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1.
Expert Opin Drug Metab Toxicol ; 15(11): 975-984, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31619082

RESUMO

Objectives: Riociguat is a soluble guanylate cyclase stimulator licensed for the treatment of pulmonary arterial hypertension (PAH), a potentially fatal complication of human immunodeficiency virus infection. This study investigated the inhibitory potency of selected antiretroviral regimens on the metabolic clearance of riociguat.Methods: The inhibitory potential of the components of six antiretroviral combinations (ATRIPLA® (efavirenz/emtricitabine/tenofovir disoproxil), COMPLERA® (rilpivirine/emtricitabine/tenofovir disoproxil), STRIBILD® (elvitegravir/cobicistat/emtricitabine/tenofovir disoproxil), TRIUMEQ® (abacavir/dolutegravir/lamivudine), and two ritonavir-boosted regimens) on riociguat metabolism were evaluated in recombinant human CYP1A1 and CYP3A4 as well as in human hepatocytes exhibiting both CYP1A1 and CYP3A4 activity. In vitro-in vivo correlation was performed between calculated and observed increases in riociguat exposure in vivo.Results: Using both in vitro systems, the predicted increase in exposure of riociguat was highest with components of TRIUMEQ® followed by COMPLERA®, ATRIPLA®, STRIBILD®, and the ritonavir-boosted regimens. Further experiments in human hepatocytes confirmed CYP1A1 to be the predominant enzyme in the metabolic clearance of riociguat.Conclusion: Antiretroviral treatment containing the potent CYP1A1 inhibitor abacavir had the greatest impact on riociguat metabolic clearance. The impact of comedications containing only strong CYP3A4 inhibitors e.g. ritonavir was less pronounced, suggesting a benefit of riociguat over PAH-targeting medications with contraindications for use with strong CYP3A4 inhibitors.


Assuntos
Fármacos Anti-HIV/farmacologia , Citocromo P-450 CYP1A1/metabolismo , Ativadores de Enzimas/metabolismo , Pirazóis/metabolismo , Pirimidinas/metabolismo , Fármacos Anti-HIV/administração & dosagem , Citocromo P-450 CYP1A1/antagonistas & inibidores , Citocromo P-450 CYP3A/efeitos dos fármacos , Citocromo P-450 CYP3A/metabolismo , Inibidores do Citocromo P-450 CYP3A/administração & dosagem , Inibidores do Citocromo P-450 CYP3A/farmacologia , Interações de Medicamentos , Ativadores de Enzimas/administração & dosagem , Hepatócitos/enzimologia , Hepatócitos/metabolismo , Humanos , Técnicas In Vitro , Pirazóis/administração & dosagem , Pirimidinas/administração & dosagem
2.
Transplant Proc ; 51(8): 2620-2623, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31474450

RESUMO

BACKGROUND: Converting to once-daily tacrolimus (Advagraf [Adv]) among renal transplant patients results in better drug adherence. Data regarding dosage and intrapatient variability changes after conversion among patients with CYP3A4/5 inhibitors (CYPinh) is lacking. METHOD: A retrospective chart review among all kidney transplant recipients at Siriraj Hospital was performed. Patients were enrolled who had been on standard release twice-daily tacrolimus and subsequently replaced it with Adv for at least 6 months with no change in CYPinh type or dosage. RESULTS: Fifty-three patients were eligible. Conversion occurred at a mean time after transplant of 51.25 (SD, 40.30) months. Ten patients (18.9%) did not receive CYPinh, while 19 (35.8%), 21 (39.6%), and 3 (5.7%) received diltiazem, ketoconazole or fluconazole, and both diltiazem and ketoconazole, respectively. After conversion, median increment of tacrolimus dosage was 14.29% (-50% to 167%), while no significant change in IPV was demonstrated (17.46% [SD, 11.25%] vs 14.83% [SD, 6.78]; P = .11). Patients receiving azole had less dosage increment than those not receiving CYPinh (P = .02). After conversion, 14 of 22 patients with IPV > 17% (63.6%) had reduced IPV to ≤ 17%, while 25.8% of patients with lower IPV had an increase in IPV > 17%. CONCLUSION: Conversion to Adv required a dosage increment of 30% to achieve the same trough level. Concomitant use of CYPinh significantly reduced tacrolimus dose increment. A trend was noted toward improved IPV after conversion. Conversion to Adv resulted in better IPV among patients with high IPV while receiving twice-daily tacrolimus.


Assuntos
Inibidores do Citocromo P-450 CYP3A/administração & dosagem , Imunossupressão/métodos , Imunossupressores/administração & dosagem , Transplante de Rim , Tacrolimo/administração & dosagem , Adulto , Protocolos Clínicos , Preparações de Ação Retardada , Relação Dose-Resposta a Droga , Esquema de Medicação , Quimioterapia Combinada , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Tailândia , Resultado do Tratamento
3.
Phytomedicine ; 60: 153010, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31301970

