Your browser doesn't support javascript.
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 22
Filtrar
Mais filtros










Base de dados
Intervalo de ano de publicação
1.
CPT Pharmacometrics Syst Pharmacol ; 8(9): 664-675, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31250974

RESUMO

The drug-drug interaction profile of atorvastatin confirms that disposition is determined by cytochrome P450 (CYP) 3A4 and organic anion transporting polypeptides (OATPs). Drugs that affect gastric emptying, including dulaglutide, also affect atorvastatin pharmacokinetics (PK). Atorvastatin is a carboxylic acid that exists in equilibrium with a lactone form in vivo. The purpose of this work was to assess gastric acid-mediated lactone equilibration of atorvastatin and incorporate this into a physiologically-based PK (PBPK) model to describe atorvastatin acid, lactone, and their major metabolites. In vitro acid-to-lactone conversion was assessed in simulated gastric fluid and included in the model. The PBPK model was verified with in vivo data including CYP3A4 and OATP inhibition studies. Altering the gastric acid-lactone equilibrium reproduced the change in atorvastatin PK observed with dulaglutide. The model emphasizes the need to include gastric acid-lactone conversion and all major atorvastatin-related species for the prediction of atorvastatin PK.

2.
Drug Metab Dispos ; 47(3): 215-226, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-30593544

RESUMO

In the present study, the beagle dog was evaluated as a preclinical model to investigate organic anion transporting polypeptide (OATP)-mediated hepatic clearance. In vitro studies were performed with nine OATP substrates in three lots of plated male dog hepatocytes ± OATP inhibitor cocktail to determine total uptake clearance (CLuptake) and total and unbound cell-to-medium concentration ratio (Kpuu). In vivo intrinsic hepatic clearances (CLint,H) were determined following intravenous drug administration (0.1 mg/kg) in male beagle dogs. The in vitro parameters were compared with those previously reported in plated human, monkey, and rat hepatocytes; the ability of cross-species scaling factors to improve prediction of human in vivo clearance was assessed. CLuptake in dog hepatocytes ranged from 9.4 to 135 µl/min/106 cells for fexofenadine and telmisartan, respectively. Active process contributed >75% to CLuptake for 5/9 drugs. Rosuvastatin and valsartan showed Kpuu > 10, whereas cerivastatin, pitavastatin, repaglinide, and telmisartan had Kpuu < 5. The extent of hepatocellular binding in dog was consistent with other preclinical species and humans. The bias (2.73-fold) obtained from comparison of predicted versus in vivo dog CLint,H was applied as an average empirical scaling factor (ESFav) for in vitro-in vivo extrapolation of human CLint,H The ESFav based on dog reduced underprediction of human CLint,H for the same data set (geometric mean fold error = 2.1), highlighting its utility as a preclinical model to investigate OATP-mediated uptake. The ESFav from all preclinical species resulted in comparable improvement of human clearance prediction, in contrast to drug-specific empirical scalars, rationalized by species differences in expression and/or relative contribution of particular transporters to drug hepatic uptake.


Assuntos
Avaliação Pré-Clínica de Medicamentos/métodos , Taxa de Depuração Metabólica , Transportadores de Ânions Orgânicos/metabolismo , Preparações Farmacêuticas/metabolismo , Especificidade da Espécie , Animais , Cães , Hepatócitos/metabolismo , Humanos , Infusões Intravenosas , Fígado/citologia , Fígado/metabolismo , Masculino , Modelos Animais , Modelos Biológicos , Preparações Farmacêuticas/administração & dosagem
3.
Clin Pharmacol Ther ; 104(3): 525-533, 2018 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-29218707

RESUMO

Rosuvastatin is commonly prescribed for the treatment of hypercholesterolemia and hepatic transporter-mediated accumulation in the liver enhances its efficacy. Current guidelines indicate no preference for fed or fasted rosuvastatin administration. We investigated the association between food intake and rosuvastatin disposition in healthy subjects and low-density lipoprotein cholesterol (LDL-C)-lowering effects among patients taking rosuvastatin. We demonstrate that administration with food resulted in a near 40% reduction of rosuvastatin exposure in healthy Asian (n = 12) and Caucasian (n = 11) subjects. Higher rosuvastatin concentrations in Asian subjects also correlated with higher allele frequency of ABCG2 c.421C>A. In mice, a greater rosuvastatin liver:plasma ratio was noted when administered with food. Among rosuvastatin patients (n = 156), there was no difference in dose needed to reach target LDL-C, measured LDL-C, or lathosterol concentrations, when administered in a fed or fasting state. Therefore, taking rosuvastatin with food could reduce systemic concentrations, and subsequent myopathy risk, without compromising LDL-C-lowering benefit.

