three-period, partial replicated crossover study was conducted with a 7-day washout interval between periods. Blood samples for fimasartan and atorvastatin were collected until 48 hours after administration in each period. PK parameters were calculated using the non-compartmental method. Geometric mean ratios (GMRs) for PK parameters of FDC to loose combination and their 90% confidence intervals (90% CIs) were estimated. RESULTS: A total of 56 subjects completed the study. GMRs (90% CIs) of the Cmax for fimasartan and atorvastatin were 1.08 (0.93-1.24) and 1.02 (0.92-1.13), respectively. The expanded 90% CIs of both drugs using the intra-subject variability was calculated range of 0.70-1.43 and 0.73-1.38, respectively. The corresponding values of area under the concentration-time curve from zero to the last measurable time point were 1.02 (0.97-1.08) and 1.02 (0.98-1.07), respectively. CONCLUSION: FDC of fimasartan 120 mg and atorvastatin 40 mg between their loose combination showed similar PK characteristics.
Assuntos
Atorvastatina/farmacocinética , Compostos de Bifenilo/farmacocinética , Pirimidinas/farmacocinética , Tetrazóis/farmacocinética , Administração Oral , Adulto , Atorvastatina/administração & dosagem , Atorvastatina/sangue , Compostos de Bifenilo/administração & dosagem , Compostos de Bifenilo/sangue , Estudos Cross-Over , Relação Dose-Resposta a Droga , Combinação de Medicamentos , Voluntários Saudáveis , Humanos , Masculino , Pessoa de Meia-Idade , Pirimidinas/administração & dosagem , Pirimidinas/sangue , República da Coreia , Comprimidos/administração & dosagem , Comprimidos/farmacocinética , Tetrazóis/administração & dosagem , Tetrazóis/sangue , Adulto JovemRESUMO
Fluorescence properties of nanoparticles can be influenced by solvent. In this work, carbon dots (CDs) were synthesized in deep eutectic solvent by microwave assisted method. Quantum yield (QY) and size of the synthesized CDs were 41.3% and 2 nm, respectively. N/Cl -doped CDs had excellent sensitivity and selectivity for atorvastatin and detection limit was 0.8 nM. Simple and low-cost synthesis method and excellent sensitivity are advantages of this detection method for atorvastatin. The as-synthesized N/Cl-doped CDs were successfully used to determine atorvastatin in blood serum.
Assuntos
Atorvastatina/análise , Carbono/química , Pontos Quânticos/química , Espectrometria de Fluorescência/métodos , Anticolesterolemiantes/análise , Anticolesterolemiantes/sangue , Anticolesterolemiantes/química , Atorvastatina/sangue , Atorvastatina/química , Colina/química , Fluorescência , Glucose/química , Humanos , Concentração de Íons de Hidrogênio , Limite de Detecção , Microscopia Eletrônica de Transmissão , Solventes/química , Espectroscopia de Infravermelho com Transformada de Fourier , Fatores de Tempo , Ureia/químicaRESUMO
Atorvastatin is a synthetic statin administered in its active form and used for the treatment of dyslipidemias. In the current study, the effects of atorvastatin were evaluated on plasma lipid profiles and the potential for adverse effects after once daily PO dosing of atorvastatin for 30 days in Hispaniolan Amazon parrots (Amazona ventralis). Sixteen adult parrots (10 female, 6 male) with hypercholesterolemia were used for this study. Birds were assigned to 2 groups (treatment and control) of 8 parrots each (3 male, 5 female) after balancing for age, sex, originating institution, and baseline plasma cholesterol values. Compounded atorvastatin oral suspension (10 mg/kg) was administered PO once daily via gavage into the crop. Equivalent volumes of placebo suspension were administered to the control group. Plasma biochemistry and plasma lipid profile analysis (total cholesterol, high-density lipoprotein cholesterol [HDL-C], low-density lipoprotein cholesterol [LDL-C], and triglycerides [TGs]) were analyzed on days 0, 14, and 30. Plasma samples and HDL-C fractions were evaluated for cholesterol and TG concentrations via enzymatic assays. Subtraction of HDL-C values from total cholesterol yielded the non-HDL-C concentration for each bird. Birds were routinely assessed for appetite, activity, and urofeces. Plasma atorvastatin concentrations were obtained from 7 of 8 birds in the treatment group from banked samples. Those samples were obtained on days 14 and 30, with drug administration 6 to 8 hours before collection. No significant differences were observed in total cholesterol, HDL-C, non-HDL-C, or TG between treatment and control groups at days 0, 14, and 30. Plasma atorvastatin concentrations were variable on day 14 (0.54-5.41 ng/ mL for 6 of 7 samples, with 1 outlier of 307 ng/mL) and on day 30 (0.79-6.74 ng/mL). No adverse effects were noted in any of the birds during the study period. When dosed PO at 10 mg/kg once daily, atorvastatin did not result in significant changes to plasma lipid profiles (eg, lowering of plasma total or non-HDL-C concentrations) at any time point during this study. Future studies to investigate pharmacokinetic and pharmacodynamic properties of atorvastatin in parrots may require increased doses and/or frequency of administration.