RESUMO

BACKGROUND: Moringa oleifera Lam. is known as a drumstick tree that is widely cultivated in various subtropical and tropical provinces. Previous studies indicated that both aqueous and methanolic extracts of M. oleifera leaves have potent inhibitory effects on two major drug metabolizing Cytochrome P450 enzymes, namely, CYP3A4 and CYP2D6. PURPOSE: The current study was aimed to isolate the secondary metabolites from M. oleifera and investigate their cytotoxicity and inhibitory effects on CYP3A4 and CYP2D6 to assess their herb-drug interaction (HDI) potential. METHODS: Chemical structure elucidation was achieved by interpreting the spectroscopic data (UV, IR, 1D, and 2D NMR experiments), confirming by HR-ESI-MS, and comparing with the previously reported data in the literature. All the isolates were evaluated for their cytotoxicity against a panel of cell lines (SK-MEL, KB, BT-549, SK-OV-3, VERO, LLC-PK1, and HepG2) and inhibition of two principal CYP isozymes (CYP3A4 and CYP2D6). RESULTS: Phytochemical investigation of M. oleifera leaves resulted in the isolation and characterization of one new compound, namely omoringone (1), along with twelve known secondary metabolites (2-13) belonging to several chemical classes including flavonoids, terpenoids, lignans, and phenylalkanoids. A plausible biosynthetic pathway for compound 1 was provided. Because of the low isolation yield and limited supply, omoringone (1) and niazirin (12) were successively synthesized. No cytotoxicity was observed on any of the tested cell lines up to 50 µM. The extract exhibited an inhibitory effect on CYP3A4 isoform (IC50 = 52.5 ±â€¯2.5 µg/ml). Among the isolates, 1-4 and 7-9 inhibited CYP3A4 with the IC50 values ranging from 41.5 to 100 µM with no remarkable effect on CYP2D6 isozyme. CONCLUSION: This work aided in ascertaining components of M. oleifera contributing to CYP3A4 inhibition exhibited by the extract using an in vitro assay. Nonetheless, further studies are warranted to determine the bioavailability of the phytochemicals and extrapolate these findings in more physiologically relevant conditions to further establish the clinical relevance of in vitro observations.


Assuntos
Citocromo P-450 CYP2D6/efeitos dos fármacos , Citocromo P-450 CYP3A/efeitos dos fármacos , Interações Ervas-Drogas , Moringa oleifera/química , Extratos Vegetais/farmacologia , Citocromo P-450 CYP2D6/metabolismo , Citocromo P-450 CYP3A/metabolismo , Inibidores do Citocromo P-450 CYP3A , Humanos , Isoenzimas/efeitos dos fármacos , Extratos Vegetais/química , Folhas de Planta/química , Árvores
4.
Drug Metab Rev ; 51(3): 247-265, 2019 08.
Artigo em Inglês | MEDLINE | ID: mdl-31215810

RESUMO

Voriconazole, a second-generation triazole frequently used for the prophylaxis and treatment of invasive fungal infections, undergoes complex metabolism mainly involving various (polymorphic) cytochrome P450 enzymes in humans. Although high inter- and intraindividual variability in voriconazole pharmacokinetics have been observed and the therapeutic range for this compound is relatively narrow, the metabolism of voriconazole has not been fully elucidated yet. The available literature data investigating the multiple different pathways and metabolites are extremely unbalanced and thus the absolute or relative contribution of the different pathways and enzymes involved in the metabolism of voriconazole remains uncertain. Furthermore, other factors such as nonlinear pharmacokinetics caused by auto-inhibition or -induction and polymorphisms of the metabolizing enzymes hinder safe and effective voriconazole dosing in clinical practice and have not yet been studied sufficiently. This review aimed at amalgamating the available literature on the pharmacokinetics of voriconazole in vitro and in vivo, with a special focus on metabolism in adults and children, in order to congregate an overall landscape of the current body of knowledge and identify knowledge gaps, opening the way towards further research in order to foster the understanding, towards better therapeutic dosing decisions.


Assuntos
Voriconazol/metabolismo , Voriconazol/farmacocinética , Animais , Inibidores do Citocromo P-450 CYP3A/metabolismo , Inibidores do Citocromo P-450 CYP3A/farmacocinética , Humanos
5.
Eur J Clin Pharmacol ; 75(8): 1077-1087, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31089768

RESUMO

AIM: The study sought to determine the effect of ketoconazole (KTZ) on the pharmacokinetics of praziquantel (PZQ) and on the formation of its major hydroxylated metabolites, cis- and trans-4-OH-PZQ, and X-OH-PZQ in healthy subjects. METHODS: Two treatments were evaluated by single-dose PK studies; the reference treatment was a 20 mg/kg dose of praziquantel given alone. The test treatment was a 20 mg/kg dose of praziquantel given in combination with 200 mg of ketoconazole. The study had a balanced and randomised cross-over design. Serial blood samples were collected between 0 and 12 h after each drug administration. PZQ, and cis- and trans-4-OH-PZQ and X-OH-PZQ concentrations in plasma were determined by LC-MS. A non-compartmental approach was used for pharmacokinetic analysis. Data were analysed using ANOVA and assessment of the 90% confidence interval of the geometric means of the log-transformed PK parameters obtained for each treatment. RESULTS: The pharmacokinetics of PZQ following the two treatments, PZQ alone and PZQ + KTZ, were not equivalent based on the assessment of the 90% CI of the geometric mean ratios of the AUC and Cmax (α = 0.05). The geometric mean ratios of the AUC and Cmax were found to be 176.8% and 227% respectively. The 90% CI of the AUC and Cmax were found to be 129.8%-239.8% and 151.4%-341.4% respectively. The AUC of PZQ was increased by 75% with KTZ co-administration (3516 vs 6172 ng h/ml) (p < 0.01). Meanwhile, the mean AUC of trans-4-OH-PZQ increased by 67% (61,749 ng h/ml vs 103,105 ng h/ml) (p < 0.01). X-OH-PZQ levels were reduced by about 57% (semi-quantified as 7311 ng h/ml vs 3109 ng h/ml by using trans-4-OH as standards) (p < 0.01) with KTZ co-administration. CONCLUSIONS: The relative bioavailability of praziquantel was increased by concomitant KTZ administration. KTZ preferentially inhibited the formation of X-OH-PZQ rather than 4-OH-PZQ, confirming in vitro data which implicates CYP3A4 in the formation of X-OH-PZQ rather than 4-OH-PZQ. The 4-hydroxylation of PZQ was shown to be the major metabolic pathway of PZQ, as evidenced by larger quantities of 4-OH-PZQ produced, thus explaining the modest albeit significant effect of ketoconazole on PZQ pharmacokinetics.


