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1.
Clin Pharmacol Drug Dev ; 8(5): 647-656, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-30748125

RESUMO

Two clinical studies were performed in healthy volunteers to investigate food and antacid effects on lesinurad, a novel selective uric acid reabsorption inhibitor approved for treatment of hyperuricemia associated with gout in combination with xanthine oxidase inhibitors. Study 1 evaluated a high-fat, high-calorie meal or high doses of antacids (3000 mg calcium carbonate or 1600 mg magnesium hydroxide/1600 mg aluminum hydroxide) on the pharmacokinetics (PK) and pharmacodynamics (PD) of 400 mg oral lesinurad. Study 2 evaluated low doses of antacids (1250 mg calcium carbonate or 800 mg magnesium hydroxide/800 mg aluminum hydroxide) on the PK and PD of 400 mg lesinurad. Food did not alter the plasma AUC of lesinurad and only reduced its Cmax by 18%. In the fasted conditions, high-dose calcium carbonate reduced the Cmax and AUC of lesinurad by 54% and 38%, respectively, whereas high-dose magnesium hydroxide/aluminum hydroxide reduced Cmax and AUC by 36% and 31%, respectively. Food enhanced the maximum serum urate (sUA)-lowering effect of lesinurad by approximately 20% despite reducing the Cmax of lesinurad. High-dose calcium carbonate decreased the urate-lowering effect approximately 20% in the first 6 hours, whereas high-dose magnesium hydroxide/aluminum hydroxide reduced the effect by 26%. Low-dose calcium carbonate or magnesium hydroxide/aluminum hydroxide in the presence of food did not significantly affect plasma lesinurad Cmax and AUC or the sUA lowering and renal handling of uric acid. In summary, study results suggest food did not meaningfully alter lesinurad PK and PD. High doses of antacids reduced lesinurad AUC up to 40% and reduced the lesinurad uric acid-lowering effect.

2.
Clin Pharmacol Drug Dev ; 8(5): 657-663, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-30758919

RESUMO

Lesinurad is a selective uric acid reabsorption inhibitor approved for use in combination with xanthine oxidase inhibitors for the treatment of hyperuricemia associated with gout. In vitro, lesinurad was shown to be a weak inhibitor of cytochrome P450 (CYP)2C9 and a weak inducer of CYP3A4. Warfarin is a widely prescribed oral coumarin-based anticoagulant commonly prescribed in gout patients. In an open-label clinical study in healthy adult male subjects, the effects of multiple daily doses of 400 mg lesinurad on the pharmacokinetics and pharmacodynamics of a single dose of 25 mg warfarin (racemic mixture of R- and S- enantiomers) were evaluated. Lesinurad had no effect on the absorption or the exposure (area under the concentration-time curve [AUC] and peak concentration) of the more active S-warfarin enantiomer. A slight reduction (19%) in overall plasma exposure (AUC) was observed for the R-warfarin enantiomer. Lesinurad had no meaningful clinical impact on anticoagulation activity as measured by prothrombin time, activated partial thromboplastin time, and international normalized ratio of prothrombin time and Factor VII clotting activity. Overall, the administration of warfarin in the presence of multiple-dose lesinurad was devoid of clinically significant drug-drug interaction.

3.
Drug Metab Dispos ; 2018 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-30442650

RESUMO

Lesinurad (Zurampic), a selective inhibitor of uric acid reabsorption transporters used clinically for the treatment of gout, is a racemate of two atropisomers. The objectives were to evaluate the stereoselectivity of the metabolism, the inhibitory potency on (URAT1 and OAT4), and the clinical pharmacokinetics of the two atropisomers. In vitro incubations with human liver microsomes (HLM) or recombinant CYP2C9 and CYP3A4 and hydrolases were carried out to characterize metabolic stereoselectivity for the formation of two major metabolites in human, M3 (hydroxylation) and M4 (a dihydrodiol metabolite). Formation of M3 and M4 were catalyzed predominately by CYP2C9. M4 was formed via an epoxide intermediate, M3c, which was subsequently hydrolyzed by microsomal epoxide hydrolase to M4. The formation of M3 with atropisomer 1 in HLM was approximately twice that formed with atropisomer 2, whereas M4 formation with atropisomer 1 was 8- to 12-fold greater than that with atropisomer 2. There were no significant differences in the plasma protein binding among lesinurad and the two atropisomers. Following oral administration of 400 mg lesinurad once daily for 14 days to healthy humans, the systemic exposure (steady state Cmax,SS and AUCtau) of atropisomer 1 was approximately 30% lower than that of atropisomer 2, whereas renal clearance was similar. In vitro cell-based assays using HEK293 cells stably expressing URAT1 and OAT4 demonstrated that atropisomer 2 was approximately 4-fold more potent against URAT1 than atropisomer 1 and equally active against OAT4. In conclusion, lesinurad atropisomers showed stereoselectivity in clinical pharmacokinetics, metabolism, and inhibitory potency against URAT1.