Assuntos
Amazona/sangue , Atorvastatina/farmacocinética , Inibidores de Hidroximetilglutaril-CoA Redutases/farmacocinética , Administração Oral , Animais , Atorvastatina/administração & dosagem , Atorvastatina/sangue , Doenças das Aves/tratamento farmacológico , Colesterol/sangue , Feminino , Inibidores de Hidroximetilglutaril-CoA Redutases/administração & dosagem , Inibidores de Hidroximetilglutaril-CoA Redutases/sangue , Hipercolesterolemia/tratamento farmacológico , Hipercolesterolemia/veterinária , MasculinoRESUMO
Atorvastatin (ATV) is frequently prescribed and generally well tolerated, but can lead to myotoxicity, especially at higher doses. A genome-wide association study of circulating levels of ATV, 2-hydroxy (2-OH) ATV, ATV lactone (ATV L), and 2-OH ATV L was performed in 590 patients who had been hospitalized with a non-ST elevation acute coronary syndrome 1 month earlier and were on high-dose ATV (80 mg or 40 mg daily). The UGT1A locus (lead single nucleotide polymorphism, rs887829) was strongly associated with both increased 2-OH ATV/ATV (P = 7.25 × 10-16 ) and 2-OH ATV L/ATV L (P = 3.95 × 10-15 ) metabolic ratios. Moreover, rs45446698, which tags CYP3A7*1C, was nominally associated with increased 2-OH ATV/ATV (P = 6.18 × 10-7 ), and SLCO1B1 rs4149056 with increased ATV (P = 2.21 × 10-6 ) and 2-OH ATV (P = 1.09 × 10-6 ) levels. In a subset of these patients whose levels of ATV and metabolites had also been measured at 12 months after hospitalization (n = 149), all of these associations remained, except for 2-OH ATV and rs4149056 (P = 0.057). Clinically, rs4149056 was associated with increased muscular symptoms (odds ratio (OR) 3.97; 95% confidence interval (CI) 1.29-12.27; P = 0.016) and ATV intolerance (OR 1.55; 95% CI 1.09-2.19; P = 0.014) in patients (n = 870) primarily discharged on high-dose ATV. In summary, both novel and recognized genetic associations have been identified with circulating levels of ATV and its major metabolites. Further study is warranted to determine the clinical utility of genotyping rs4149056 in patients on high-dose ATV.
Assuntos
Atorvastatina/sangue , Inibidores de Hidroximetilglutaril-CoA Redutases/sangue , Variantes Farmacogenômicos , Polimorfismo de Nucleotídeo Único , Atorvastatina/efeitos adversos , Atorvastatina/análogos & derivados , Atorvastatina/farmacocinética , Biotransformação , Citocromo P-450 CYP3A/genética , Citocromo P-450 CYP3A/metabolismo , Feminino , Estudo de Associação Genômica Ampla , Glucuronosiltransferase/genética , Glucuronosiltransferase/metabolismo , Humanos , Inibidores de Hidroximetilglutaril-CoA Redutases/efeitos adversos , Inibidores de Hidroximetilglutaril-CoA Redutases/farmacocinética , Lactonas/sangue , Transportador 1 de Ânion Orgânico Específico do Fígado/genética , Transportador 1 de Ânion Orgânico Específico do Fígado/metabolismo , Masculino , Pessoa de Meia-Idade , Doenças Musculares/induzido quimicamente , Doenças Musculares/genética , Farmacogenética , Estudos Prospectivos , Medição de Risco , Fatores de Risco , Reino UnidoRESUMO
Background Statins are used to treat and prevent cardiovascular diseases (CVDs) by reducing the total serum cholesterol concentration. Unfortunately, dose-related side effects and sub-optimal response, attributed to non-adherence amongst others, were described. Therefore, a fast and sensitive liquid chromatography-high-resolution tandem mass spectrometry (LC-HRMS/MS) method for adherence testing and therapeutic drug monitoring of all currently marketed statins and their active metabolites in human blood plasma should be developed, validated and tested for applicability. Methods Atorvastatin, fluvastatin, lovastatin, pitavastatin, pravastatin, rosuvastatin, and simvastatin, as well as ortho- and para-hydroxy-atorvastatin, lovastatin hydroxy acid and simvastatin hydroxy acid were included and several internal standards (IS) tested. Validation was performed according to the guideline of the European Medicines Agency including selectivity, carry-over, accuracy, precision, matrix effects, dilution integrity and analyte stability. Finally, applicability was tested using 14 patient samples submitted for regular toxicological analysis. Results Due to an analytical interference of atorvastatin-d5, diazepam-d5 and pentobarbital-d5 were chosen as IS for positive and negative ionization mode, respectively. All statins and metabolites fulfilled the validation acceptance criteria except for fluvastatin, which could not be quantified reliably and reproducibly, most probably due to instability. Analyses of human plasma samples revealed concentrations of statins and metabolites below the reference plasma concentrations in the case of eight patients. However, nothing was known concerning patients' adherence and time between intake and sampling. Conclusions An LC-HRMS/MS method for identification and quantification of atorvastatin, lovastatin, pitavastatin, pravastatin, rosuvastatin, simvastatin and four active metabolites was successfully developed and applicability demonstrated.