4.
AAPS J ; 20(1): 21, 2017 12 26.
Artigo em Inglês | MEDLINE | ID: mdl-29280004

RESUMO

The drug of abuse γ-hydroxybutyric acid (GHB) demonstrates complex toxicokinetics with dose-dependent metabolic and renal clearance. GHB is a substrate of monocarboxylate transporters (MCTs) which are responsible for the saturable renal reabsorption of GHB. MCT expression is observed in many tissues and therefore may impact the tissue distribution of GHB. The objective of the present study was to evaluate the tissue distribution kinetics of GHB at supratherapeutic doses. GHB (400, 600, and 800 mg/kg iv) or GHB 600 mg/kg plus L-lactate (330 mg/kg iv bolus followed by 121 mg/kg/h infusion) was administered to rats and blood and tissues were collected for up to 330 min post-dose. K p values for GHB varied in both a tissue- and dose-dependent manner and were less than 0.5 (except in the kidney). Nonlinear partitioning was observed in the liver (0.06 at 400 mg/kg to 0.30 at 800 mg/kg), kidney (0.62 at 400 mg/kg to 0.98 at 800 mg/kg), and heart (0.15 at 400 mg/kg to 0.29 at 800 mg/kg), with K p values increasing with dose consistent with saturation of transporter-mediated efflux. In contrast, lung partitioning decreased in a dose-dependent manner (0.43 at 400 mg/kg to 0.25 at 800 mg/kg) suggesting saturation of active uptake. L-lactate administration decreased K p values in liver, striatum, and hippocampus and increased K p values in lung and spleen. GHB demonstrates tissue-specific nonlinear distribution consistent with the involvement of monocarboxylate transporters. These observed complexities are likely due to the involvement of MCT1 and 4 with different affinities and directionality for GHB transport.

5.
AAPS J ; 19(6): 1878-1889, 2017 11.
Artigo em Inglês | MEDLINE | ID: mdl-29019117

RESUMO

In the present investigations, we evaluate in vitro hepatocyte uptake and partitioning for the prediction of in vivo clearance and liver partitioning. Monkeys were intravenously co-dosed with rosuvastatin and bosentan, substrates of the organic anion transporting polypeptides (OATPs), and metformin, a substrate of organic cation transporter 1 (OCT1). Serial plasma and liver samples were collected over time. Liver and plasma unbound fraction was determined using equilibrium dialysis. In vivo unbound partitioning (Kpu,u) for rosuvastatin, bosentan, and metformin, calculated from total concentrations in the liver and plasma, were 243, 553, and 15, respectively. A physiologically based pharmacokinetic monkey model that incorporates active and passive hepatic uptake was developed to fit plasma and liver concentrations. In addition, a two-compartment model was used to fit in vitro hepatic uptake curves in suspended monkey hepatocyte to determine active uptake, passive diffusion, and intracellular unbound fraction parameters. At steady-state in the model, in vitro Kpu,u was determined. The results demonstrated that in vitro values under-predicted in vivo active uptake for rosuvastatin, bosentan, and metformin by 6.7-, 28-, and 1.5-fold, respectively, while passive diffusion was over-predicted. In vivo Kpu,u values were under-predicted from in vitro data by 30-, 79-, and 3-fold. In conclusion, active uptake and liver partitioning in monkeys for OATP substrates were greatly under-predicted from in vitro hepatocyte uptake, while OCT-mediated uptake and partitioning scaled reasonably well from in vitro, demonstrating substrate- and transporter-dependent scaling factors. The combination of in vitro experimental and modeling approaches proved useful for assessing prediction of in vivo intracellular partitioning.


Assuntos
Fígado/metabolismo , Transportadores de Ânions Orgânicos/fisiologia , Transportador 1 de Cátions Orgânicos/fisiologia , Animais , Bosentana , Macaca fascicularis , Metformina/farmacocinética , Modelos Biológicos , Rosuvastatina Cálcica/farmacocinética , Sulfonamidas/farmacocinética
6.
Am J Drug Alcohol Abuse ; 43(6): 686-693, 2017 11.
Artigo em Inglês | MEDLINE | ID: mdl-28662343