Assuntos
Anti-Helmínticos/farmacocinética , Inibidores do Citocromo P-450 CYP3A/farmacocinética , Citocromo P-450 CYP3A/metabolismo , Cetoconazol/farmacocinética , Praziquantel/farmacocinética , Adulto , Anti-Helmínticos/administração & dosagem , Anti-Helmínticos/metabolismo , Disponibilidade Biológica , Estudos Cross-Over , Inibidores do Citocromo P-450 CYP3A/administração & dosagem , Interações de Medicamentos , Estudos de Viabilidade , Voluntários Saudáveis , Humanos , Cetoconazol/administração & dosagem , Masculino , Praziquantel/administração & dosagem , Praziquantel/metabolismo , Adulto Jovem
6.
Eur J Clin Pharmacol ; 75(8): 1099-1108, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31011758

RESUMO

PURPOSE: To assess the effect of ethnicity, food, and itraconazole (strong CYP3A4 inhibitor) on the pharmacokinetics of ivosidenib after single oral doses in healthy subjects. METHODS: Three phase 1 open-label studies were performed. Study 1: Japanese and Caucasian subjects received single doses of 250, 500, or 1000 mg ivosidenib (NCT03071770). Part 1 of study 2 (a two-period crossover study): subjects received 500 mg ivosidenib after either an overnight fast or a high-fat meal. Subjects received 1000 mg ivosidenib after an overnight fast in the single period of part 2 (NCT02579707). Study 3: in period 1, subjects received 250 mg ivosidenib; then, in period 2, subjects received oral itraconazole (200 mg once daily) on days 1-18, plus 250 mg ivosidenib on day 5 (NCT02831972). RESULTS: Ivosidenib was well tolerated in all three studies. Study 1: pharmacokinetic profiles were generally comparable, although AUC and Cmax were slightly lower in Japanese subjects than in Caucasian subjects, by ~ 30 and 17%, respectively. Study 2: AUC increased by ~ 25% and Cmax by ~ 98%, when ivosidenib was administered with a high-fat meal compared with a fasted state. Study 3: co-administration of itraconazole increased ivosidenib AUC by 169% (90% CI 145-195) but had no effect on ivosidenib Cmax. CONCLUSIONS: No ivosidenib dose adjustment is deemed necessary for Japanese subjects. High-fat meals should be avoided when ivosidenib is taken with food. When co-administered with strong CYP3A4 inhibitors, monitoring for QT interval prolongation (a previously defined adverse event of interest) is recommended and an ivosidenib dose interruption or reduction may be considered. CLINICALTRIALS.GOV : NCT03071770, NCT02579707, and NCT02831972.


Assuntos
Antineoplásicos/farmacocinética , Inibidores do Citocromo P-450 CYP3A/farmacologia , Glicina/análogos & derivados , Itraconazol/farmacologia , Síndrome do QT Longo/epidemiologia , Piridinas/farmacocinética , Administração Oral , Adulto , Antineoplásicos/administração & dosagem , Antineoplásicos/efeitos adversos , Área Sob a Curva , Grupo com Ancestrais do Continente Asiático , Estudos Cross-Over , Relação Dose-Resposta a Droga , Interações de Medicamentos/etnologia , Feminino , Interações Alimento-Droga/etnologia , Glicina/administração & dosagem , Glicina/efeitos adversos , Glicina/farmacocinética , Voluntários Saudáveis , Humanos , Itraconazol/administração & dosagem , Leucemia Mieloide Aguda/tratamento farmacológico , Síndrome do QT Longo/diagnóstico , Síndrome do QT Longo/etiologia , Masculino , Pessoa de Meia-Idade , Piridinas/administração & dosagem , Piridinas/efeitos adversos
7.
Biopharm Drug Dispos ; 40(5-6): 176-187, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-30985942