Assuntos
Cromatografia Líquida de Alta Pressão/métodos , Monitoramento de Medicamentos/métodos , Inibidores de Hidroximetilglutaril-CoA Redutases/sangue , Adesão à Medicação , Espectrometria de Massas em Tandem/métodos , Atorvastatina/sangue , Atorvastatina/metabolismo , Atorvastatina/normas , Atorvastatina/uso terapêutico , Doenças Cardiovasculares/tratamento farmacológico , Cromatografia Líquida de Alta Pressão/normas , Guias como Assunto , Humanos , Inibidores de Hidroximetilglutaril-CoA Redutases/metabolismo , Inibidores de Hidroximetilglutaril-CoA Redutases/normas , Inibidores de Hidroximetilglutaril-CoA Redutases/uso terapêutico , Limite de Detecção , Lovastatina/sangue , Lovastatina/metabolismo , Lovastatina/normas , Lovastatina/uso terapêutico , Pravastatina/sangue , Pravastatina/normas , Pravastatina/uso terapêutico , Controle de Qualidade , Padrões de Referência , Espectrometria de Massas em Tandem/normasRESUMO
AIMS: Objective methods to monitor statin adherence are needed. We have established a liquid chromatography-tandem mass spectrometry assay for quantification of atorvastatin and its metabolites in blood. This study aimed to develop an objective drug exposure variable with cut-off values to discriminate among adherence, partial adherence and nonadherence to atorvastatin therapy in patients with coronary heart disease. METHODS: Twenty-five patients treated with atorvastatin 10 mg (n = 5), 20 mg (n = 6), 40 mg (n = 7) and 80 mg (n = 7) participated in a directly observed atorvastatin therapy study to confirm baseline adherence. After the directly observed therapy, half of the patients (test group) were instructed to stop taking atorvastatin and return for blood sample collection the subsequent 3 days. Levels of atorvastatin and metabolites were compared between the test group and the adherent control group. RESULTS: The sum of parent drug and all measured primary metabolites correlated well with the atorvastatin dose administered (Spearman's rho = 0.71, 95% CI 0.44-0.87). The dose-normalized atorvastatin plus metabolites concentrations completely separated the partially adherent test group from the controls at 0.18 nM/mg after 3 days without atorvastatin. To reduce the risk of misinterpreting adherent patients as partially adherent, a corresponding cut-off at 0.10 nM/mg is proposed. A metabolite level of 2-OH atorvastatin acid <0.014 nmol/L provided the optimal cut-off for nonadherence. CONCLUSION: A direct method to discriminate among adherence, partial adherence and nonadherence to atorvastatin therapy in patients with coronary heart disease has been developed. This tool may be important for novel studies on adherence and potentially useful in clinical practice.