RESUMO

BACKGROUND: γ-hydroxybutyrate (GHB) has a high potential for illicit use; overdose of this compound results in sedation, respiratory depression and death. Tolerance to the hypnotic/sedative and electroencephalogram effects of GHB occurs with chronic GHB administration; however, tolerance to respiratory depression has not been evaluated. GHB toxicodynamic effects are mediated predominantly by GABAB receptors. Chronic treatment may affect monocarboxylate transporters (MCTs) and alter the absorption, renal clearance and brain uptake of GHB. OBJECTIVES: To determine effects of chronic GHB dosing on GHB toxicokinetics, GHB-induced respiratory depression, and MCT expression. METHODS: Rats were administered GHB 600 mg/kg intravenously daily for 5 days. Plasma, urine and tissue samples and respiratory measurements were obtained on days 1 and 5. Plasma and urine were analyzed for GHB by LC/MS/MS and tissue samples for expression of MCT1, 2 and 4 and their accessory proteins by QRT-PCR. RESULTS: No differences in GHB pharmacokinetics or respiratory depression were observed between days 1 and 5. Opposing changes in MCT1 and MCT4 mRNA expression were observed in kidney samples on day 5 compared to GHB-naïve animals, and MCT4 expression was increased in the intestine. CONCLUSIONS: The lack of tolerance observed with GHB-induced respiratory depression, in contrast to the tolerance reported for the sedative/hypnotic and electroencephalogram effects, suggests that different GABAB receptor subtypes may be involved in different GABAB-mediated toxicodynamic effects of GHB. Chronic or binge users of GHB may be at no less risk for fatality from respiratory arrest with a GHB overdose than with a single dose of GHB.


Assuntos
Transportadores de Ácidos Monocarboxílicos/biossíntese , Insuficiência Respiratória/induzido quimicamente , Oxibato de Sódio/efeitos adversos , Oxibato de Sódio/farmacocinética , Animais , Células Cultivadas , Hipnóticos e Sedativos/efeitos adversos , Hipnóticos e Sedativos/sangue , Hipnóticos e Sedativos/farmacocinética , Hipnóticos e Sedativos/urina , Masculino , Ratos , Oxibato de Sódio/sangue , Oxibato de Sódio/urina , Fatores de Tempo , Toxicocinética
7.
Mol Pharm ; 14(1): 310-318, 2017 01 03.
Artigo em Inglês | MEDLINE | ID: mdl-27977217

RESUMO

Trimethylamine-N-oxide (TMAO) is a recently identified predictor of cardiovascular and chronic kidney disease. TMAO is primarily generated through gut-microbiome mediated conversion of dietary choline and carnitine to TMA, which is converted to TMAO by hepatic flavin monooxygenase 3 (FMO3) and subsequently undergoes renal elimination. We investigated the role of uptake and efflux drug transporters in TMAO disposition in vitro and in vivo. After screening a large array of uptake transporters, we show organic cation transporter 2 (OCT2) is the key transporter for TMAO cellular uptake. In Oct1/2 knockout mice, we observed increased plasma TMAO levels with reduced renal retention, suggesting the importance of Oct2 in facilitating the uptake of TMAO into renal tubular cells in vivo. Multiple transporters of the ATP-binding cassette (ABC) family, including ABCG2 (BCRP) and ABCB1 (MDR1), were capable of TMAO efflux. In human subjects, clinical, dietary, and pharmacogenetic covariates were evaluated for contribution to TMAO levels in a cohort of dyslipidemic patients (n = 405). Interestingly, genetic variation in ABCG2, but not other transporters, appeared to play a role in modulating TMAO exposure.


Assuntos
Proteínas de Membrana Transportadoras/metabolismo , Metilaminas/metabolismo , Óxidos/metabolismo , Transportadores de Cassetes de Ligação de ATP/metabolismo , Animais , Transporte Biológico , Carnitina/metabolismo , Humanos , Masculino , Camundongos , Camundongos Knockout , Proteínas de Transporte de Cátions Orgânicos/metabolismo , Oxigenases/metabolismo
8.
Kidney Int ; 89(5): 1144-1152, 2016 May.
Artigo em Inglês | MEDLINE | ID: mdl-27083288