RESUMO

We previously verified a physiologically based pharmacokinetic (PBPK) model for mirabegron in healthy subjects using the Simcyp Simulator by incorporating data on the inhibitory effect on cytochrome P450 (CYP) 2D6 and a multi-elimination pathway mediated by CYP3A4, uridine 5'-diphosphate-glucuronosyltransferase (UGT) 2B7 and butyrylcholinesterase (BChE). The aim of this study was to use this PBPK model to assess the magnitude of drug-drug interactions (DDIs) in an elderly population with severe renal impairment (sRI), which has not been evaluated in clinical trials. We first determined the system parameters, and meta-analyses of literature data suggested that the abundance of UGT2B7 and the BChE activity in an elderly population with sRI was almost equivalent to and 20% lower than that in healthy young subjects, respectively. Other parameters, such as the CYP3A4 abundance, for an sRI population were used according to those built into the Simcyp Simulator. Second, we confirmed that the PBPK model reproduced the plasma concentration-time profile for mirabegron in an sRI population (simulated area under the plasma concentration-time curve (AUC) was within 1.5-times that of the observed value). Finally, we applied the PBPK model to simulate DDIs in an sRI population. The PBPK model predicted that the AUC for mirabegron with itraconazole (a CYP3A4 inhibitor) was 4.12-times that in healthy elderly subjects administered mirabegron alone, and predicted that the proportional change in AUC for desipramine (a CYP2D6 substrate) with mirabegron was greater than that in healthy subjects. In conclusion, the PBPK model was verified for the purpose of DDI assessment in an elderly population with sRI.


Assuntos
Acetanilidas/farmacocinética , Agonistas de Receptores Adrenérgicos beta 3/farmacocinética , Modelos Biológicos , Insuficiência Renal/metabolismo , Tiazóis/farmacocinética , Acetanilidas/sangue , Adolescente , Agonistas de Receptores Adrenérgicos beta 3/sangue , Adulto , Idoso , Envelhecimento/metabolismo , Butirilcolinesterase/metabolismo , Inibidores do Citocromo P-450 CYP2D6/sangue , Inibidores do Citocromo P-450 CYP2D6/farmacocinética , Citocromo P-450 CYP3A/metabolismo , Inibidores do Citocromo P-450 CYP3A/sangue , Inibidores do Citocromo P-450 CYP3A/farmacocinética , Desipramina/sangue , Desipramina/farmacocinética , Interações de Medicamentos , Feminino , Genfibrozila/sangue , Genfibrozila/farmacocinética , Glucuronosiltransferase/metabolismo , Humanos , Itraconazol/sangue , Itraconazol/farmacocinética , Lorazepam/sangue , Lorazepam/farmacocinética , Masculino , Pessoa de Meia-Idade , Insuficiência Renal/sangue , Tiazóis/sangue , Adulto Jovem , Zidovudina/sangue , Zidovudina/farmacocinética
8.
Phytomedicine ; 59: 152915, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-30981185

RESUMO

BACKGROUND: The consumption of botanical dietary supplements (BDS) is a common practice among the US population. However, the potential for botanical-drug interactions exists, and their mechanisms have not been thoroughly studied. CYP3A4 is an important enzyme that contributes to the metabolism of about 60% of clinically used drugs. PURPOSE: To investigate the potential for botanical-drug interactions of Lepidium meyenii Walpers (maca) root and Euterpe oleracea Mart. (açaí) berries, two commonly used BDS, when co-administered with CYP3A4-metabolized drugs. METHODS: In an attempt to decrease the general discrepancy between in vivo and in vitro studies, the absorption profiles, particularly for passive diffusion, of plant extracts were investigated. Specifically, the parallel artificial membrane permeability assay (PAMPA) model was utilized to simulate intestinal filtration of passively diffused constituents of açaí and maca extracts. These were subsequently screened for in vitro liver CYP3A4 inhibition and induction. In the inhibition assay, midazolam was used as the probe substrate on genotyped human liver microsomes (CYP3A5 null), and the production of its 1'-substituted metabolite when co-cultured with extract treatments was monitored. In the induction assay, extract treatments were applied to human primary hepatocytes, and quantitative PCR analysis was performed to determine CYP3A4 mRNA expression. RESULTS: Passively diffused constituents of the methanol açaí extract (IC50 of 28.03 µg/µl) demonstrated the highest inhibition potential, and, at 1.5 µg/µl, induced significant changes in CYP3A4 gene expression. The composition of this extract was further investigated using the chemometric tool Mass Profiler Professional (MPP) on liquid chromatography-mass spectroscopy (LC-MS) data. Subsequently, five compounds of interest characterized by high abundance or high permeability were extracted for further study. This included efforts in effective passive permeability determination and structural elucidation by tandem mass spectrometry (MS/MS). CONCLUSION: The passively absorbable portion of a methanol açaí extract exhibited inhibition and induction effects on CYP3A4 suggesting the potential to produce botanical-drug interactions.


