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1.
Xenobiotica ; 51(1): 105-114, 2021 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-32820679

RESUMO

Mycophenolic acid (MPA) has become a cornerstone of immunosuppressive therapy, in particular for transplant patients. In the gastrointestinal tract, the liver and the kidney, MPA is mainly metabolized into phenyl-ß-d glucuronide (MPAG). Knowledge about the interactions between MPA/MPAG and membrane transporters is still fragmented. The aim of the present study was to explore these interactions with the basolateral hepatic MRP4 transporter. The inhibition of the MRP4-driven transport by various drugs which can be concomitantly prescribed was also evaluated. In vitro experiments using vesicles overexpressing MRP4 showed an ATP-dependent transport of MPAG driven by MRP4 (Michaelis-Menten constant of 233.9 ± 32.8 µM). MPA was not effluxed by MRP4. MRP4-mediated transport of MPAG was inhibited (from -43% to -84%) by ibuprofen, cefazolin, cefotaxime and micafungin. An in silico approach based on molecular docking and molecular dynamics simulations rationalized the mode of binding of MPAG to MRP4. The presence of the glucuronide moiety in MPAG was highlighted as key, being prone to make electrostatic and H-bond interactions with specific residues of the MRP4 protein chamber. This explains why MPAG is a substrate of MRP4 whereas MPA is not.


Assuntos
Glucuronídeos/metabolismo , Proteínas Associadas à Resistência a Múltiplos Medicamentos/metabolismo , Ácido Micofenólico/análogos & derivados , Transporte Biológico , Hepatócitos/metabolismo , Humanos , Rim/metabolismo , Fígado/metabolismo , Proteínas de Membrana Transportadoras/metabolismo , Simulação de Acoplamento Molecular , Ácido Micofenólico/metabolismo
2.
Nat Prod Res ; 34(9): 1206-1212, 2020 May.
Artigo em Inglês | MEDLINE | ID: mdl-30760051

RESUMO

Mycophenolic acid (MPA) is a group of metabolite derived from several species of Penicillium, which shows potent bioactivity. In this study, a new derivative of MPA compound named penicacid D (1), was isolated from the marine derived fungus Penicillium sp. SCSIO sof101, along with seven known compounds (2-8). Their structures were elucidated based on the HR-ESI-MS and NMR data. Moreover, the 1H and 13C NMR data of compound 2 and the 13C NMR data of compound 3 are reported. Compounds 1, 4 and 6 exhibited weak activities against Escherichia coli (clinical isolation number 100385570) and Acinetobacter baumannii (clinical isolation number 100069).


Assuntos
Ácido Micofenólico/isolamento & purificação , Penicillium/química , Acinetobacter baumannii/efeitos dos fármacos , Antibacterianos/isolamento & purificação , Antibacterianos/farmacologia , Escherichia coli/efeitos dos fármacos , Fungos/química , Estrutura Molecular , Ácido Micofenólico/análogos & derivados , Ácido Micofenólico/química , Ácido Micofenólico/farmacologia , Análise Espectral/métodos
3.
Biopharm Drug Dispos ; 40(9): 325-340, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31674040

RESUMO

BACKGROUND: Mycophenolic acid (MPA) is used widely to prevent graft rejection in kidney-transplant patients. Therapeutic drug monitoring (TDM) in plasma requires an invasive procedure that is inconvenient, especially in pediatric patients. TDM in saliva is a more convenient non-invasive alternative compared with plasma. METHODS: A population physiologically based pharmacokinetic (Pop-PBPK) model of mycophenolate mofetil (MMF) and MPA with enterohepatic recycling was built and verified using previously published plasma, saliva, and kidney biopsy data in healthy and kidney-transplant adult patients. The verified model was then used to predict experimentally observed plasma and saliva MMF and MPA TDM data in Jordanian pediatric kidney transplant patients measured using LC-MS/MS. A correlation was established between plasma and saliva exposures in pediatrics. RESULTS: The developed LCMS was sensitive to both MMF and MPA in plasma and saliva. The developed Pop-PBPK model predicted well the previously reported MMF and MPA levels in plasma, saliva, and kidney tissue and those observed in the current study (more than 75% of observed data points were within 90% predictive interval of population simulations). A statistically significant correlation was found between plasma and saliva exposures for both MMF (Pop-PBPK predicted and observed) and MPA (Pop-PBPK predicted). CONCLUSION: Both MPA and MMF can be classified as class III compounds in the Salivary Excretion Classification System. Saliva is an alternative body fluid to plasma that can be used for TDM of MPA and MMF in kidney-transplant patients in pediatrics. Exposure to MPA and MMF in plasma, saliva, and kidney tissue was reliably predicted using the developed Pop-PBPK model.