4.
Xenobiotica ; : 1-12, 2018 Sep 12.
Artigo em Inglês | MEDLINE | ID: mdl-30117757

RESUMO

The objectives of this study were to determine the absolute bioavailability of lesinurad and to characterized its disposition in humans. The oral bioavailability assessment was performed using a clinical design of simultaneous dosing of a therapeutic oral dose of lesinurad with an intravenous infusion of [14C]lesinurad microdose. The bioavailability of lesinurad was determined to be 100%. The disposition of lesinurad in humans involves hepatic oxidation and renal elimination following administration of oral [14C]lesinurad dose. Metabolism of lesinurad occurred post-systemically with low circulating levels of metabolites <3% of total radioactivity as 74.2% of total radioactivity was attributed to lesinurad. In vitro metabolism studies identified CYP2C9 as the predominant isoform, and summation of metabolites indicated that it was responsible for ∼50% of metabolism.

5.
Clin Drug Investig ; 38(8): 703-713, 2018 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-29949102

RESUMO

BACKGROUND AND OBJECTIVE: Verinurad (RDEA3170) is a high-affinity, selective URAT1 transporter inhibitor in development for treating gout and asymptomatic hyperuricemia. This Phase I, single-dose study investigated the pharmacokinetics, pharmacodynamics, and safety of verinurad in adults with renal impairment and controls with normal renal function. METHODS: Males aged 18-85 years were enrolled with serum urate (sUA) 4.5-10 mg/dl and creatinine clearance 60- < 90, 30- < 60, 15- < 30, or ≥ 90 ml/min (mild, moderate, severe renal impairment and controls, respectively; n = 7/8). Verinurad 15 mg was administered orally under fasted conditions. Serial plasma/serum and urine samplings were 30 min pre-dose to 72 h post-dose. RESULTS: Compared to controls, verinurad maximum observed plasma concentration increased by 53, 73, and 128% and area under the concentration-time curve increased by 24, 148, and 130%, in subjects with mild, moderate, and severe renal impairment, respectively; renal clearance decreased by 5, 42, and 79%. Exposures of major verinurad metabolites also increased with increasing renal impairment. Verinurad decreased sUA in all groups, with greater maximal changes in control and mild renal impairment than moderate and severe impairment groups (- 38.3, - 36.9, - 20.5, - 12.6%, respectively). There were no adverse event-related withdrawals or clinically meaningful changes in laboratory values. CONCLUSION: Exposures of verinurad and metabolites increased with decreasing renal function. Consistent with the renal-dependent mechanism of action of verinurad, increasing severity of renal impairment was associated with decreased sUA lowering. Verinurad safety assessments were similar regardless of renal impairment. Continued investigation of verinurad is warranted in patients with gout and renal impairment. CLINICALTRIALS. GOV IDENTIFIER: NCT02219516.


Assuntos
Transportadores de Ânions Orgânicos/metabolismo , Proteínas de Transporte de Cátions Orgânicos/metabolismo , Insuficiência Renal/tratamento farmacológico , Insuficiência Renal/metabolismo , Ácido Úrico/metabolismo , Uricosúricos/metabolismo , Uricosúricos/uso terapêutico , Adulto , Idoso , Idoso de 80 Anos ou mais , Humanos , Rim/efeitos dos fármacos , Rim/metabolismo , Masculino , Pessoa de Meia-Idade , Transportadores de Ânions Orgânicos/antagonistas & inibidores , Proteínas de Transporte de Cátions Orgânicos/antagonistas & inibidores , Ácido Úrico/antagonistas & inibidores , Uricosúricos/farmacologia
6.
Clin Pharmacol Ther ; 104(5): 781-784, 2018 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-29761830

RESUMO

Metformin drug-drug interaction (DDI) studies are conducted during development of drugs that inhibit organic cation transporters and/or multidrug and toxin extrusion proteins (OCTs/MATEs). Monitoring solely changes in systemic exposure, the typical DDI study endpoint appears inadequate for metformin, which is metabolically stable, has poor passive membrane permeability, and undergoes transporter-mediated tissue distribution and clearance. Evaluation of renal clearance, antihyperglycemic effects, and potentially lactate as an exploratory safety marker, can support rational metformin dose adjustment. The proposed DDI study design aims to adequately inform metformin dosing during comedication.

7.
Toxicology ; 404-405: 10-24, 2018 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-29738843

RESUMO

The role of plasma membrane transporters in the nephrotoxicity of two antiretroviral drugs, cidofovir and tenofovir, was studied in primary cultures of human proximal tubular (hPT) cells. Cells were grown on Transwell filter inserts to maintain epithelial polarity and access to either the apical or basolateral plasma membrane. The function of relevant membrane transporters, organic anion transporter 1 and 3 (OAT1/3), P-glycoprotein (multidrug resistance protein-1; P-gp or MDR1), and organic cation transporter 2 (OCT2), was validated by measurements of apical-to-basolateral and basolateral-to-apical fluxes of furosemide, digoxin, and metformin, respectively. Acute cytotoxicity of cidofovir (0, 10, 50, 150, or 300 µM) in the absence or presence of 500 µM probenecid, tenofovir disoproxil fumarate (0, 20, 90, 180, or 360 µM) in the absence or presence of 500 µM probenecid, or cisplatin (0, 20, 90, 180, or 360 µM) as a positive control in the absence or presence of 500 µM cimetidine, was assessed after 4-h incubations by determinations of release of lactate dehydrogenase (LDH), γ-glutamyltransferase (GGT), N-acetyl-ß-d-glucosaminidase (NAG), or Kidney Injury Molecule-1 (KIM-1). Cell death generally agreed with each of the four biomarkers, was generally greater when cidofovir or tenofovir was added to the upper compartment, and was markedly diminished in the presence of the appropriate transport inhibitor. Additionally, the extent of cytotoxicity caused by the two antiviral drugs was similar to that caused by cisplatin. The results demonstrate the importance of plasma membrane transport of antiviral drugs to elicit cytotoxicity in the hPT cell.