RESUMO

Cardiovascular disease is more common in patients with chronic kidney disease (CKD), and traditional risk factors do not adequately predict those at risk for cardiovascular (CV) events. Recent evidence suggests elevated trimethylamine N-oxide (TMAO), created by gut microflora from dietary L-carnitine and choline, is associated with CV events. We investigated the relationship of TMAO levels in patients with stages 3b and 4 CKD to ischemic CV events using the CanPREDDICT cohort, a Canada-wide observational study with prospective 3-year follow-up of adjudicated CV events. Baseline samples were obtained for 2529 CKD patients. TMAO, choline, and L-carnitine levels were measured using tandem mass spectrometry. Baseline median TMAO level was high for the whole cohort (20.41 µM; interquartile range [IQR]: 12.82-32.70 µM). TMAO was independently associated with CV events (hazard ratio 1.23; 95% confidence interval: 1.06-1.42 / 1 SD lnTMAO) after adjusting for all potential CV risk factors. Those in the highest TMAO quartile had significantly higher risk of CV events (adjusted hazard ratio 1.59; 95% confidence interval: 1.04-2.43; P = 0.0351) in the analysis of recurring ischemic events. Among those with stage 3b CKD (hazard ratio 1.45; 95% confidence interval: 1.12-1.87 / 1 SD lnTMAO), independent of kidney function, TMAO levels identified those at highest risk for events. Our results suggest that TMAO may represent a new potentially modifiable CV risk factor for CKD patients. Further studies are needed to determine sources of variability and if lowering of TMAO reduces CV risk in CKD.


Assuntos
Doenças Cardiovasculares/etiologia , Metilaminas/sangue , Insuficiência Renal Crônica/sangue , Idoso , Idoso de 80 Anos ou mais , Biomarcadores/sangue , Canadá , Doenças Cardiovasculares/diagnóstico , Intervalo Livre de Doença , Feminino , Taxa de Filtração Glomerular , Humanos , Estimativa de Kaplan-Meier , Rim/fisiopatologia , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Insuficiência Renal Crônica/complicações , Insuficiência Renal Crônica/diagnóstico , Insuficiência Renal Crônica/fisiopatologia , Medição de Risco , Fatores de Risco , Índice de Gravidade de Doença , Espectrometria de Massas em Tandem , Fatores de Tempo , Regulação para Cima
10.
Drug Metab Dispos ; 43(11): 1788-94, 2015 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-26341276

RESUMO

Unbound plasma concentrations may not reflect those in target tissues, and there is a need for methods to predict tissue partitioning. Here, we investigate the unbound liver partitioning (Kpu,u) of rosuvastatin, a substrate of hepatic organic anion transporting peptides, in cynomolgus monkeys and compare it with that determined using hepatocytes in vitro. Rosuvastatin (3 mg/kg) was administered orally to monkeys and plasma and liver (by ultrasound-guided biopsy) collected over time. Uptake into monkey hepatocytes was evaluated up to steady state. Binding in monkey plasma, liver, and hepatocytes was determined using equilibrium dialysis. Mean in vivo Kpu,u was 118 after correcting total liver partitioning by plasma and liver binding. In vitro uptake data were analyzed by compartmental modeling to determine active uptake clearance, passive diffusion, the intracellular unbound fraction, and Kpu,u. In vitro Kpu,u underpredicted that in vivo, resulting in the need for an empirical in vitro to in vivo scaling factor of 10. Adjusting model parameters using hypothetical scaling factors for transporter expression and surface area or assuming no effect of protein binding on active transport increased partitioning values by 1.1-, 6-, and 9-fold, respectively. In conclusion, in vivo rosuvastatin unbound liver partitioning in monkeys was underpredicted using hepatocytes in vitro. Modeling approaches that allow integrating corrections from passive diffusion or protein binding on active uptake could improve the estimation of in vivo intracellular partitioning of this organic anion transporting peptide substrate. A similar assessment of other active hepatic transport mechanisms could confirm and determine the extent to which limited accumulation in isolated hepatocytes needs to be considered in drug development.


Assuntos
Hepatócitos/efeitos dos fármacos , Hepatócitos/metabolismo , Rosuvastatina Cálcica/metabolismo , Rosuvastatina Cálcica/farmacologia , Animais , Feminino , Previsões , Células HEK293 , Humanos , Macaca fascicularis , Masculino , Ligação Proteica/fisiologia
11.
Dig Dis Sci ; 60(12): 3620-30, 2015 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-26160437