Assuntos
Rim/metabolismo , Ácido Micofenólico/sangue , Ácido Micofenólico/farmacocinética , Saliva/metabolismo , Adolescente , Antibióticos Antineoplásicos/farmacocinética , Criança , Pré-Escolar , Monitoramento de Medicamentos/métodos , Feminino , Humanos , Transplante de Rim/métodos , Masculino , Modelos Biológicos , Ácido Micofenólico/análogos & derivados
4.
J Pharm Pharm Sci ; 22(1): 407-417, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31430249

RESUMO

PURPOSE: The dose of mycophenolate mofetil (MMF) used to prevent rejection after lung transplantation is often adjusted based on the 12-hour area under the concentration-time curve (AUC0-12) of mycophenolic acid (MPA). A limited sampling strategy (LSS) is useful to define the pharmacokinetic (PK) profiles of MPA and mycophenolic acid acyl glucuronide (AcMPAG). Therefore, this study aimed to design a LSS based on multiple linear regression for estimating the AUC0-12 of MPA and AcMPAG at the minimum blood sampling points in Japanese lung transplant patients with concomitant tacrolimus. METHODS: Forty-five lung transplantation recipients were enrolled in a PK study of MPA, mycophenolic acid glucuronide (MPAG), and AcMPAG. The plasma MPA, MPAG, and AcMPAG concentrations were determined just before and at 0.5, 1, 2, 4, 8, and 12 hours after dosing. The AUC0-12 of MPA and AcMPAG was calculated using a linear trapezoidal rule from the plasma concentration of each blood sampling time. LSS was used to develop models for estimated AUC in the model group (n = 23) and was evaluated in the validation group (n = 22). RESULTS: The best three time-point equation was 4.04 + 1.64·C1 + 3.08·C4 + 5.17·C8 for MPA, and -0.13 + 3.01·C1 + 3.51·C4 + 5.74·C8 for AcMPAG. The prediction errors (PE) and the absolute prediction errors (APE) were within the clinically acceptable ± 5% and 15% range, respectively (MPA: PE = 2.00%, APE = 11.66%, AcMPAG: PE = 0.98%, APE = 14.69%). The percentage of estimated AUC0-12 within ± 15% of the observed AUC0-12 was 77.27% for MPA and 81.82% for AcMPAG. CONCLUSION: LSS using three time-point (C1, C4, and C8) provides the most reliable and accurate simultaneous estimation of the AUC0-12 of MPA and AcMPAG in Japanese lung transplant patients.


Assuntos
Rejeição de Enxerto/prevenção & controle , Transplante de Rim/efeitos adversos , Ácido Micofenólico/análise , Transplantados , Adulto , Feminino , Humanos , Japão , Masculino , Ácido Micofenólico/análogos & derivados , Ácido Micofenólico/metabolismo , Estudos Prospectivos , Fatores de Tempo
5.
J Vet Intern Med ; 33(5): 2020-2028, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31423655

RESUMO

BACKGROUND: Mycophenolate mofetil (MMF) is an immunosuppressant used in human and veterinary medicine. Little pharmacokinetic and pharmacodynamic information on MMF is available in cats. OBJECTIVE: To evaluate the plasma disposition of mycophenolic acid (MPA) and assess its effect on total peripheral blood mononuclear cells and CD4+ /CD8+ ratios after PO administration of MMF. ANIMALS: Healthy cats (n = 10). METHODS: Mycophenolate mofetil was administered at a dosage of 10 mg/kg q12h (n = 3), 15 mg/kg q12h (n = 3), and 15 mg/kg q8h (n = 4) for 7 days. Concentrations of MPA and derivatives were determined using ultra-high-performance liquid chromatography. Flow cytometry was used to assess CD4+ /CD8+ T-cell ratios. RESULTS: All cats biotransformed MMF into MPA. Half of the cats (5/10) had adverse effects within 1 week of MMF administration. Area under the curve limit of quantification (AUC0-LOQh ) of MPA ranged from 1.27 to 2.03 hours·µg/mL and from 1.77 to 8.54 hours·µg/mL after the first and last PO dose of 10 mg/kg. The AUC0-loqh of MPA ranged from 2.18 to 31 hours·µg/mL after the first dose of 15 mg/kg of MMF. Before the first dose of MMF, the average total number of PBMC ranged from 1.2 to 9.3 million/mL. At the last dose of MMF, the average total number of PBMC ranged from 3 to 5 million/mL. CONCLUSION: Mycophenolic acid was detected in all cats. The dose 10 mg/kg given q12h for 1 week was tolerated (n = 3). The efficacy of MMF as an immunosuppressant and long-term safety in cats of this dosage regimen is unknown.


Assuntos
Gatos , Imunossupressores/farmacocinética , Leucócitos Mononucleares/efeitos dos fármacos , Ácido Micofenólico/análogos & derivados , Ácido Micofenólico/farmacocinética , Administração Oral , Animais , Área Sob a Curva , Linfócitos T CD4-Positivos , Linfócitos T CD8-Positivos , Imunossupressores/administração & dosagem , Imunossupressores/efeitos adversos , Ácido Micofenólico/efeitos adversos
6.
J Sep Sci ; 42(16): 2650-2659, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31197944

RESUMO

Mycophenolate mofetil is an antiproliferative immunosuppressive agent. Since its clinical efficacy and safety highly depend on the quality, the stability, and impurity profiles of mycophenolate mofetil are paid ever-increasing attention. However, there are few published studies reporting the complete characterization of both the process-related substances and degradation products in mycophenolate mofetil. In the present study, a highly specific and efficient liquid chromatography coupled with quadrupole-time of flight mass spectrometry method was developed for the separation and identification of all the potential impurities in mycophenolate mofetil. According to the ICH Q1A (R2) guideline, the forced degradation studies were conducted to elucidate the stability and degradation pathways of mycophenolate mofetil. A total of 15 related substances, including the process-related substances and stress degradation products were characterized by the established hyphenated method, 11 of them have not been reported before. In view of the synthetic route and degradation pathways of mycophenolate mofetil, the origins and formation mechanisms of these related substances were discussed. Based on the obtained stability and impurity profiles, key points of the manufacturing process were proposed to deliver mycophenolate mofetil with high purity.