8.
Drug Metab Dispos ; 46(5): 532-541, 2018 05.
Artigo em Inglês | MEDLINE | ID: mdl-29490903

RESUMO

Verinurad (RDEA3170) is a second generation selective uric acid reabsorption inhibitor for the treatment of gout and asymptomatic hyperuricemia. Following a single oral solution of 10-mg dose of [14C]verinurad (500 µCi), verinurad was rapidly absorbed with a median time to occurrence of maximum observed concentration (Tmax) of 0.5 hours and terminal half-life of 15 hours. In plasma, verinurad constituted 21% of total radioactivity. Recovery of radioactivity in urine and feces was 97.1%. Unchanged verinurad was the predominant component in the feces (29.9%), whereas levels were low in the urine (1.2% excreted). Acylglucuronide metabolites M1 (direct glucuronidation) and M8 (glucuronidation of N-oxide) were formed rapidly after absorption of verinurad with terminal half-life values of approximately 13 and 18 hours, respectively. M1 and M8 constituted 32% and 31% of total radioactivity in plasma and were equimolar to verinurad on the basis of AUC ratios. M1 and M8 formed in the liver were biliary cleared with complete hydrolysis in the GI tract, as metabolites were not detected in the feces and/or efflux across the sinusoidal membrane; M1 and M8 accounted for 29.2% and 32.5% of the radioactive dose in urine, respectively. In vitro studies demonstrated that CYP3A4 mediated the formation of the N-oxide metabolite (M4), which was further metabolized by glucuronyl transferases (UGTs) to form M8, as M4 was absent in plasma and only trace levels were present in the urine. Several UGTs mediated the formation of M1, which could also be further metabolized by CYP2C8. Overall, the major clearance route of verinurad is metabolism via UGTs and CYP3A4 and CYP2C8.


Assuntos
Ácido Úrico/metabolismo , Uricosúricos/metabolismo , Radioisótopos de Carbono/metabolismo , Citocromo P-450 CYP2C8/metabolismo , Citocromo P-450 CYP3A/metabolismo , Fezes , Trato Gastrointestinal/metabolismo , Glucuronídeos/metabolismo , Glucuronosiltransferase/metabolismo , Gota/tratamento farmacológico , Gota/metabolismo , Meia-Vida , Humanos , Hidrólise/efeitos dos fármacos , Hiperuricemia/tratamento farmacológico , Hiperuricemia/metabolismo , Fígado/efeitos dos fármacos , Fígado/metabolismo , Masculino , Taxa de Depuração Metabólica/efeitos dos fármacos , Taxa de Depuração Metabólica/fisiologia , Uricosúricos/uso terapêutico
9.
Drug Metab Dispos ; 46(2): 189-196, 2018 02.
Artigo em Inglês | MEDLINE | ID: mdl-29138286

RESUMO

Protein expression of major hepatobiliary drug transporters (NTCP, OATPs, OCT1, BSEP, BCRP, MATE1, MRPs, and P-gp) in cancerous (C, n = 8) and adjacent noncancerous (NC, n = 33) liver tissues obtained from patients with chronic hepatitis C with hepatocellular carcinoma (HCV-HCC) were quantified by LC-MS/MS proteomics. Herein, we compare our results with our previous data from noninfected, noncirrhotic (control, n = 36) and HCV-cirrhotic (n = 30) livers. The amount of membrane protein yielded from NC and C HCV-HCC tissues decreased (31%, 67%) relative to control livers. In comparison with control livers, with the exception of NTCP, MRP2, and MATE1, transporter expression decreased in NC (38%-76%) and C (56%-96%) HCV-HCC tissues. In NC HCV-HCC tissues, NTCP expression increased (113%), MATE1 expression decreased (58%), and MRP2 expression was unchanged relative to control livers. In C HCV-HCC tissues, NTCP and MRP2 expression decreased (63%, 56%) and MATE1 expression was unchanged relative to control livers. Compared with HCV-cirrhotic livers, aside from NTCP, OCT1, BSEP, and MRP2, transporter expression decreased in NC (41%-71%) and C (54%-89%) HCV-HCC tissues. In NC HCV-HCC tissues, NTCP and MRP2 expression increased (362%, 142%), whereas OCT1 and BSEP expression was unchanged. In C HCV-HCC tissues, OCT1 and BSEP expression decreased (90%, 80%) relative to HCV-cirrhotic livers, whereas NTCP and MRP2 expression was unchanged. Expression of OATP2B1, BSEP, MRP2, and MRP3 decreased (56%-72%) in C HCV-HCC tissues in comparison with matched NC tissues (n = 8), but the expression of other transporters was unchanged. These data will be helpful in the future to predict transporter-mediated hepatocellular drug concentrations in patients with HCV-HCC.