RESUMO

BACKGROUND: The gastrointestinal (GI) microbiome is recognized for potential clinical relevance in inflammatory bowel disease (IBD). Data suggest that there is a disease-dependent loss of microbial diversity in IBD. Trimethylamine-N-oxide (TMAO) is generated by GI anaerobes through the digestion of dietary phosphatidylcholine and carnitine in a microbial-mammalian co-metabolic pathway. IBD-related changes in the gut microbiome may result in disease-specific changes in TMAO plasma concentrations. AIM: To determine whether TMAO plasma levels in IBD are altered compared to controls and whether they correlate with disease presence or activity. METHODS: Liquid chromatography-tandem mass spectrometry was used to measure TMAO, choline, and carnitine plasma levels in 479 subjects (373 non-IBD controls, 106 IBD). Subjects were also genotyped for the flavin monooxygenase (FMO)3 variants, E158K and E308G. RESULTS: Plasma TMAO levels were 2.27 µM lower in the IBD population compared to the control population (p = 0.0001). Lower TMAO levels were similarly seen in active ulcerative colitis (UC) (1.56 µM) versus inactive disease (3.40 µM) (p = 0.002). No difference was seen in active Crohn's disease (CD) versus inactive CD. No intergroup variation existed in plasma TMAO levels based on FMO3 genotype. Choline levels were higher in IBD, while carnitine levels were similar between the two groups, suggesting that lower TMAO levels in IBD were not due to dietary differences. CONCLUSIONS: Decreased TMAO levels are seen in IBD compared to a non-IBD population. These data suggest that TMAO may have potential as a biomarker to support IBD diagnosis as well as to assess disease activity in UC.


Assuntos
Doenças Inflamatórias Intestinais/sangue , Doenças Inflamatórias Intestinais/diagnóstico , Metilaminas/sangue , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Biomarcadores/sangue , Estudos de Casos e Controles , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Adulto Jovem
12.
Drug Metab Dispos ; 43(7): 984-93, 2015 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-25904762

RESUMO

The contribution of organic anion transporter OAT2 (SLC22A7) to the renal tubular secretion of creatinine and its exact localization in the kidney are reportedly controversial. In the present investigation, the transport of creatinine was assessed in human embryonic kidney (HEK) cells that stably expressed human OAT2 (OAT2-HEK) and isolated human renal proximal tubule cells (HRPTCs). The tubular localization of OAT2 in human, monkey, and rat kidney was characterized. The overexpression of OAT2 significantly enhanced the uptake of creatinine in OAT2-HEK cells. Under physiologic conditions (creatinine concentrations of 41.2 and 123.5 µM), the initial rate of OAT2-mediated creatinine transport was approximately 11-, 80-, and 80-fold higher than OCT2, multidrug and toxin extrusion protein (MATE)1, and MATE2K, respectively, resulting in approximately 37-, 1850-, and 80-fold increase of the intrinsic transport clearance when normalized to the transporter protein concentrations. Creatinine intracellular uptake and transcellular transport in HRPTCs were decreased in the presence of 50 µM bromosulfophthalein and 100 µM indomethacin, which inhibited OAT2 more potently than other known creatinine transporters, OCT2 and multidrug and toxin extrusion proteins MATE1 and MATE2K (IC50: 1.3 µM vs. > 100 µM and 2.1 µM vs. > 200 µM for bromosulfophthalein and indomethacin, respectively) Immunohistochemistry analysis showed that OAT2 protein was localized to both basolateral and apical membranes of human and cynomolgus monkey renal proximal tubules, but appeared only on the apical membrane of rat proximal tubules. Collectively, the findings revealed the important role of OAT2 in renal secretion and possible reabsorption of creatinine and suggested a molecular basis for potential species difference in the transporter handling of creatinine.


Assuntos
Creatinina/metabolismo , Túbulos Renais/metabolismo , Transportadores de Ânions Orgânicos Sódio-Independentes/metabolismo , Animais , Antiporters/metabolismo , Células HEK293 , Humanos , Imuno-Histoquímica , Indometacina/farmacologia , Túbulos Renais Proximais/metabolismo , Cinética , Macaca fascicularis , Masculino , Transportadores de Ânions Orgânicos Sódio-Independentes/antagonistas & inibidores , Proteínas de Transporte de Cátions Orgânicos/metabolismo , Ratos , Ratos Sprague-Dawley , Especificidade da Espécie , Sulfobromoftaleína/farmacologia
13.
Pharm Res ; 32(6): 1894-906, 2015 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-25480120