Assuntos
Ácido Micofenólico/isolamento & purificação , Cromatografia Líquida , Espectrometria de Massas , Estrutura Molecular , Ácido Micofenólico/análogos & derivados , Ácido Micofenólico/química , Fatores de Tempo
7.
Eur J Clin Pharmacol ; 75(4): 553-559, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30610275

RESUMO

PURPOSE: Mycophenolic acid is one of the most used immunosuppressive drugs in solid organ transplant treatments in the world. Developing a highly sensitive analytical method to analyse the drug and its metabolites in oral fluid and plasma is important to evaluate the possibility of using oral fluid as a biological matrix in therapeutic drug monitoring, instead of plasma. METHOD: The liquid chromatography coupled to mass spectrometry (LC-MS) method was developed and validated for determining mycophenolic acid (MPA) and its glucuronide metabolite (MPAG) in oral fluid and plasma, with both matrices presenting a detection limit of 1 ng/mL for MPA and 5 ng/mL for MPAG. Both analytes were analysed after a simple protein precipitation procedure. Transplanted-kidney samples of oral fluid and blood were collected from 13 patients that were hospitalised and kept at - 80 °C until analyses. RESULTS: The proposed method was linear in the concentration range of 5-500 ng/mL for MPA and 10-500 ng/mL for MPAG, with correlation coefficients (r) between 0.9925 and 0.9973. It was then applied to samples collected from kidney-transplanted patients and used for calculation of pharmacokinetics parameters. CONCLUSION: After comparing plasma and oral fluid concentrations as well as performing a non-compartmental pharmacokinetic analysis of the average curves, it is possible to suggest that oral fluid concentration may be used as an alternative for MPA and MPAG monitoring in kidney transplant patients.


Assuntos
Glucuronídeos/metabolismo , Transplante de Rim , Ácido Micofenólico/análogos & derivados , Ácido Micofenólico/farmacocinética , Saliva/metabolismo , Cromatografia Líquida/métodos , Glucuronídeos/análise , Glucuronídeos/sangue , Glucuronídeos/farmacocinética , Humanos , Ácido Micofenólico/análise , Ácido Micofenólico/sangue , Espectrometria de Massas em Tandem/métodos
8.
J Asian Nat Prod Res ; 21(2): 178-185, 2019 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-29607657

RESUMO

New conjugates of mycophenolic acid (MPA) and adenosine derivatives were synthesized and assessed as potential immunosuppressants on Jurkat cell line and peripheral blood mononuclear cells (PBMC) from healthy donors. As compared to MPA, all compounds were found to be more active against Jurkat cell line. The antiproliferative activities were compared with MPA and adenosine, in both 2',3'-O-isopropylidene protected and free hydroxyl groups possessing forms. The obtained results were also discussed in terms of selectivity index, defined as SI = IC50/EC50.


Assuntos
Adenosina/análogos & derivados , Adenosina/síntese química , Imunossupressores/síntese química , Imunossupressores/farmacologia , Ácido Micofenólico/análogos & derivados , Ácido Micofenólico/síntese química , Adenosina/química , Adenosina/farmacologia , Proliferação de Células/efeitos dos fármacos , Humanos , Células Jurkat , Ácido Micofenólico/química , Ácido Micofenólico/farmacologia
9.
Am J Vet Res ; 79(10): 1093-1099, 2018 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-30256137

RESUMO

OBJECTIVE To evaluate the plasma disposition of mycophenolic acid (MPA) and its derivatives MPA glucuronide and MPA glucoside after twice-daily infusions of mycophenolate mofetil (MMF) in healthy cats for 3 days and to assess the effect of MMF administration on peripheral blood mononuclear cell (PBMC) counts and CD4+-to-CD8+ ratios. ANIMALS 5 healthy adult cats. PROCEDURES MMF was administered to each cat (10 mg/kg, IV, q 12 h for 3 days). Each dose of MMF was diluted with 5% dextrose in water and then administered over a 2-hour period with a syringe pump. Blood samples were collected for analysis. A chromatographic method was used to quantitate concentrations of MPA and its metabolites. Effects of MMF on PBMC counts and CD4+-to-CD8+ ratios were assessed by use of flow cytometry. RESULTS All cats biotransformed MMF into MPA. The MPA area under the plasma concentration-time curve from 0 to 14 hours ranged from 14.6 to 37.6 mg·h/L and from 14.4 to 22.3 mg·h/L after the first and last infusion, respectively. Total number of PBMCs was reduced in 4 of 5 cats (mean ± SD reduction, 25.9 ± 15.8% and 26.7 ± 19.3%) at 24 and 48 hours after the end of the first infusion of MMF, respectively. CONCLUSIONS AND CLINICAL RELEVANCE Plasma disposition of MPA after twice-daily IV infusions for 3 days was variable in all cats. There were no remarkable changes in PBMC counts and CD4+-to-CD8+ ratios.