Assuntos
Carcinoma Hepatocelular/metabolismo , Hepatite C Crônica/metabolismo , Neoplasias Hepáticas/metabolismo , Fígado/metabolismo , Transportadores de Cassetes de Ligação de ATP/metabolismo , Cromatografia Líquida/métodos , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Proteínas Associadas à Resistência a Múltiplos Medicamentos/metabolismo , Transportadores de Ânions Orgânicos/metabolismo , Proteômica/métodos , Espectrometria de Massas em Tandem/métodos
10.
J Pharm Sci ; 106(12): 3442-3452, 2017 12.
Artigo em Inglês | MEDLINE | ID: mdl-28927987

RESUMO

Regulatory agencies have recently issued drug-drug interaction guidelines, which require determination of plasma protein binding (PPB). To err on the conservative side, the agencies recommend that a 0.01 lower limit of fraction unbound (fu) be used for highly bound compounds (>99%), irrespective of the actual measured values. While this may avoid false negatives, the recommendation would likely result in a high rate of false positive predictions, resulting in unnecessary clinical studies and more stringent inclusion/exclusion criteria, which may add cost and time in delivery of new medicines to patients. In this perspective, we provide a review of current approaches to measure PPB, and important determinants in enabling the accuracy and precision in these measurements. The ability to measure fu is further illustrated by a cross-company data comparison of PPB for warfarin and itraconazole, demonstrating good concordance of the measured fu values. The data indicate that fu values of ≤0.01 may be determined accurately across laboratories when appropriate methods are used. These data, along with numerous other examples presented in the literature, support the use of experimentally measured fu values for drug-drug interaction predictions, rather than using the arbitrary cutoff value of 0.01 as recommended in current regulatory guidelines.


Assuntos
Proteínas Sanguíneas/metabolismo , Interações de Medicamentos/fisiologia , Preparações Farmacêuticas/química , Preparações Farmacêuticas/normas , Ligação Proteica/fisiologia , Animais , Indústria Farmacêutica/normas , Humanos , Preparações Farmacêuticas/metabolismo , Plasma/metabolismo
11.
Drug Des Devel Ther ; 10: 3555-3562, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-27843295

RESUMO

INTRODUCTION: Lesinurad is a selective uric acid reabsorption inhibitor approved for the treatment of gout in combination with a xanthine oxidase inhibitor (XOI) in patients who have not achieved target serum uric acid (sUA) levels with an XOI alone. Most people with gout have chronic kidney disease. The pharmacokinetics, pharmacodynamics, and safety of lesinurad were assessed in subjects with impaired renal function. METHODS: Two Phase I, multicenter, open-label, single-dose studies enrolled subjects with normal renal function (estimated creatinine clearance [eCrCl] >90 mL/min; N=12) or mild (eCrCl 60-89 mL/min; N=8), moderate (eCrCl 30-59 mL/min; N=16), or severe (eCrCl <30 mL/min; N=6) renal impairment. Subjects were given a single oral lesinurad dose of 200 mg (N=24) or 400 mg (N=18). Blood and urine samples were analyzed for plasma lesinurad concentrations and serum and urine uric acid concentrations. Safety was assessed by adverse events and laboratory data. RESULTS: Mild, moderate, and severe renal impairment increased lesinurad plasma area under the plasma concentration-time curve by 34%, 54%-65%, and 102%, respectively. Lesinurad plasma Cmax was unaffected by renal function status. Lower renal clearance and urinary excretion of lesinurad were associated with the degree of renal impairment. The sUA-lowering effect of a single dose of lesinurad was similar between mild renal impairment and normal function, reduced in moderate impairment, and greatly diminished in severe impairment. Lesinurad increased urinary urate excretion in normal function and mild renal impairment; the increase was less with moderate or severe renal impairment. Lesinurad was well tolerated by all subjects. CONCLUSION: Lesinurad exposure increased with decreasing renal function; however, the effects of lesinurad on sUA were attenuated in moderate to severe renal impairment.


Assuntos
Taxa de Filtração Glomerular , Supressores da Gota/farmacocinética , Nefropatias/fisiopatologia , Rim/fisiopatologia , Tioglicolatos/farmacocinética , Triazóis/farmacocinética , Administração Oral , Adulto , Idoso , Área Sob a Curva , Disponibilidade Biológica , Biomarcadores/sangue , Biomarcadores/urina , Creatinina/sangue , Feminino , Supressores da Gota/administração & dosagem , Supressores da Gota/efeitos adversos , Humanos , Nefropatias/sangue , Nefropatias/diagnóstico , Masculino , Taxa de Depuração Metabólica , Pessoa de Meia-Idade , Eliminação Renal , Índice de Gravidade de Doença , Tioglicolatos/administração & dosagem , Tioglicolatos/efeitos adversos , Triazóis/administração & dosagem , Triazóis/efeitos adversos , Ácido Úrico/sangue , Ácido Úrico/urina
12.
Drug Des Devel Ther ; 10: 3509-3517, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-27826183