RESUMO

PURPOSE: Monocarboxylate transporter (MCT) inhibition represents a potential treatment strategy for γ-hydroxybutyric acid (GHB) overdose by blocking its renal reabsorption in the kidney. This study further evaluated the effects of a novel, highly potent MCT inhibitor, AR-C155858, on GHB toxicokinetics/toxicodynamics (TK/TD). METHODS: Rats were administered GHB (200, 600 or 1500 mg/kg i.v. or 1500 mg/kg po) with and without AR-C155858. Breathing frequency was continuously monitored using whole-body plethysmography. Plasma and urine samples were collected up to 8 h. The effect of AR-C155858 on GHB brain/plasma partitioning was also assessed. RESULTS: AR-C155858 treatment significantly increased GHB renal and total clearance after intravenous GHB administration at all the GHB doses used in this study. GHB-induced respiratory depression was significantly improved by AR-C155858 as demonstrated by an improvement in the respiratory rate. AR-C155858 treatment also resulted in a significant reduction in brain/plasma partitioning of GHB (0.1 ± 0.03) when compared to GHB alone (0.25 ± 0.02). GHB CLR and CLoral (CL/F) following oral administration were also significantly increased following AR-C155858 treatment (from 1.82 ± 0.63 to 5.74 ± 0.86 and 6.52 ± 0.88 to 10.2 ± 0.75 ml/min/kg, respectively). CONCLUSION: The novel and highly potent MCT inhibitor represents a potential treatment option for GHB overdose.


Assuntos
Antídotos/farmacologia , Overdose de Drogas/tratamento farmacológico , Rim/efeitos dos fármacos , Transportadores de Ácidos Monocarboxílicos/antagonistas & inibidores , Insuficiência Respiratória/tratamento farmacológico , Oxibato de Sódio/toxicidade , Tiofenos/farmacologia , Uracila/análogos & derivados , Administração Intravenosa , Administração Oral , Animais , Encéfalo/metabolismo , Linhagem Celular , Overdose de Drogas/metabolismo , Rim/metabolismo , Masculino , Taxa de Depuração Metabólica , Transportadores de Ácidos Monocarboxílicos/metabolismo , Ratos Sprague-Dawley , Reabsorção Renal/efeitos dos fármacos , Insuficiência Respiratória/induzido quimicamente , Insuficiência Respiratória/metabolismo , Insuficiência Respiratória/fisiopatologia , Taxa Respiratória/efeitos dos fármacos , Oxibato de Sódio/administração & dosagem , Oxibato de Sódio/farmacocinética , Distribuição Tecidual , Uracila/farmacologia
14.
Crit Rev Clin Lab Sci ; 52(1): 1-11, 2015 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-25181036

RESUMO

Personalized medicine is an emerging field with a goal of applying genomic information as a predictor of disease risk as well as individualization of drug therapy. For optimization of drug therapy, significant progress has been made in the past decade in linking genetic variation in genes associated with drug disposition to prediction of drug response and adverse reactions. For most drugs in clinical use, the interplay of many factors, including genetics, demographics, drug-drug interactions, disease states and the environment, result in the interindividual variability observed during drug therapy. Broadly speaking, such determinants of drug response are mediated through modulation of drug concentrations reflective of pharmacokinetic factors, as well as drug targets, often referred to as pharmacodynamics. It is clear that for personalized medicine to become clinically meaningful, genomic as well as clinical and environmental influences must be considered together. We show, for a number of drugs in clinical use, that genomics-guided treatment options not only are becoming feasible but are also on the cusp of showing superiority in terms of clinical outcomes as well as cost-benefit. One of the most widely studied drugs with regard to genomics-guided dosing options is the oral anticoagulant, warfarin. Genetic polymorphisms in the gene encoding cytochrome P450 2C9 (CYP2C9) and those in the target gene responsible for the warfarin anticoagulant effect, vitamin K epoxide reductase (VKORC1), account for much of the variability in the warfarin maintenance dose; however, routine genotyping in warfarin therapy remains controversial. We will outline the importance of understanding all of the variables that mediate warfarin response as the prerequisite to successful utilization of genotype-guided warfarin therapy. Similarly, HMG Co-A reductase inhibitors, commonly known as statins, also display wide interindividual variability in plasma concentration, response and toxicity due in part to polymorphisms in transporter genes, including SLCO1B1 and ABCG2. Genetic factors are also important considerations in treatment with other therapeutic agents discussed, including clopidogrel and tamoxifen. Implementation of personalized medicine-based treatment options for these and other drugs, the pharmacokinetics or pharmacodynamics of which are impacted by functional genetic variations, will require overcoming a number of challenges, including cost, turnaround time, and demonstration of clinical benefit, as well as better training of health care professionals about genomics in general, and pharmacogenomics in particular.