Assuntos
Gatos/metabolismo , Imunossupressores/farmacologia , Imunossupressores/farmacocinética , Leucócitos Mononucleares/efeitos dos fármacos , Ácido Micofenólico/farmacologia , Ácido Micofenólico/farmacocinética , Animais , Área Sob a Curva , Gatos/sangue , Esquema de Medicação/veterinária , Feminino , Citometria de Fluxo/veterinária , Glucuronídeos/sangue , Imunossupressores/administração & dosagem , Infusões Intravenosas/veterinária , Masculino , Ácido Micofenólico/administração & dosagem , Ácido Micofenólico/análogos & derivados , Ácido Micofenólico/sangue
11.
Mar Drugs ; 16(7)2018 Jul 07.
Artigo em Inglês | MEDLINE | ID: mdl-29986508

RESUMO

Mycophenolic acid (MPA) is a potent inosine-5′-monophosphate dehydrogenase (IMPDH) inhibitor for immunosuppressive chemotherapy. Most importantly, as the 2-morpholinoethyl ester prodrug of MPA, mycophenolate mofetil (MMF) is a well-known immunosuppressant used to prevent rejection in organ transplantations. Nevertheless, due to its frequently occurred side effects, searching for new therapeutic agents is ongoing. In our current work, by virtue of efficient bioassay-guided fractionation and purification, eleven mycophenolic acid derivatives, including five previously unreported metabolites (3⁻7) and six known compounds (1, 2, and 8⁻11), were obtained from the coral-derived fungus Penicillium bialowiezense. Their structures were elucidated by means of extensive spectroscopic analyses (including 1D and 2D NMR and HRESIMS data) and comparison of the NMR and other physical data with those reported in the literature in the case of the known compounds. All the isolates 1⁻11 were evaluated for the immunosuppressive activity, and 1⁻3 showed potent IMPDH2 inhibitory potency with IC50 values of 0.84⁻0.95 μM, which were comparable to that of MPA (the positive control), while 4⁻10 showed significant inhibitory potency with IC50 values of 3.27⁻24.68 μM. All the MPA derivatives showed promising immunosuppressive activity, endowing them as potential drug leads for organ transplantations and autoimmune related diseases.


Assuntos
Antozoários/microbiologia , Inibidores Enzimáticos/farmacologia , IMP Desidrogenase/antagonistas & inibidores , Imunossupressores/farmacologia , Ácido Micofenólico/farmacologia , Penicillium/química , Animais , Ensaios Enzimáticos , Inibidores Enzimáticos/química , Inibidores Enzimáticos/isolamento & purificação , Humanos , Imunossupressores/química , Imunossupressores/isolamento & purificação , Concentração Inibidora 50 , Espectroscopia de Ressonância Magnética , Camundongos , Camundongos Endogâmicos BALB C , Simulação de Acoplamento Molecular , Ácido Micofenólico/análogos & derivados , Ácido Micofenólico/química , Ácido Micofenólico/isolamento & purificação , Cultura Primária de Células , Baço/citologia , Linfócitos T/efeitos dos fármacos
12.
Cochrane Database Syst Rev ; 6: CD002922, 2018 06 29.
Artigo em Inglês | MEDLINE | ID: mdl-29957821