RESUMO

INTRODUCTION: Lesinurad is a selective uric acid reabsorption inhibitor approved in the United States and Europe for treatment of gout in combination with a xanthine oxidase inhibitor. A maximum tolerated dose study was conducted to determine the lesinurad supratherapeutic dose, followed by a thorough QTc study to characterize the effect of lesinurad on cardiac repolarization. METHODS: The maximum tolerated dose study was a randomized, double-blind, placebo-controlled, single-ascending dose study that enrolled 35 healthy men and women. Lesinurad plasma exposure (maximum observed plasma concentration and area under the plasma concentration versus time curve) was determined at doses of 800 mg, 1,200 mg, and 1,600 mg. The thorough QTc study was a double-blind, four-period, placebo-controlled crossover study with 54 healthy men and women who received single doses of lesinurad 1,600 mg (supratherapeutic dose), lesinurad 400 mg, moxifloxacin 400 mg, and placebo in randomized sequence. Digital 12-lead electrocardiograms were recorded at eleven time points over 24 hours in each treatment period. QT intervals were corrected for heart rate using an individual-specific correction factor (QTcI). RESULTS: The upper bound of the one-sided 95% confidence interval for time-matched, placebo-subtracted, baseline-adjusted QTcI intervals (ΔΔQTcI) was <10 ms for both the lesinurad 400 mg and 1,600 mg doses. ΔΔQTcI was independent of lesinurad concentrations. No QTcI thresholds >480 ms or QTcI increases >30 ms were observed. Moxifloxacin mean QTcI intervals were >5 ms, and the lower bounds of the 90% confidence interval were >5 ms at 2 hours, 3 hours, and 4 hours, confirming assay sensitivity. CONCLUSION: Lesinurad, at supratherapeutic doses, does not have a significant effect on the QT interval in healthy male or female subjects.


Assuntos
Frequência Cardíaca/efeitos dos fármacos , Tioglicolatos/farmacologia , Triazóis/farmacologia , Ácido Úrico/antagonistas & inibidores , Ácido Úrico/metabolismo , Xantina Oxidase/antagonistas & inibidores , Estudos Cross-Over , Relação Dose-Resposta a Droga , Método Duplo-Cego , Eletrocardiografia , Europa (Continente) , Feminino , Humanos , Masculino , Estatística como Assunto , Tioglicolatos/química , Triazóis/química , Ácido Úrico/química , Xantina Oxidase/química , Xantina Oxidase/metabolismo
13.
Drug Metab Dispos ; 43(4): 490-509, 2015 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-25587128

RESUMO

Breast cancer resistance protein (BCRP; ABCG2) limits intestinal absorption of low-permeability substrate drugs and mediates biliary excretion of drugs and metabolites. Based on clinical evidence of BCRP-mediated drug-drug interactions (DDIs) and the c.421C>A functional polymorphism affecting drug efficacy and safety, both the US Food and Drug Administration and European Medicines Agency recommend preclinical evaluation and, when appropriate, clinical assessment of BCRP-mediated DDIs. Although many BCRP substrates and inhibitors have been identified in vitro, clinical translation has been confounded by overlap with other transporters and metabolic enzymes. Regulatory recommendations for BCRP-mediated clinical DDI studies are challenging, as consensus is lacking on the choice of the most robust and specific human BCRP substrates and inhibitors and optimal study design. This review proposes a path forward based on a comprehensive analysis of available data. Oral sulfasalazine (1000 mg, immediate-release tablet) is the best available clinical substrate for intestinal BCRP, oral rosuvastatin (20 mg) for both intestinal and hepatic BCRP, and intravenous rosuvastatin (4 mg) for hepatic BCRP. Oral curcumin (2000 mg) and lapatinib (250 mg) are the best available clinical BCRP inhibitors. To interrogate the worst-case clinical BCRP DDI scenario, study subjects harboring the BCRP c.421C/C reference genotype are recommended. In addition, if sulfasalazine is selected as the substrate, subjects having the rapid acetylator phenotype are recommended. In the case of rosuvastatin, subjects with the organic anion-transporting polypeptide 1B1 c.521T/T genotype are recommended, together with monitoring of rosuvastatin's cholesterol-lowering effect at baseline and DDI phase. A proof-of-concept clinical study is being planned by a collaborative consortium to evaluate the proposed BCRP DDI study design.


Assuntos
Transportadores de Cassetes de Ligação de ATP/antagonistas & inibidores , Interações de Medicamentos , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/metabolismo , Proteínas de Neoplasias/antagonistas & inibidores , Preparações Farmacêuticas/metabolismo , Farmacocinética , Membro 2 da Subfamília G de Transportadores de Cassetes de Ligação de ATP , Transportadores de Cassetes de Ligação de ATP/genética , Ensaios Clínicos como Assunto , Resistência a Múltiplos Medicamentos , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/genética , Humanos , Proteínas de Neoplasias/genética , Polimorfismo de Nucleotídeo Único , Guias de Prática Clínica como Assunto , Projetos de Pesquisa , Especificidade por Substrato
14.
Drug Metab Dispos ; 41(8): 1575-83, 2013 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-23729661