Assuntos
Inibidores do Citocromo P-450 CYP3A/farmacologia , Euterpe/química , Frutas/química , Lepidium/química , Extratos Vegetais/farmacologia , Permeabilidade da Membrana Celular , Citocromo P-450 CYP3A/metabolismo , Suplementos Nutricionais , Humanos , Membranas Artificiais , Microssomos Hepáticos/efeitos dos fármacos , Microssomos Hepáticos/metabolismo , Extratos Vegetais/química , Espectrometria de Massas em Tandem/métodos
11.
Artigo em Inglês | MEDLINE | ID: mdl-30851617

RESUMO

A continuous effort has been given to find out a new drug that is effective against tuberculosis (TB) from both susceptible and resistant strains of Mycobacterium tuberculosis. Bedaquiline represents a recently approved anti-TB drug, which has a unique mechanism of action to fight against multi drug resistance (MDR). Some severe side effects and drug-drug interactions are associated with the treatment of bedaquiline. Moreover, World Health Organisation (WHO) has also been provided guidelines in the year of 2013 for the use of bedaquiline and encourages additional investigation into it. Hence, the pharmacokinetics of bedaquiline upon coadministration with the drug has to be explored in the preclinical model and for which a liquid chromatography tandem mass spectrometry (LC-MS/MS) based bioanalytical method for quantitation of bedaquiline will be useful. A simple, sensitive and rapid LC-MS/MS method was developed, validated and successfully applied to drug interactions of bedaquiline upon coadministration with cytochrome P450 3A4 (CYP3A4) inducers/inhibitors orally in Wistar rats. Results reveal that ciprofloxacin and fluconazole have marked effect to hinder the pharmacokinetics of bedaquiline but isoniazid, verapamil and carbamazepine have no significant effect on bedaquiline pharmacokinetics. Overall, this new bioanalytical method for estimation of bedaquiline in rat plasma was found to be helpful to assess the pharmacokinetics of bedaquiline and very much useful for evaluation of preclinical drug-drug interaction before considering costly and perilous clinical exploration.


Assuntos
Antituberculosos/farmacocinética , Cromatografia Líquida/métodos , Diarilquinolinas/farmacocinética , Espectrometria de Massas em Tandem/métodos , Animais , Antituberculosos/sangue , Antituberculosos/química , Inibidores do Citocromo P-450 CYP3A/sangue , Inibidores do Citocromo P-450 CYP3A/química , Inibidores do Citocromo P-450 CYP3A/farmacocinética , Diarilquinolinas/sangue , Diarilquinolinas/química , Interações de Medicamentos , Feminino , Modelos Lineares , Ratos , Ratos Wistar , Reprodutibilidade dos Testes , Sensibilidade e Especificidade
12.
Bioorg Med Chem ; 27(5): 790-799, 2019 03 01.
Artigo em Inglês | MEDLINE | ID: mdl-30704835

RESUMO

Protein kinase C theta (PKCθ) plays a critical role in T cell signaling and has therapeutic potential for T cell-mediated diseases such as transplant rejection and rheumatoid arthritis. PKCθ inhibitors have emerged as effective immunomodulative agents for the prevention of transplant rejection. We previously reported that the 2,4-diamino-5-cyanopyrimidine derivative 2 was a potent PKCθ inhibitor; however, it exhibited CYP3A4 time-dependent inhibition (TDI). Here, we report the structural modification of compound 2 into 34 focusing on mitigating CYP3A4 TDI. Compound 34 exhibited potent in vitro activity with mitigated CYP3A4 TDI and efficacy in vivo transplant model.


Assuntos
Diaminas/farmacologia , Proteína Quinase C-theta/metabolismo , Inibidores de Proteínas Quinases/farmacologia , Pirimidinas/farmacologia , Animais , Inibidores do Citocromo P-450 CYP3A/síntese química , Inibidores do Citocromo P-450 CYP3A/farmacocinética , Inibidores do Citocromo P-450 CYP3A/farmacologia , Diaminas/síntese química , Diaminas/farmacocinética , Descoberta de Drogas , Interações de Medicamentos , Feminino , Rejeição de Enxerto/prevenção & controle , Haplorrinos , Humanos , Células Jurkat , Microssomos Hepáticos/metabolismo , Midazolam/farmacologia , Estrutura Molecular , Inibidores de Proteínas Quinases/síntese química , Inibidores de Proteínas Quinases/farmacocinética , Pirimidinas/síntese química , Pirimidinas/farmacocinética , Ratos Endogâmicos ACI , Ratos Endogâmicos Lew , Ratos Sprague-Dawley , Relação Estrutura-Atividade
13.
Eur J Pharm Sci ; 131: 195-207, 2019 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-30776469

RESUMO

Physiologically-based pharmacokinetic (PBPK) models provide a framework for in vitro-in vivo extrapolation of metabolic drug clearance. Many of the concepts in PBPK can have consequential impact on more mechanistic systems pharmacology models. In the gut wall, turnover of enzymes and enterocytes are typically lumped into one rate constant that describes the time dependent enzyme activity. This assumption may influence predictability of any sustained and dynamic effects such as mechanism-based inhibition (MBI), particularly when considering translation from healthy to gut disease. A novel multi-level systems PBPK model was developed. This model comprised a 'nested enzyme-within enterocyte' (NEWE) turnover model to describe levels of drug-metabolising enzymes. The ability of the model to predict gut metabolism following MBI and gut disease was investigated and compared to the conventional modelling approach. For MBI, the default NEWE model performed comparably to the conventional model. However, when drug-specific spatial crypt-villous absorption was considered, up to approximately 50% lower impact of MBI was simulated for substrates highly metabolised by cytochrome P450 (CYP) 3A4, interacting with potent inhibitors. Further, the model showed potential in predicting the disease effect of gastrointestinal mucositis and untreated coeliac disease when compared to indirect clinical pharmacokinetic parameters. Considering the added complexity of the NEWE model, it does not provide an attractive solution for improving upon MBI predictions in healthy individuals. However, nesting turnover may enable extrapolation to gut disease-drug interactions. The principle detailed herein may be useful for modelling drug interactions with cellular targets where turnover is significant enough to affect this process.