RESUMO

BACKGROUND: Cyclophosphamide, in combination with corticosteroids, has been first-line treatment for inducing disease remission for proliferative lupus nephritis, reducing death at five years from over 50% in the 1950s and 1960s to less than 10% in recent years. Several treatment strategies designed to improve remission rates and minimise toxicity have become available. Treatments, including mycophenolate mofetil (MMF) and calcineurin inhibitors, alone and in combination, may have equivalent or improved rates of remission, lower toxicity (less alopecia and ovarian failure) and uncertain effects on death, end-stage kidney disease (ESKD) and infection. This is an update of a Cochrane review first published in 2004 and updated in 2012. OBJECTIVES: Our objective was to assess the evidence and evaluate the benefits and harms of different immunosuppressive treatments in people with biopsy-proven lupus nephritis. The following questions relating to management of proliferative lupus nephritis were addressed: 1) Are new immunosuppressive agents superior to or as effective as cyclophosphamide plus corticosteroids? 2) Which agents, dosages, routes of administration and duration of therapy should be used? 3) Which toxicities occur with the different treatment regimens? SEARCH METHODS: We searched the Cochrane Kidney and Transplant Specialised Register up to 2 March 2018 with support from the Cochrane Information Specialist using search terms relevant to this review. Studies in the Specialised Register are identified through searches of CENTRAL, MEDLINE, and EMBASE, conference proceedings, the International Clinical Trials Register (ICTRP) Search Portal and ClinicalTrials.gov. SELECTION CRITERIA: Randomised controlled trials (RCTs) and quasi-RCTs comparing any immunosuppressive treatment for biopsy-proven class III, IV, V+III and V+VI lupus nephritis in adult or paediatric patients were included. DATA COLLECTION AND ANALYSIS: Data were abstracted and the risks of bias were assessed independently by two authors. Dichotomous outcomes were calculated as risk ratio (RR) and measures on continuous scales calculated as mean differences (MD) with 95% confidence intervals (CI). The primary outcomes were death (all causes) and complete disease remission for induction therapy and disease relapse for maintenance therapy. Evidence certainty was determined using GRADE. MAIN RESULTS: In this review update, 26 new studies were identified, to include 74 studies involving 5175 participants overall. Twenty-nine studies included children under the age of 18 years with lupus nephritis, however only two studies exclusively examined the treatment of lupus nephritis in patients less than 18 years of age.Induction therapy Sixty-seven studies (4791 participants; median 12 months duration (range 2.5 to 48 months)) reported induction therapy. The effects of all treatment strategies on death (all causes) and ESKD were uncertain (very low certainty evidence) as this outcome occurred very infrequently. Compared with intravenous (IV) cyclophosphamide, MMF may have increased complete disease remission (RR 1.17, 95% CI 0.97 to 1.42; low certainty evidence), although the range of effects includes the possibility of little or no difference.Compared to IV cyclophosphamide, MMF is probably associated with decreased alopecia (RR 0.29, 95% CI 0.19 to 0.46; 170 less (129 less to 194 less) per 1000 people) (moderate certainty evidence), increased diarrhoea (RR 2.42, 95% CI 1.64 to 3.58; 142 more (64 more to 257 more) per 1000 people) (moderate certainty evidence) and may have made little or no difference to major infection (RR 1.02, 95% CI 0.67 to 1.54; 2 less (38 less to 62 more) per 1000 people) (low certainty evidence). It is uncertain if MMF decreased ovarian failure compared to IV cyclophosphamide because the certainty of the evidence was very low (RR 0.36, 95% CI 0.06 to 2.18; 26 less (39 less to 49 more) per 1000 people). Studies were not generally designed to measure ESKD.MMF combined with tacrolimus may have increased complete disease remission (RR 2.38, 95% CI 1.07 to 5.30; 336 more (17 to 1048 more) per 1000 people (low certainty evidence) compared with IV cyclophosphamide, however the effects on alopecia, diarrhoea, ovarian failure, and major infection remain uncertain. Compared to standard of care, the effects of biologics on most outcomes were uncertain because of low to very low certainty of evidence.Maintenance therapyNine studies (767 participants; median 30 months duration (range 6 to 63 months)) reported maintenance therapy. In maintenance therapy, disease relapse is probably increased with azathioprine compared with MMF (RR 1.75, 95% CI 1.20 to 2.55; 114 more (30 to 236 more) per 1000 people (moderate certainty evidence). Multiple other interventions were compared as maintenance therapy, but patient-outcome data were sparse leading to imprecise estimates. AUTHORS' CONCLUSIONS: In this review update, studies assessing treatment for proliferative lupus nephritis were not designed to assess death (all causes) or ESKD. MMF may lead to increased complete disease remission compared with IV cyclophosphamide, with an acceptable adverse event profile, although evidence certainty was low and included the possibility of no difference. Calcineurin combined with lower dose MMF may improve induction of disease remission compared with IV cyclophosphamide, but the comparative safety profile of these therapies is uncertain. Azathioprine may increase disease relapse as maintenance therapy compared with MMF.


Assuntos
Ciclofosfamida/uso terapêutico , Imunossupressores/uso terapêutico , Nefrite Lúpica/tratamento farmacológico , Ácido Micofenólico/análogos & derivados , Adulto , Azatioprina/efeitos adversos , Azatioprina/uso terapêutico , Calcineurina/uso terapêutico , Criança , Ciclofosfamida/efeitos adversos , Feminino , Glucocorticoides/efeitos adversos , Glucocorticoides/uso terapêutico , Humanos , Imunossupressores/efeitos adversos , Quimioterapia de Indução/métodos , Quimioterapia de Manutenção/métodos , Masculino , Ácido Micofenólico/uso terapêutico , Ensaios Clínicos Controlados Aleatórios como Assunto , Recidiva , Tacrolimo/efeitos adversos , Tacrolimo/uso terapêutico
13.
Ther Drug Monit ; 40(5): 572-580, 2018 10.
Artigo em Inglês | MEDLINE | ID: mdl-29847459

RESUMO

BACKGROUND: The aim of this study was to characterize the pharmacokinetics of mycophenolic acid (MPA) and MPA glucuronide (MPAG) in Chinese renal transplant patients taking enteric-coated mycophenolate sodium (EC-MPS). Limited sampling strategies (LSSs) were developed to estimate the area under the concentration curve from 0 to 12 hours (AUC0-12h) of total and free MPA. Another objective was to investigate the correlation between high-performance liquid chromatography (HPLC) and enzyme-multiplied immunoassay technology (EMIT) for total MPA determination. METHODS: Serial blood samples were collected over 12 hours from 15 patients who were administered multiple doses of EC-MPS. LSS was developed by multiple stepwise regression analysis. Measurement by HPLC and EMIT was compared using Passing-Bablok regression and Bland-Altman analysis. RESULTS: Normalized to 720 mg twice daily, the AUC0-12h of total MPA and MPAG was 43.0 ± 17.4 and 653 ± 329 mg·h/L, respectively, whereas the free MPA AUC0-12h was 1.368 ± 0.988 mg·h/L. The free fraction of MPA was 3.01% ± 3.15%. The combination of C2h-C4h-C6h and C2h-C4h-C6h-C8h was found to be superior to estimate total and free MPA simultaneously. The EMIT showed an acceptable correlation with HPLC, with an AUC0-12h overestimation of 11.32% ± 15.77%. CONCLUSIONS: The pharmacokinetic profile of total and free MPA and its main metabolite MPAG was examined in Chinese adult renal transplant patients receiving EC-MPS. The use of LSS to estimate individual free and total MPA exposure could be useful in optimizing patient care.