RESUMO

Axitinib is an inhibitor of tyrosine kinase vascular endothelin growth factor receptors 1, 2, and 3. The ATP-binding cassette (ABC) and solute carrier (SLC) transport properties of axitinib were determined in selected cellular systems. Axitinib exhibited high passive permeability in all cell lines evaluated (Papp ≥ 6 × 10(-6) cm/s). Active efflux was observed in Caco-2 cells, and further evaluation in multidrug resistance gene 1 (MDR1) or breast cancer resistance protein (BCRP) transfected Madin-Darby canine kidney cells type 2 (MDCK) cells indicated that axitinib is at most only a weak substrate for P-glycoprotein (P-gp) but not BCRP. Axitinib showed incomplete inhibition of P-gp-mediated transport of digoxin in Caco-2 cells and BCRP transport of topotecan in BCRP-transfected MDCK cells with IC50 values of 3 µM and 4.4 µM, respectively. Axitinib (10 mg) did not pose a risk for systemic drug interactions with P-gp or BCRP per regulatory guidance. A potential risk for drug interactions through inhibition of P-gp and BCRP in the gastrointestinal tract was identified because an axitinib dose of 10 mg divided by 250 mL was greater than 10-fold the IC50 for each transporter. However, a GastroPlus simulation that considered the low solubility of axitinib resulted in lower intestinal concentrations and suggested a low potential for gastrointestinal interactions with P-gp and BCRP substrates. Organic anion transporting polypeptide 1B1 (OATP1B1) and OATP1B3 transfected human embryonic kidney 293 (HEK293) cells transported axitinib to a minor extent but uptake into suspended hepatocytes was not inhibited by rifamycin SV suggesting that high passive permeability predominates. Mouse whole-body autoradiography revealed that [(14)C]axitinib-equivalents showed rapid absorption and distribution to all tissues except the brain. This suggests that efflux transport of axitinib may occur at the mouse blood-brain barrier.


Assuntos
Membro 1 da Subfamília B de Cassetes de Ligação de ATP/fisiologia , Transportadores de Cassetes de Ligação de ATP/fisiologia , Imidazóis/metabolismo , Indazóis/metabolismo , Fígado/metabolismo , Proteínas de Neoplasias/fisiologia , Inibidores de Proteínas Quinases/metabolismo , Membro 1 da Subfamília B de Cassetes de Ligação de ATP/antagonistas & inibidores , Membro 2 da Subfamília G de Transportadores de Cassetes de Ligação de ATP , Transportadores de Cassetes de Ligação de ATP/antagonistas & inibidores , Animais , Autorradiografia , Axitinibe , Células CACO-2 , Interações de Medicamentos , Hepatócitos/metabolismo , Humanos , Imidazóis/química , Indazóis/química , Camundongos , Proteínas de Neoplasias/antagonistas & inibidores , Permeabilidade , Medição de Risco , Solubilidade
15.
Drug Metab Dispos ; 41(7): 1367-74, 2013 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-23620486

RESUMO

In the 2012 Food and Drug Administration (FDA) draft guidance on drug-drug interactions (DDIs), a new molecular entity that inhibits P-glycoprotein (P-gp) may need a clinical DDI study with a P-gp substrate such as digoxin when the maximum concentration of inhibitor at steady state divided by IC50 ([I1]/IC50) is ≥0.1 or concentration of inhibitor based on highest approved dose dissolved in 250 ml divide by IC50 ([I2]/IC50) is ≥10. In this article, refined criteria are presented, determined by receiver operating characteristic analysis, using IC50 values generated by 23 laboratories. P-gp probe substrates were digoxin for polarized cell-lines and N-methyl quinidine or vinblastine for P-gp overexpressed vesicles. Inhibition of probe substrate transport was evaluated using 15 known P-gp inhibitors. Importantly, the criteria derived in this article take into account variability in IC50 values. Moreover, they are statistically derived based on the highest degree of accuracy in predicting true positive and true negative digoxin DDI results. The refined criteria of [I1]/IC50 ≥ 0.03 and [I2]/IC50 ≥ 45 and FDA criteria were applied to a test set of 101 in vitro-in vivo digoxin DDI pairs collated from the literature. The number of false negatives (none predicted but DDI observed) were similar, 10 and 12%, whereas the number of false positives (DDI predicted but not observed) substantially decreased from 51 to 40%, relative to the FDA criteria. On the basis of estimated overall variability in IC50 values, a theoretical 95% confidence interval calculation was developed for single laboratory IC50 values, translating into a range of [I1]/IC50 and [I2]/IC50 values. The extent by which this range falls above the criteria is a measure of risk associated with the decision, attributable to variability in IC50 values.


Assuntos
Digoxina/farmacocinética , Membro 1 da Subfamília B de Cassetes de Ligação de ATP/antagonistas & inibidores , Árvores de Decisões , Interações de Medicamentos , Humanos , Curva ROC , Estados Unidos , United States Food and Drug Administration
16.
Drug Metab Dispos ; 40(5): 943-51, 2012 May.
Artigo em Inglês | MEDLINE | ID: mdl-22328583