Assuntos
Citocromo P-450 CYP3A/metabolismo , Enterócitos/metabolismo , Enteropatias/metabolismo , Mucosa Intestinal/metabolismo , Modelos Biológicos , Citrus paradisi , Inibidores do Citocromo P-450 CYP3A/farmacologia , Sucos de Frutas e Vegetais , Preparações Farmacêuticas/metabolismo
14.
J Clin Pharm Ther ; 44(3): 381-383, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-30714173

RESUMO

WHAT IS KNOWN AND OBJECTIVE: SLCO1B1 T521>C variant carriers are susceptible to simvastatin-induced myopathy. We report a patient who developed rhabdomyolysis possibly triggered by a drug-drug and/or herb-drug interaction. CASE DESCRIPTION: A 69-year-old man presented with myalgia and weakness progressing to severe rhabdomyolysis. He had been taking 40 mg simvastatin daily for 10 years and recently consumed supplements, including Stevia rebaudiana and linagliptin. Genotyping revealed he carried one copy of SLCO1B1 T521>C and two copies of ABCG2 C421>A. WHAT IS NEW AND CONCLUSION: Despite apparent long-term safe administration, co-ingestion of simvastatin and other CYP3A4 inhibitors may result in severe myopathy in those at increased genetic risk.


Assuntos
Predisposição Genética para Doença/genética , Linagliptina/administração & dosagem , Transportador 1 de Ânion Orgânico Específico do Fígado/genética , Doenças Musculares/induzido quimicamente , Doenças Musculares/genética , Polimorfismo de Nucleotídeo Único/genética , Sinvastatina/efeitos adversos , Idoso , Inibidores do Citocromo P-450 CYP3A/administração & dosagem , Interações de Medicamentos/genética , Interações Ervas-Drogas/genética , Humanos , Masculino , Stevia
15.
Clin Drug Investig ; 39(5): 441-451, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-30810914

RESUMO

BACKGROUND AND OBJECTIVES: Suvorexant is an orexin receptor antagonist indicated for the treatment of insomnia, characterized by difficulties with sleep onset and/or sleep maintenance. As suvorexant is metabolized primarily by Cytochrome P450 3A (CYP3A), and its pharmacokinetics may be affected by CYP3A modulators, the effects of CYP3A inhibitors (ketoconazole or diltiazem) or an inducer (rifampin [rifampicin]) on the pharmacokinetics, safety, and tolerability of suvorexant were investigated. METHODS: In two Phase I, open-label, fixed-sequence trials (Studies P008 and P038), healthy subjects received a single oral dose of suvorexant followed by co-administration with multiple once-daily doses of strong/moderate CYP3A inhibitors (ketoconazole/diltiazem) or a strong CYP3A inducer (rifampin). Treatments were administered in the morning: suvorexant 4 mg with ketoconazole 400 mg (Study P008; N = 10), suvorexant 20 mg with diltiazem 240 mg (Study P038; N = 20), and suvorexant 40 mg with rifampin 600 mg (Study P038; N = 10). Area under the plasma concentration-time curve from time zero to infinity (AUC0-∞), maximum plasma concentration (Cmax), half-life (t½), and time to Cmax (tmax) were derived from plasma concentrations of suvorexant collected at prespecified time points up to 10 days following CYP3A inhibitor/inducer co-administration. Adverse events (AEs) were recorded. RESULTS: Co-administration with ketoconazole resulted in increased exposure to suvorexant [AUC0-∞: geometric mean ratio (GMR); 90% confidence interval (CI) 2.79 (2.35, 3.31)] while co-administration with diltiazem resulted in a lesser effect [GMR (90% CI): 2.05 (1.82, 2.30)]. Co-administration with rifampin led to a marked decrease (88%) in suvorexant exposure. Consistent with morning administration and known suvorexant pharmacology, somnolence was the most frequently reported AE. CONCLUSIONS: These results are consistent with expectations that strong CYP3A inhibitors and inducers exert marked effects on suvorexant pharmacokinetics. In the context of a limited sample size, single suvorexant doses were generally well tolerated in healthy subjects when co-administered with/without a CYP3A inhibitor/inducer.


Assuntos
Azepinas/farmacocinética , Indutores do Citocromo P-450 CYP3A/farmacocinética , Inibidores do Citocromo P-450 CYP3A/farmacocinética , Interações de Medicamentos/fisiologia , Antagonistas dos Receptores de Orexina/farmacocinética , Triazóis/farmacocinética , Administração Oral , Adulto , Diltiazem/farmacocinética , Voluntários Saudáveis , Humanos , Cetoconazol/farmacocinética , Masculino , Pessoa de Meia-Idade , Rifampina/administração & dosagem , Adulto Jovem
16.
Biochemistry ; 58(7): 930-939, 2019 02 19.
Artigo em Inglês | MEDLINE | ID: mdl-30676743