Assuntos
Anticolesterolemiantes/sangue , Atorvastatina/sangue , Doença das Coronárias/sangue , Terapia Diretamente Observada/métodos , Adesão à Medicação , Idoso , Anticolesterolemiantes/administração & dosagem , Anticolesterolemiantes/metabolismo , Anticolesterolemiantes/uso terapêutico , Atorvastatina/administração & dosagem , Atorvastatina/metabolismo , Atorvastatina/uso terapêutico , Cromatografia Líquida , Doença das Coronárias/prevenção & controle , Relação Dose-Resposta a Droga , Feminino , Humanos , Masculino , Espectrometria de Massas em TandemRESUMO
Atorvastatin and its lactone form metabolite are reported to be associated with statin-induced myopathy (SIM) such as myalgia and life-threatening rhabdomyolysis. Though the statin-induced rhabdomyolysis is not common during statin therapy, its incidence will significantly increase due to pharmacokinetic drug-drug interactions (DDIs) with inhibitor drugs which inhibit atorvastatin's and its lactone's metabolism and hepatic uptake. Thus, the quantitative analysis of DDIs of atorvastatin and its lactone with cytochrome P450 3A4 (CYP3A4) and organic anion-transporting polypeptide (OATP) inhibitors is of great importance. This study aimed to predict pharmacokinetic DDIs possibly causing atorvastatin-induced rhabdomyolysis using Physiologically Based Pharmacokinetic (PBPK) Modelling. Firstly, we refined the PBPK models of atorvastatin and atorvastatin lactone for predicting the DDIs with CYP3A4 and OATP inhibitors. Thereafter, we predicted the exposure changes of atorvastatin and atorvastatin lactone originating from the case reports of atorvastatin-induced rhabdomyolysis using the refined models. The simulation results show that pharmacokinetic DDIs of atorvastatin and its lactone with fluconazole, palbociclib diltiazem and cyclosporine are significant. Consequently, clinicians should be aware of necessary dose adjustment of atorvastatin being used with these four inhibitor drugs.
Assuntos
Atorvastatina/efeitos adversos , Atorvastatina/farmacocinética , Modelos Biológicos , Rabdomiólise/induzido quimicamente , Idoso , Atorvastatina/sangue , Atorvastatina/química , Simulação por Computador , Interações Medicamentosas , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Músculos/efeitos dos fármacos , Músculos/patologiaRESUMO
Atorvastatin (ATV) and its two active metabolites, o-hydroxy atorvastatin acid (o-OH-ATV) and p-hydroxy atorvastatin acid (p-OH-ATV) are responsible for its HMG-CoA (3-hydroxy-3-methylglutaryl-coenzyme-A) reductase inhibitory activity, while its corresponding inactive lactone forms (LAC) are related to the manifestation of myopathy. The present study reports the development and validation of a method for the simultaneous analysis of ATV and its five metabolites (o-OH-ATV, p-OH-ATV, ATV-LAC, o-OH-ATV-LAC, p-OH-ATV-LAC) as total plasma concentration and ATV as unbound plasma concentration using UPLC-MS/MS. The method was applied in a pharmacokinetic study following administration of a single oral 20, 40 or 80â¯mg ATV dose in healthy volunteers (nâ¯=â¯15). ATV and its five metabolites were separated on a C18 column using as mobile phase a mixture of 0.2% formic acid and acetonitrile (55:45, v/v) at a flow of 0.4â¯mL/min. The method showed linearity from 25â¯pg/mL to 200â¯ng/mL plasma as total concentration and from 6.25â¯pg to 25â¯ng/mL plasma ultrafiltrate as ATV unbound concentration. The coefficients of variation and the relative standard errors of the accuracy and precision analyses were <15%. The method allowed quantification of plasma concentrations of ATV and its five metabolites up to 36â¯h after 20, 40 or 80â¯mg ATV administration. The pharmacokinetic parameters dose normalized to 20â¯mg are presented as follow (nâ¯=â¯15, mean): unbound fraction 9.38%, maximum plasma concentration 9.52â¯ng/mL, time to reach maximum plasma concentration 0.98â¯h, apparent total clearance 742.90â¯L/h, apparent distribution volume 9005â¯L, and AUC metabolite/ATV ratios 0.06 for p-OH-ATV, 0.94 for o-OH-ATV, 1.43 for ATV-LAC, 0.25 for p-OH-ATV-LAC and 1.75 for o-OH-ATV-LAC. In conclusion, the methods for simultaneous analysis of ATV and its five metabolites as total plasma concentration and ATV as the unbound plasma concentration showed sensitivity, linearity, precision and accuracy compatible with application in pharmacokinetic studies of single oral dose of 20, 40 or 80â¯mg ATV.