RESUMO

CYP2J2, an arachidonic acid epoxygenase, is recognized for its role in the first-pass metabolism of astemizole and ebastine. To fully assess the role of CYP2J2 in drug metabolism, a selective substrate and potent specific chemical inhibitor are essential. In this study, we report amiodarone 4-hydoxylation as a specific CYP2J2-catalyzed reaction with no CYP3A4, or other drug-metabolizing enzyme, involvement. Amiodarone 4-hydroxylation enabled the determination of liver relative activity factor and intersystem extrapolation factor for CYP2J2. Amiodarone 4-hydroxylation correlated with astemizole O-demethylation but not with CYP2J2 protein content in a sample of human liver microsomes. To identify a specific CYP2J2 inhibitor, 138 drugs were screened using terfenadine and astemizole as probe substrates with recombinant CYP2J2. Forty-two drugs inhibited CYP2J2 activity by ≥50% at 30 µM, but inhibition was substrate-dependent. Of these, danazol was a potent inhibitor of both hydroxylation of terfenadine (IC(50) = 77 nM) and O-demethylation of astemizole (K(i) = 20 nM), and inhibition was mostly competitive. Danazol inhibited CYP2C9, CYP2C8, and CYP2D6 with IC(50) values of 1.44, 1.95, and 2.74 µM, respectively. Amiodarone or astemizole were included in a seven-probe cocktail for cytochrome P450 (P450) drug-interaction screening potential, and astemizole demonstrated a better profile because it did not appreciably interact with other P450 probes. Thus, danazol, amiodarone, and astemizole will facilitate the ability to determine the metabolic role of CYP2J2 in hepatic and extrahepatic tissues.


Assuntos
Amiodarona/metabolismo , Astemizol/metabolismo , Sistema Enzimático do Citocromo P-450/metabolismo , Danazol , Inibidores Enzimáticos , Microssomos Hepáticos/enzimologia , Terfenadina/metabolismo , Amiodarona/química , Astemizol/química , Cromatografia Líquida de Alta Pressão , Citocromo P-450 CYP3A/metabolismo , Inibidores das Enzimas do Citocromo P-450 , Sistema Enzimático do Citocromo P-450/genética , Danazol/química , Danazol/metabolismo , Danazol/farmacologia , Descoberta de Drogas , Interações de Medicamentos , Inibidores Enzimáticos/química , Inibidores Enzimáticos/metabolismo , Inibidores Enzimáticos/farmacologia , Humanos , Hidroxilação , Técnicas In Vitro , Metilação , Microssomos Hepáticos/metabolismo , Modelos Biológicos , Estrutura Molecular , Especificidade por Substrato , Espectrometria de Massas em Tandem , Terfenadina/química
17.
Drug Metab Dispos ; 39(11): 2093-102, 2011 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-21849517

RESUMO

Digoxin, an orally administered cardiac glycoside cardiovascular drug, has a narrow therapeutic window. Circulating digoxin levels (maximal concentration of ∼1.5 ng/ml) require careful monitoring, and the potential for drug-drug interactions (DDI) is a concern. Increases in digoxin plasma exposure caused by inhibition of P-glycoprotein (P-gp) have been reported. Digoxin has also been described as a substrate of various organic anion-transporting polypeptide (OATP) transporters, posing a risk that inhibition of OATPs may result in a clinically relevant DDI similar to what has been observed for P-gp. Although studies in rats have shown that Oatps contribute to the disposition of digoxin, the role of OATPs in the disposition of digoxin in humans has not been clearly defined. Using two methods, Boehringer Ingelheim, GlaxoSmithKline, Pfizer, and Solvo observed that digoxin is not a substrate of OATP1A2, OATP1B1, OATP1B3, and OATP2B1. However, digoxin inhibited the uptake of probe substrates of OATP1B1 (IC(50) of 47 µM), OATP1B3 (IC(50) > 8.1 µM), and OATP2B1 (IC(50) > 300 µM), but not OATP1A2 in transfected cell lines. It is interesting to note that digoxin is a substrate of a sodium-dependent transporter endogenously expressed in HEK293 cells because uptake of digoxin was significantly greater in cells incubated with sodium-fortified media compared with incubations conducted in media in which sodium was absent. Thus, although digoxin is not a substrate for the human OATP transporters evaluated in this study, in addition to P-gp-mediated efflux, its uptake and pharmacokinetic disposition may be partially facilitated by a sodium-dependent transporter.


Assuntos
Digoxina/metabolismo , Transportadores de Ânions Orgânicos Sódio-Independentes/metabolismo , Transportadores de Ânions Orgânicos/metabolismo , Membro 1 da Subfamília B de Cassetes de Ligação de ATP/metabolismo , Animais , Transporte Biológico , Células CHO , Células Cultivadas , Cricetinae , Interações de Medicamentos , Células HEK293 , Humanos , Transportador 1 de Ânion Orgânico Específico do Fígado , Transportadores de Ânions Orgânicos/genética , Transportadores de Ânions Orgânicos Sódio-Independentes/genética , RNA Mensageiro/genética , Sódio/metabolismo , Membro 1B3 da Família de Transportadores de Ânion Orgânico Carreador de Soluto , Especificidade por Substrato
18.
Expert Opin Drug Metab Toxicol ; 6(5): 603-19, 2010 May.
Artigo em Inglês | MEDLINE | ID: mdl-20397967

RESUMO

IMPORTANCE OF THE FIELD: P-glycoprotein (P-gp) is the most characterized drug transporter in terms of its clinical relevance for pharmacokinetic disposition and interaction with other medicines. Clinically significant P-gp related drug interactions appear restricted to digoxin. P-gp may act as a major barrier to current and effective drug treatment in a number of diseases including cancer, AIDS, Alzheimer's and epilepsy due to its expression in tumors, lymphocytes, cell membranes of brain capillaries and the choroid plexus. AREAS COVERED IN THIS REVIEW: This review summarizes the current understanding of P-gp structure/function, clinical importance of P-gp related drug interactions and the modulatory role this transporter may contribute towards drug efficacy in disease states such as cancer, AIDS, Alzheimer's and epilepsy. WHAT THE READER WILL GAIN: The reader will gain an understanding that the clinical relevance of P-gp in drug interactions is limited. In certain disease states, P-gp in barrier tissues can modulate changes in regional distribution. TAKE HOME MESSAGE: P-gp inhibition in isolation will not result in clinically important alterations in systemic exposure; however, P-gp transport may be of significance in barrier tissues (tumors, lymphocytes, brain) resulting in attenuated efficacy.