RESUMO

Binding of small inhibitory compounds to human cytochrome P450 3A4 (CYP3A4) could interfere with drug metabolism and lead to drug-drug interactions, the underlying mechanism of which is not fully understood due to insufficient structural information. This study investigated the interaction of recombinant CYP3A4 with a nonspecific inhibitor metyrapone, antifungal drug fluconazole, and protease inhibitor phenylmethanesulfonyl fluoride (PMSF). Metyrapone and fluconazole are classic type II ligands that inhibit CYP3A4 with medium strength by ligating to the heme iron, whereas PMSF, lacking the heme-ligating moiety, acts as a weak type I ligand and inhibitor of CYP3A4. High-resolution crystal structures revealed that the orientation of metyrapone is similar but not identical to that in the previously reported 1W0G model, whereas the flexible fluconazole adapts a conformer markedly different from that observed in the target CYP51 enzymes, which could explain its high potential for cross-reactivity. Besides hydrophobic and aromatic interactions with the heme and active site residues, both drugs establish water-mediated contacts that stabilize the inhibitory complexes. PMSF also binds near the catalytic center, with the phenyl group parallel to the heme. However, it does not displace the water ligand and is held in place via strong H-bonds formed by the sulfofluoride moiety with Ser119 and Arg212. Collectively, our data suggest that PMSF might have multiple binding sites and likely occupies the high-affinity site in the crystal structure. Moreover, its hydrolysis product, phenylmethanesulfonic acid, can also access and be retained in the CYP3A4 active site. Therefore, to avoid experimental artifacts, PMSF should be excluded from purification and assay solutions.


Assuntos
Inibidores do Citocromo P-450 CYP3A/química , Inibidores do Citocromo P-450 CYP3A/metabolismo , Citocromo P-450 CYP3A/química , Citocromo P-450 CYP3A/metabolismo , Sítios de Ligação , Cristalografia por Raios X , Inibidores do Citocromo P-450 CYP3A/farmacologia , Fluconazol/química , Fluconazol/metabolismo , Fluconazol/farmacologia , Humanos , Hidrólise , Interações Hidrofóbicas e Hidrofílicas , Inativação Metabólica , Metirapona/química , Metirapona/metabolismo , Metirapona/farmacologia , Fluoreto de Fenilmetilsulfonil/química , Fluoreto de Fenilmetilsulfonil/metabolismo , Fluoreto de Fenilmetilsulfonil/farmacologia , Serina/química , Serina/metabolismo
17.
Eur J Pharm Biopharm ; 136: 120-130, 2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-30660696

RESUMO

Lorlatinib, a novel generation oral anaplastic lymphoma kinase (ALK) and ROS1 inhibitor with high membrane and blood-brain barrier permeability, recently received accelerated approval for treatment of ALK-rearranged non-small-cell lung cancer (NSCLC), and its further clinical development is ongoing. We previously found that the efflux transporter P-glycoprotein (MDR1/ABCB1) restricts lorlatinib brain accumulation and that the drug-metabolizing enzyme cytochrome P450-3A (CYP3A) limits its oral availability. Using genetically modified mouse models, we investigated the impact of targeted pharmacological inhibitors on lorlatinib pharmacokinetics and bioavailability. Upon oral administration of lorlatinib, the plasma AUC0-8h in CYP3A4-humanized mice was ∼1.8-fold lower than in wild-type and Cyp3a-/- mice. Oral coadministration of the CYP3A inhibitor ritonavir caused reversion to the AUC0-8h levels seen in wild-type and Cyp3a-/- mice, without altering the relative tissue distribution of lorlatinib. Moreover, simultaneous pharmacological inhibition of P-glycoprotein and CYP3A4 with oral elacridar and ritonavir in CYP3A4-humanized mice profoundly increased lorlatinib brain concentrations, but not its oral availability or other relative tissue distribution. Oral lorlatinib pharmacokinetics was not significantly affected by absence of the multispecific Oatp1a/1b drug uptake transporters. The absolute oral bioavailability of lorlatinib over 8 h in wild-type, Cyp3a-/-, and CYP3A4-humanized mice was 81.6%, 72.9%, and 58.5%, respectively. Lorlatinib thus has good oral bioavailability, which is markedly restricted by human CYP3A4 but not by mouse Cyp3a. Pharmacological inhibition of CYP3A4 reversed these effects, and simultaneous P-gp inhibition with elacridar boosted absolute brain levels of lorlatinib by 16-fold without obvious toxicity. These insights may help to optimize the clinical application of lorlatinib.


Assuntos
Acridinas/metabolismo , Quinase do Linfoma Anaplásico/metabolismo , Encéfalo/metabolismo , Lactamas Macrocíclicas/metabolismo , Proteínas Proto-Oncogênicas/metabolismo , Receptores Proteína Tirosina Quinases/metabolismo , Ritonavir/metabolismo , Tetra-Hidroisoquinolinas/metabolismo , Acridinas/administração & dosagem , Administração Intravenosa , Administração Oral , Quinase do Linfoma Anaplásico/antagonistas & inibidores , Animais , Disponibilidade Biológica , Encéfalo/efeitos dos fármacos , Inibidores do Citocromo P-450 CYP3A/administração & dosagem , Inibidores do Citocromo P-450 CYP3A/metabolismo , Interações de Medicamentos/fisiologia , Sinergismo Farmacológico , Lactamas Macrocíclicas/administração & dosagem , Camundongos , Camundongos Knockout , Proteínas Proto-Oncogênicas/antagonistas & inibidores , Receptores Proteína Tirosina Quinases/antagonistas & inibidores , Ritonavir/administração & dosagem , Tetra-Hidroisoquinolinas/administração & dosagem
18.
J Asian Nat Prod Res ; 21(4): 351-363, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-29667422