Assuntos
Tratamento Farmacológico/métodos , Variação Genética , Genômica/métodos , Medicina de Precisão/métodos , Medicina de Precisão/tendências , Clopidogrel , Tratamento Farmacológico/tendências , Genômica/tendências , Humanos , Inibidores de Hidroximetilglutaril-CoA Redutases/farmacologia , Farmacocinética , Tamoxifeno/farmacologia , Ticlopidina/análogos & derivados , Ticlopidina/farmacologia , Varfarina/farmacologia
15.
AAPS J ; 16(4): 756-70, 2014 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-24854892

RESUMO

Overdose of γ-hydroxybutyrate (GHB) can result in severe respiratory depression. Monocarboxylate transporter (MCT) inhibitors, including L-lactate, increase GHB clearance and represent a potential treatment for GHB intoxication. GHB can also affect L-lactate clearance, and L-lactate has been reported to affect respiration. In this research, we characterize these toxicokinetic/toxicodynamic interactions between GHB and L-lactate using mechanistic modeling. Plasma, urine, and respiration data were taken from our previous study in which GHB and sodium L-lactate were administered alone and concomitantly in rats. A model incorporating active renal reabsorption for both agents fit GHB and L-lactate toxicokinetic data. The Km for renal reabsorption of GHB (650 µg/mL) was close to its Km for the proton-dependent MCT1 and that for L-lactate (13.5 µg/mL) close to its Km for the sodium-dependent SMCT1. Inhibition of reabsorption by both agents was necessary to model concomitant drug administration. The metabolic Km for L-lactate closely resembled that for MCT-mediated hepatic uptake in vitro, and GHB inhibited this process. L-lactate significantly inhibited respiration at a high dose, and an indirect response model was used to fit these data. GHB toxicodynamics was modeled as a direct effect delayed by nonlinear transport into the brain extracellular fluid, with a Km value of 1,865 µg/mL for brain uptake which is similar to the in vitro Km value determined in rat brain endothelial cells. This model was useful for characterizing multiple MCT-mediated interactions. Incorporation of many parameters that can be determined in vitro may allow for clinical translation of these interactions.


Assuntos
Anestésicos Intravenosos/farmacocinética , Anestésicos Intravenosos/toxicidade , Ácido Láctico/farmacocinética , Ácido Láctico/toxicidade , Transportadores de Ácidos Monocarboxílicos/química , Oxibato de Sódio/farmacocinética , Oxibato de Sódio/toxicidade , Simportadores/química , Animais , Simulação por Computador , Relação Dose-Resposta a Droga , Overdose de Drogas/prevenção & controle , Ácido Láctico/metabolismo , Masculino , Ratos , Ratos Sprague-Dawley , Mecânica Respiratória/efeitos dos fármacos , Toxicocinética
16.
J Pharmacol Exp Ther ; 346(3): 504-13, 2013 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-23814094

RESUMO

γ-Hydroxybutyrate (GHB), a common drug of abuse, is often coingested with ethanol. Increasing renal clearance via monocarboxylate transporter (MCT) inhibition represents a potential therapeutic strategy in GHB overdose, as does inhibition of GABAB receptors. In this study, we investigate toxicokinetic/toxicodynamic interactions between GHB-ethanol and efficacy of treatment options for GHB-ethanol intoxication in rats. Sedation was assessed using the endpoint of return-to-righting reflex. Respiration was assessed using plethysmography. Coadministration of 2.0 g/kg ethanol i.v. with 600 mg/kg GHB i.v. increased sleep time compared with GHB alone. Administration of ethanol to steady-state concentrations of 0.1-0.2% and 0.3-0.4% (w/v) did not affect toxicokinetics of 600 mg/kg GHB i.v., or respiratory rate, but did result in significantly lower peak tidal volumes compared with GHB alone. Oral administration of 2.5 g/kg ethanol had no significant effect on toxicokinetics of 1500 mg/kg orally administered GHB. Pretreatment with specific receptor inhibitors indicated no effect of GABAA receptor inhibition on sleep time or respiratory depression in GHB-ethanol intoxication. GABAB receptor inhibition partially prevented sedation and completely prevented respiratory depression. Ethanol increased fatality when administered at 0.1-0.2% (4 of 10) and 0.3-0.4% (9 of 10) versus 1500 mg/kg GHB i.v. alone (0 of 10). Treatment with the MCT inhibitor, l-lactate, significantly decreased sleep time after GHB-ethanol and decreased fatality at 0.1-0.2% (0 of 10) and 0.3-0.4% ethanol (5 of 10). Treatment with a GABAB receptor antagonist completely prevented fatality at 0.3-0.4% (0 of 10). These data indicate that ethanol potentiates the sedative and respiratory depressant effects of GHB, increasing the risk of fatality. MCT and GABAB receptor inhibition represent potentially effective treatments in GHB-ethanol intoxication.