Assuntos
Glucuronídeos/farmacocinética , Transplante de Rim , Ácido Micofenólico/análogos & derivados , Ácido Micofenólico/farmacocinética , Adolescente , Adulto , Área Sob a Curva , Grupo com Ancestrais do Continente Asiático , Cromatografia Líquida de Alta Pressão , Inibidores Enzimáticos/sangue , Inibidores Enzimáticos/farmacocinética , Técnica de Imunoensaio Enzimático de Multiplicação , Feminino , Glucuronídeos/sangue , Humanos , Masculino , Pessoa de Meia-Idade , Ácido Micofenólico/sangue , Comprimidos com Revestimento Entérico/farmacocinética , Adulto Jovem
14.
Curr Protoc Toxicol ; 75: 18.21.1-18.21.8, 2018 02 21.
Artigo em Inglês | MEDLINE | ID: mdl-29512127

RESUMO

Mycophenolic acid (MPA) is an immunosuppressant that is used in renal, liver, and heart transplantation. Due to its narrow therapeutic range, monitoring of MPA levels is essential to avoid toxicity and organ rejection. Although immunoassays are available for the determination of MPA, due to their higher specificity, mass spectrometry methods are preferred. In this unit, we describe a liquid chromatography tandem mass spectrometry (LC/MS/MS) method utilizing positive ionization electrospray and multiple reaction monitoring (MRM) for the quantification of levels of MPA and its conjugate MPA glucuronide (MPAG). Blood collected in a plain, EDTA, or heparin-containing tube is centrifuged to separate the serum or plasma. Proteins are precipitated using a solution containing zinc sulfate and acetonitrile that has been spiked with deuterated internal standards. The resulting protein-free supernatant is injected into the LC/MS/MS system for analysis. The chromatography involves the use of a C18 column and ammonium acetate/water/formic acid and ammonium acetate/methanol/formic acid mobile phases. Quantification of MPA and MPAG levels is achieved by comparing the MRM peak area ratios of analytes and internal standards, consisting of specific precursor/product pairs, with those of calibrators at various concentrations. Calibration curves are constructed from the MRM peak area ratios of calibrators and internal standards versus concentration. © 2018 by John Wiley & Sons, Inc.


Assuntos
Cromatografia Líquida/métodos , Glucuronídeos/sangue , Ácido Micofenólico/análogos & derivados , Ácido Micofenólico/sangue , Espectrometria de Massas em Tandem/métodos , Humanos
15.
J Vet Intern Med ; 31(6): 1827-1832, 2017 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-28892209

RESUMO

BACKGROUND: Mycophenolate mofetil (MMF), the prodrug of mycophenolic acid (MPA), is becoming increasingly popular as an alternative immunosuppressant in feline medicine. Pharmacokinetic information is not available for cats. OBJECTIVE: The purpose of this study was to determine whether MMF is biotransformed into the active metabolite MPA and to evaluate the disposition of MPA after a 2-hour constant rate intravenous (IV) infusion of MMF in healthy cats. ANIMALS: Healthy cats (n = 6). METHODS: This was a prospective pilot study. All cats were administered MMF at 20 mg/kg every 12 hours over a 2-hour constant rate infusion for 1 day. The concentrations of MPA and its derivatives in blood were determined using a validated UHPLC-UV method. RESULTS: All cats biotransformed MMF into MPA. The mean AUC0-14 h ranged from 6 to 50 h*mg/L after IV dosing of MMF. Transient large bowel diarrhea was recorded in 2 of 6 cats after medication administration. CONCLUSION AND CLINICAL IMPORTANCE: The disposition of MPA in plasma was highly variable, which could result in high interindividual variability in the safety and efficacy of treatment with MMF in cats.


Assuntos
Imunossupressores/farmacocinética , Ácido Micofenólico/análogos & derivados , Ácido Micofenólico/farmacocinética , Animais , Área Sob a Curva , Gatos , Diarreia/veterinária , Feminino , Imunossupressores/administração & dosagem , Infusões Intravenosas/veterinária , Masculino , Ácido Micofenólico/administração & dosagem , Projetos Piloto , Estudos Prospectivos
16.
Genet Mol Res ; 16(2)2017 May 31.
Artigo em Inglês | MEDLINE | ID: mdl-28613375

RESUMO

Mycophenolate mofetil (MMF) is a prodrug active only after its hydrolysis to mycophenolic acid (MPA). The UGT1A9 enzyme is of special interest since it is the main enzyme involved in the glucuronidation of MPA. Single nucleotide polymorphisms (SNPs) in the UGT1A9 gene may be responsible for individual differences in the pharmacokinetics of MMF. Expression levels and the activity of UGT1A9 may depend on the presence of some SNPs located in the gene promoter region (-2152C>T and -275T>A), as well as changes in the coding region (c.98T>C). The objective of this study was to evaluate the effect of allelic variants of the UGT1A9 c.98T>C polymorphism (rs72551330; g. 87289T>C) on MMF metabolism in renal transplant patients. MPA and MPA 7-O glucuronide (MPAG) levels were determined on plasma samples of kidney transplant patients (N = 39) by high-performance liquid chromatography using ultraviolet detection. DNA was isolated from leukocytes and stored at -20°C. The presence of SNPs was investigated using polymerase chain reaction, followed by amplicon sequencing. The analysis of the UGT1A9 c.98T>C polymorphism revealed that all study patients presented the TT genotype. Diverse MPA and MPAG plasma concentrations were detected, including therapeutic, subtherapeutic, and toxic levels. A standardized molecular method permitted identification of UGT1A9 c.98T>C polymorphism genotypes in the examined renal transplant patients. All individuals of the study group presented the same genotype (c.98TT) for that polymorphism. Thereby, no association between the c.98T>C polymorphism and MPA and MPAG plasma levels could be evaluated, despite different levels of these compounds being observed.