RESUMO

The intestinal permeability of mitragynine was investigated in situ using a single pass intestinal perfusion (SPIP) absorption model, in small intestine of rat using mitragynine in the absence/presence of the permeability markers, P-gp and/or CYP3A4 inhibitors. Mitragynine demonstrated high intestinal permeability (Peff of 1.11 × 10-4 cm/s) that is in the range of highly permeable drugs such as propranolol (Peff of 1.27 × 10-4 cm/s) indicating that it readily crosses the intestine. The addition of azithromycin (P-glycoprotein inhibitor) and ciprofloxacin (CYP3A4 inhibitor) or combination of both has no effect on intestinal permeability of mitragynine across the rat small intestine.


Assuntos
Absorção Intestinal , Alcaloides de Triptamina e Secologanina/farmacocinética , Animais , Azitromicina/farmacologia , Ciprofloxacino/farmacologia , Inibidores do Citocromo P-450 CYP3A/farmacologia , Masculino , Permeabilidade , Ratos , Ratos Sprague-Dawley
19.
Clin Pharmacol Ther ; 105(1): 219-228, 2019 01.
Artigo em Inglês | MEDLINE | ID: mdl-29696643

RESUMO

Dasabuvir is mainly metabolized by cytochrome P450 (CYP) 2C8 and is predominantly used in a regimen containing ritonavir. Ritonavir and clopidogrel are inhibitors of CYP3A4 and CYP2C8, respectively. In a randomized, crossover study in 12 healthy subjects, we examined the impact of clinical doses of ritonavir (for 5 days), clopidogrel (for 3 days), and their combination on dasabuvir pharmacokinetics, and the effect of ritonavir on clopidogrel. Clopidogrel, but not ritonavir, increased the geometric mean AUC0-∞ of dasabuvir 4.7-fold; range 2.0-10.1-fold (P = 8·10-7 ), compared with placebo. Clopidogrel and ritonavir combination increased dasabuvir AUC0-∞ 3.9-fold; range 2.1-7.9-fold (P = 2·10-6 ), compared with ritonavir alone. Ritonavir decreased the AUC0-4h of clopidogrel active metabolite by 51% (P = 0.0001), and average platelet inhibition from 51% without ritonavir to 31% with ritonavir (P = 0.0007). In conclusion, clopidogrel markedly elevates dasabuvir concentrations, and patients receiving ritonavir are at risk for diminished clopidogrel response.


Assuntos
Clopidogrel/sangue , Inibidores do Citocromo P-450 CYP3A/sangue , Inibidores da Agregação de Plaquetas/sangue , Ritonavir/sangue , Sulfonamidas/sangue , Uracila/análogos & derivados , Adulto , Clopidogrel/administração & dosagem , Estudos Cross-Over , Inibidores do Citocromo P-450 CYP3A/administração & dosagem , Sinergismo Farmacológico , Quimioterapia Combinada , Feminino , Humanos , Masculino , Inibidores da Agregação de Plaquetas/administração & dosagem , Ritonavir/administração & dosagem , Sulfonamidas/administração & dosagem , Uracila/administração & dosagem , Uracila/sangue , Adulto Jovem
20.
Clin Pharmacol Ther ; 105(1): 229-241, 2019 01.
Artigo em Inglês | MEDLINE | ID: mdl-29717476

RESUMO

We report physiologically based pharmacokinetic-modeling analyses to determine olaparib (tablet or capsule) drug-drug interactions (DDIs). Verified DDI simulations provided dose recommendations for olaparib coadministration with clinically relevant CYP3A4 modulators to eliminate potential risk to patient safety or olaparib efficacy. When olaparib is given with strong/moderate CYP3A inhibitors, the dose should be reduced to 100/150 mg b.i.d. (tablet), and 150/200 mg b.i.d. (capsule). Olaparib administration is not recommended with strong/moderate CYP3A inducers. No dose reductions are required with weak CYP3A inhibitors/inducers. Olaparib was shown to be a weak inhibitor of CYP3A (1.6-fold increase in exposure of a sensitive CYP3A probe) and to have no effect on P-glycoprotein or UGT1A1 substrates. Finally, this model was used to simulate exposure in scenarios where clinical data of olaparib are lacking, such as severe renal or hepatic impairment populations, and provided initial dosing recommendations in pediatric patients.


Assuntos
Indutores do Citocromo P-450 CYP3A/farmacocinética , Inibidores do Citocromo P-450 CYP3A/farmacocinética , Modelos Biológicos , Ftalazinas/farmacocinética , Piperazinas/farmacocinética , Inibidores de Poli(ADP-Ribose) Polimerases/farmacocinética , Indutores do Citocromo P-450 CYP3A/química , Inibidores do Citocromo P-450 CYP3A/química , Relação Dose-Resposta a Droga , Composição de Medicamentos , Interações de Medicamentos/fisiologia , Humanos , Ftalazinas/química , Piperazinas/química , Inibidores de Poli(ADP-Ribose) Polimerases/química
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