Assuntos
Atorvastatina/sangue , Atorvastatina/farmacocinética , Cromatografia Líquida de Alta Pressão/métodos , Espectrometria de Massas em Tandem/métodos , Administração Oral , Atorvastatina/administração & dosagem , Atorvastatina/metabolismo , Humanos , Modelos Lineares , Reprodutibilidade dos Testes , Sensibilidade e EspecificidadeRESUMO
AIM: The PLANET trials showed that atorvastatin 80 mg but not rosuvastatin at either 10 or 40 mg reduced urinary protein to creatinine ratio (UPCR) at similar effects on LDL-cholesterol. However, individual changes in both UPCR and LDL-cholesterol during treatment with these statins varied widely between patients. This inter-individual variability could not be explained by patients' physical or biochemical characteristics. We assessed whether the plasma concentrations of both statins were associated with LDL-cholesterol and UPCR response. MATERIALS AND METHODS: The PLANET trials randomized patients with a UPCR of 500-5000 mg/g and fasting LDL-cholesterol >2.33 mmol/L to a 52-week treatment with atorvastatin 80 mg, rosuvastatin 10 mg or 40 mg. For the current analysis, patients with available samples at week 52 and treatment compliance >80% by pill count were included (N = 295). The main outcome measurements were percentage change in UPCR and absolute change in LDL-cholesterol (delta LDL) from baseline to week 52. RESULTS: Median (interquartile range) plasma concentration at week 52 for atorvastatin 80 mg was 3.9 ng/mL (IQR: 2.1 to 8.7), for rosuvastatin 10 mg 1.0 ng/mL (IQR: 0.7 to 2.0) and for rosuvastatin 40 mg 3.5 ng/mL (IQR: 2.0 to 6.8). Higher plasma concentration of statin was associated with larger LDL-cholesterol reductions at week 52 [rosuvastatin r = -0.40 (P < .001); atorvastatin r = -0.28 (P = .006)]. The plasma concentration of both statins did not correlate with UPCR change [rosuvastatin r = 0.07 (P = .30); atorvastatin r = 0.16 (P = .13)]. CONCLUSIONS: Individual variation in plasma concentrations of rosuvastatin and atorvastatin was associated with LDL-cholesterol changes in patients. The individual variation in UPCR change was not associated with the plasma concentration of both statins.
Assuntos
Anticolesterolemiantes , Atorvastatina , LDL-Colesterol/sangue , Proteinúria , Rosuvastatina Cálcica , Adulto , Idoso , Anticolesterolemiantes/administração & dosagem , Anticolesterolemiantes/efeitos adversos , Anticolesterolemiantes/sangue , Anticolesterolemiantes/uso terapêutico , Atorvastatina/administração & dosagem , Atorvastatina/efeitos adversos , Atorvastatina/sangue , Atorvastatina/uso terapêutico , Creatinina/urina , Complicações do Diabetes/tratamento farmacológico , Feminino , Humanos , Testes de Função Renal , Masculino , Pessoa de Meia-Idade , Proteinúria/epidemiologia , Insuficiência Renal Crônica , Rosuvastatina Cálcica/administração & dosagem , Rosuvastatina Cálcica/efeitos adversos , Rosuvastatina Cálcica/sangue , Rosuvastatina Cálcica/uso terapêuticoRESUMO
Thanks to highly active antiretroviral treatments, HIV infection is now considered as a chronic condition. Consequently, people living with HIV (PLWH) live longer and encounter more age-related chronic co-morbidities, notably cardiovascular diseases, leading to polypharmacy. As the management of drug-drug interactions (DDIs) constitutes a key aspect of the care of PLWH, the magnitude of pharmacokinetic DDIs between cardiovascular and anti-HIV drugs needs to be more thoroughly characterized. To that endeavour, an UHPLC-MS/MS bioanalytical method has been developed for the simultaneous determination in human plasma of amlodipine, metoprolol, pravastatin, rosuvastatin, atorvastatin and its active metabolites. Plasma samples were subjected to protein precipitation with methanol, followed by evaporation at room temperature under nitrogen of the supernatant, allowing to attain measurable plasma concentrations down to sub-nanogram per milliliter levels. Stable isotope-labelled analytes were used as internal standards. The five drugs and two metabolites were analyzed using a 6-min liquid chromatographic run coupled to electrospray triple quadrupole mass spectrometry detection. The method was validated over the clinically relevant concentrations ranging from 0.3 to 480 ng/mL for amlodipine, atorvastatin and p-OH-atorvastatin, and 0.4 to 480 ng/mL for pravastatin, 0.5 to 480 ng/mL for rosuvastatin and o-OH-atorvastatin, and 3 to 4800 ng/mL for metoprolol. Validation performances such as trueness (95.4-110.8%), repeatability (1.5-13.4%) and intermediate precision (3.6-14.5%) were in agreement with current international recommendations. Accuracy profiles (total error approach) were lying within the limits of ±30% accepted in bioanalysis. This rapid and robust UHPLC-MS/MS assay allows the simultaneous quantification in plasma of the major currently used cardiovascular drugs and offers an efficient analytical tool for clinical pharmacokinetics as well as DDIs studies.