Assuntos
Glucuronídeos/sangue , Glucuronosiltransferase/genética , Rejeição de Enxerto/sangue , Transplante de Rim/efeitos adversos , Ácido Micofenólico/análogos & derivados , Polimorfismo de Nucleotídeo Único , Adulto , Feminino , Glucuronídeos/genética , Rejeição de Enxerto/genética , Humanos , Masculino , Pessoa de Meia-Idade , Ácido Micofenólico/sangue
17.
Eur J Drug Metab Pharmacokinet ; 42(6): 993-1004, 2017 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-28536776

RESUMO

BACKGROUND AND OBJECTIVE: Mycophenolic acid (MPA) provides effective treatment for lupus nephritis patients. Owing to its large pharmacokinetic variability, it is questionable whether standard fixed dose therapy can achieve optimal MPA exposure. The aim of this study was to develop a population pharmacokinetic model of MPA and its metabolite, 7-O-MPA-ß-glucuronide (MPAG), to identify important covariate influences and better predict patient dosing requirements. METHODS: MPA and MPAG concentration-time profiles were collected from 25 patients receiving mycophenolate mofetil (MMF) with or without cyclosporine (CsA) co-therapy. Samples were collected pre-dose and at 1, 2, 4, 6 and 8 h post-dose on one or two occasions. RESULTS: A total of 225 and 226 concentration-time measurements of MPA and MPAG, respectively, were used to develop the model, utilizing NONMEM® software. A two-compartment model with first-order absorption and elimination for MPA and a one-compartment model with first-order elimination and enterohepatic circulation (EHC) for MPAG best described the data. Apparent clearance of MPAG (CL/F MPAG) significantly decreased with reducing renal function and extent of EHC was reduced with concomitant CsA use. Simulations using the final model showed that a 70-kg subject with a creatinine clearance of 90 mL/min receiving concomitant CsA would require 1.25 g of MMF twice daily while a similar subject who did not receive concomitant CsA would require 0.75 g twice daily to achieve a MPA area under the concentration-time curve from 0 to 12 h (AUC0-12) of 45 mg·h/L. CONCLUSION: A 'tiered' dosing approach considering patient renal function and CsA co-therapy, rather than a 'one dose fits all' approach, would help individualize MMF therapy in adult lupus nephritis patients to ensure more patients have optimal MPA exposure.


Assuntos
Cálculos da Dosagem de Medicamento , Nefrite Lúpica/tratamento farmacológico , Ácido Micofenólico/farmacocinética , Ácido Micofenólico/uso terapêutico , Adulto , Simulação por Computador , Ciclosporina/farmacologia , Interações Medicamentosas , Feminino , Glucuronídeos/sangue , Glucuronídeos/farmacocinética , Humanos , Imunossupressores/sangue , Imunossupressores/farmacocinética , Imunossupressores/uso terapêutico , Nefrite Lúpica/sangue , Masculino , Pessoa de Meia-Idade , Modelos Biológicos , Ácido Micofenólico/análogos & derivados , Ácido Micofenólico/sangue , Adulto Jovem
18.
Transplant Proc ; 49(3): 490-496, 2017 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-28340819

RESUMO

BACKGROUND: Most patients have serious digestive complications after renal transplantation. Therefore, it is important to protect gastrointestinal function to improve the survival rate of transplant patients. Proton pump inhibitors (PPIs) such as lansoprazole and rabeprazole are widely administered to renal transplant patients with mycophenolic acid (MPA) in the perioperative period. PPIs are metabolized by cytochrome (CYP) 2C19 enzymes. Mycophenolate sodium (MYF) and mycophenolate mofetil (MMF) have been used in immunosuppression. Clinically relevant drug-drug interactions have been described between immunosuppressive drugs. In the present study, we investigated the drug interaction between MPA and lansoparazole or rabeprazole and the impact of CYP2C19 polymorphisms on these drug interactions after renal transplantation. MATERIALS AND METHODS: A total of 125 renal transplant patients taking MPA derivatives between 2012 and 2016 were included in this study. The 125 patients were divided into 6 groups: MMF/tacrolimus/steroid together with lansoprazole or rabeprazole; MYF/tacrolimus/steroid together with lansoprazole or rabeprazole and without PPI. The single nucleotide polymorphisms of CYP2C19 were determined by the polymerase chain reaction-restriction fragment length polymorphism. Plasma concentrations of MPA were measured by cloned enzyme donor immunoassay. Clinical parameters such as incidence of delayed graft function and acute rejection, the rate of change of serum creatinine, toxicity, and gastrointestinal adverse effects were analyzed retrospectively. RESULTS: The mean concentrations of MPA in the MYF group were higher than those in the MMF group. The mean dose-adjusted blood concentration of MPA coadministered with lansoprazole was lower than that of MPA with rabeprazole or without PPI in MMF and MYF groups (P < .05). In patients with the CYP2C19*2/*2 genotype, the mean concentrations of MMF with lansoprazole were significantly lower than those with rabeprazole with MMF or without PPI (P < .05). Gastrointestinal side effects were significantly higher in MMF with lansoprazole group than in MYF with lansoprazole group (P < .05). However, no differences were found according to genotype distribution in all groups (P > .05). CONCLUSION: Polymorphisms in CYP2C19 are related to the metabolic oxidation of drugs to varying degrees. Both genetic and clinical factors in pharmacokinetics may help to make further progress toward individualized therapy to yield maximum efficacy with minimal side effects.