Assuntos
Membro 1 da Subfamília B de Cassetes de Ligação de ATP/metabolismo , Preparações Farmacêuticas/metabolismo , Membro 1 da Subfamília B de Cassetes de Ligação de ATP/genética , Animais , Sítios de Ligação , Transporte Biológico , Digoxina/farmacocinética , Interações de Medicamentos , Expressão Gênica , Humanos , Polimorfismo Genético , Ligação Proteica
19.
Nat Rev Drug Discov ; 9(3): 215-36, 2010 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-20190787

RESUMO

Membrane transporters can be major determinants of the pharmacokinetic, safety and efficacy profiles of drugs. This presents several key questions for drug development, including which transporters are clinically important in drug absorption and disposition, and which in vitro methods are suitable for studying drug interactions with these transporters. In addition, what criteria should trigger follow-up clinical studies, and which clinical studies should be conducted if needed. In this article, we provide the recommendations of the International Transporter Consortium on these issues, and present decision trees that are intended to help guide clinical studies on the currently recognized most important drug transporter interactions. The recommendations are generally intended to support clinical development and filing of a new drug application. Overall, it is advised that the timing of transporter investigations should be driven by efficacy, safety and clinical trial enrolment questions (for example, exclusion and inclusion criteria), as well as a need for further understanding of the absorption, distribution, metabolism and excretion properties of the drug molecule, and information required for drug labelling.


Assuntos
Descoberta de Drogas/métodos , Avaliação Pré-Clínica de Medicamentos/métodos , Proteínas de Membrana Transportadoras/efeitos dos fármacos , Proteínas de Membrana Transportadoras/metabolismo , Medicamentos sob Prescrição/farmacocinética , Animais , Simulação por Computador , Árvores de Decisões , Aprovação de Drogas , Interações de Medicamentos , Humanos , Proteínas de Membrana Transportadoras/genética , Camundongos , Camundongos Knockout , Medicamentos sob Prescrição/efeitos adversos
20.
Drug Metab Dispos ; 38(2): 347-56, 2010 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-19923256

RESUMO

Several antihistamine drugs including terfenadine, ebastine, and astemizole have been identified as substrates for CYP2J2. The overall importance of this enzyme in drug metabolism has not been fully explored. In this study, 139 marketed therapeutic agents and compounds were screened as potential CYP2J2 substrates. Eight novel substrates were identified that vary in size and overall topology from relatively rigid structures (amiodarone) to larger complex structures (cyclosporine). The substrates displayed in vitro intrinsic clearance values ranging from 0.06 to 3.98 mul/min/pmol CYP2J2. Substrates identified for CYP2J2 are also metabolized by CYP3A4. Extracted ion chromatograms of metabolites observed for albendazole, amiodarone, astemizole, thioridazine, mesoridazine, and danazol showed marked differences in the regioselectivity of CYP2J2 and CYP3A4. CYP3A4 commonly metabolized compounds at multiple sites, whereas CYP2J2 metabolism was more restrictive and limited, in general, to a single site for large compounds. Although the CYP2J2 active site can accommodate large substrates, it may be more narrow than CYP3A4, limiting metabolism to moieties that can extend closer toward the active heme iron. For albendazole, CYP2J2 forms a unique metabolite compared with CYP3A4. Albendazole and amiodarone were evaluated in various in vitro systems including recombinant CYP2J2 and CYP3A4, pooled human liver microsomes (HLM), and human intestinal microsomes (HIM). The Michaelis-Menten-derived intrinsic clearance of N-desethyl amiodarone was 4.6 greater in HLM than in HIM and 17-fold greater in recombinant CYP3A4 than in recombinant CYP2J2. The resulting data suggest that CYP2J2 may be an unrecognized participant in first-pass metabolism, but its contribution is minor relative to that of CYP3A4.


Assuntos
Sistema Enzimático do Citocromo P-450/metabolismo , Preparações Farmacêuticas/metabolismo , Algoritmos , Domínio Catalítico , Cromatografia Líquida de Alta Pressão , Citocromo P-450 CYP3A/química , Citocromo P-450 CYP3A/metabolismo , Inibidores do Citocromo P-450 CYP3A , Inibidores das Enzimas do Citocromo P-450 , Sistema Enzimático do Citocromo P-450/química , Inibidores Enzimáticos/farmacologia , Humanos , Mucosa Intestinal/metabolismo , Isoenzimas/química , Isoenzimas/metabolismo , Cinética , Fígado/metabolismo , Microssomos/metabolismo , Modelos Estruturais , Especificidade de Órgãos , Preparações Farmacêuticas/química , Proteínas Recombinantes/metabolismo , Espectrometria de Massas por Ionização por Electrospray , Especificidade por Substrato , Espectrometria de Massas em Tandem
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