Assuntos
Citocromo P-450 CYP2C19/genética , Imunossupressores/farmacocinética , Transplante de Rim , Ácido Micofenólico/farmacocinética , Inibidores da Bomba de Prótons/uso terapêutico , Adulto , Interações Medicamentosas , Quimioterapia Combinada , Feminino , Genótipo , Humanos , Imunossupressores/uso terapêutico , Lansoprazol/uso terapêutico , Masculino , Pessoa de Meia-Idade , Ácido Micofenólico/análogos & derivados , Ácido Micofenólico/uso terapêutico , Polimorfismo de Fragmento de Restrição , Polimorfismo de Nucleotídeo Único , Rabeprazol/uso terapêutico , Estudos Retrospectivos , Tacrolimo/uso terapêutico
19.
Mar Drugs ; 15(2)2017 Feb 17.
Artigo em Inglês | MEDLINE | ID: mdl-28218640

RESUMO

Four new compounds (1-4), including two brevianamides and two mycochromenic acid derivatives along with six known compounds were isolated from the deep-sea-derived fungus Penicillium brevicompactum DFFSCS025. Their structures were elucidated by spectroscopic analysis. Moreover, the absolute configurations of 1 and 2 were determined by quantum chemical calculations of the electronic circular dichroism (ECD) spectra. Compound 9 showed moderate cytotoxicity against human colon cancer HCT116 cell line with IC50 value of 15.6 µM. In addition, 3 and 5 had significant antifouling activity against Bugula neritina larval settlement with EC50 values of 13.7 and 22.6 µM, respectively. The NMR data of 6, 8, and 9 were assigned for the first time.


Assuntos
Antibióticos Antineoplásicos/farmacologia , Organismos Aquáticos/química , Incrustação Biológica , Alcaloides Indólicos/farmacologia , Ácido Micofenólico/análogos & derivados , Penicillium/química , Animais , Antibióticos Antineoplásicos/química , Antibióticos Antineoplásicos/isolamento & purificação , Briozoários/efeitos dos fármacos , Dicroísmo Circular , Células HCT116 , Humanos , Alcaloides Indólicos/química , Alcaloides Indólicos/isolamento & purificação , Concentração Inibidora 50 , Larva/efeitos dos fármacos , Estrutura Molecular , Ressonância Magnética Nuclear Biomolecular
20.
Int Immunopharmacol ; 44: 137-142, 2017 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-28092865

RESUMO

The main activity of mycophenolic acid 1 (MPA) and its analogs is the inhibition of proliferation of T cells. Here, we hypothesized that MPA and its conjugates inhibits also the activity of antigen-presenting cells (APC) including dendritic cells (DCs). We tested the effect of novel amino acid derivatives of MPA and conjugates of MPA with acridines/acridones on DCs by flow cytometry, ELISA and MLR assay. Both acridines/acridone derivatives could inhibit the maturation of DC, as shown by the decreased expression of B7 family receptors. It was confirmed in the mixed leucocyte reaction (MLR), in which T cells challenged with DCs pretreated with the analogs showed decreased proliferation and reduced cytokine secretion. The most interesting activity in this series of studies, that is, the suppression of CD86 receptor expression, decreased cytokine production and suppressed mixed leucocyte reaction, exhibited (mycophenoyl-N-3-propyl)-9-acridone-4-carboxamide ester 5a and (mycophenoyl-N-5-pentyl)-9-acridone-4-carboxamide ester 5b. These compounds reduced also the secretion of IL-2 and IL-15. In addition, they increased secretion of suppressive IL-10. Equally promising results were obtained for the N-mycophenoyl-D-glutamic acid 4b, which previously gave the highest value of selectivity. Acridone derivatives of MPA are therefore good immunosuppressive drug candidates for further testing.


Assuntos
Doenças Autoimunes/tratamento farmacológico , Células Dendríticas/efeitos dos fármacos , Rejeição de Enxerto/tratamento farmacológico , Imunossupressores/farmacologia , Ácido Micofenólico/farmacologia , Transplante de Órgãos , Linfócitos T/imunologia , Acridonas/química , Antígeno B7-2/genética , Antígeno B7-2/metabolismo , Diferenciação Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Células Cultivadas , Células Dendríticas/imunologia , Humanos , Interleucina-10/metabolismo , Interleucina-2/metabolismo , Ativação Linfocitária/efeitos dos fármacos , Teste de Cultura Mista de Linfócitos , Ácido Micofenólico/análogos & derivados , Ácido Micofenólico/química
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