Assuntos
Depressores do Sistema Nervoso Central/farmacocinética , Depressores do Sistema Nervoso Central/toxicidade , Etanol/farmacocinética , Etanol/toxicidade , Hipnóticos e Sedativos/farmacocinética , Hipnóticos e Sedativos/toxicidade , Envenenamento/tratamento farmacológico , Oxibato de Sódio/farmacocinética , Oxibato de Sódio/toxicidade , Animais , Sedação Consciente/mortalidade , Overdose de Drogas/tratamento farmacológico , Antagonistas de Receptores de GABA-B/farmacologia , Ácido Láctico/uso terapêutico , Masculino , Transportadores de Ácidos Monocarboxílicos/antagonistas & inibidores , Transportadores de Ácidos Monocarboxílicos/metabolismo , Pletismografia , Ratos , Ratos Sprague-Dawley , Insuficiência Respiratória/induzido quimicamente , Insuficiência Respiratória/tratamento farmacológico , Insuficiência Respiratória/mortalidade , Mecânica Respiratória/efeitos dos fármacos
17.
J Pharmacol Exp Ther ; 345(1): 102-10, 2013 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-23392755

RESUMO

Respiratory depression and death secondary to respiratory arrest have occurred after oral overdoses of γ-hydroxybutyrate (GHB) and its precursor γ-butyrolactone (GBL). GHB is a substrate for monocarboxylate transporters (MCTs), and increasing GHB renal clearance or decreasing GHB absorption via MCT inhibition represents a potential treatment strategy for GHB/GBL overdose. In these studies, GHB and GBL were administered in doses of 1.92, 5.77, and 14.4 mmol/kg orally with and without MCT inhibition to determine effects of this treatment strategy on the oral toxicokinetics and toxicodynamics of GHB and GBL. The competitive MCT inhibitor l-lactate was administered by intravenous infusion starting 1 hour after GHB and GBL administration. Oral administration of l-lactate and the MCT inhibitor luteolin was also evaluated. Respiratory depression was measured using plethysmography. Intravenous l-lactate, but not oral treatments, significantly increased GHB renal and/or oral clearances. At the low dose of GHB and GBL, i.v. l-lactate increased GHB renal clearance. Due to the increased contribution of renal clearance to total clearance at the moderate dose, increased renal clearance translated to an increase in oral clearance. At the highest GHB dose, oral clearance was increased without a significant change in renal clearance. The lack of effect of i.v. l-lactate on renal clearance after a high oral GHB dose suggests possible effects of i.v. l-lactate on MCT-mediated absorption. The resulting increases in oral clearance improved respiratory depression. Intravenous l-lactate also reduced mortality with the high GBL dose. These data indicate i.v. l-lactate represents a potential treatment strategy in oral overdose of GHB and GBL.


Assuntos
4-Butirolactona , Overdose de Drogas/tratamento farmacológico , Ácido Láctico/uso terapêutico , Transportadores de Ácidos Monocarboxílicos/antagonistas & inibidores , Insuficiência Respiratória/prevenção & controle , Oxibato de Sódio , 4-Butirolactona/farmacocinética , 4-Butirolactona/toxicidade , Absorção , Administração Oral , Animais , Relação Dose-Resposta a Droga , Overdose de Drogas/etiologia , Overdose de Drogas/metabolismo , Humanos , Injeções Intravenosas , Rim/efeitos dos fármacos , Rim/metabolismo , Ácido Láctico/administração & dosagem , Ácido Láctico/farmacologia , Masculino , Taxa de Depuração Metabólica , Ratos , Ratos Sprague-Dawley , Insuficiência Respiratória/induzido quimicamente , Insuficiência Respiratória/metabolismo , Oxibato de Sódio/farmacocinética , Oxibato de Sódio/toxicidade
18.
Mol Pharmacol ; 82(2): 226-35, 2012 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-22561075

RESUMO

Overdose of γ-hydroxybutyrate (GHB) frequently causes respiratory depression, occasionally resulting in death; however, little is known about the dose-response relationship or effects of potential overdose treatment strategies on GHB-induced respiratory depression. In these studies, the parameters of respiratory rate, tidal volume, and minute volume were measured using whole-body plethysmography in rats administered GHB. Intravenous doses of 200, 600, and 1500 mg/kg were administered to assess the dose-dependent effects of GHB on respiration. To determine the receptors involved in GHB-induced respiratory depression, a specific GABA(B) receptor antagonist, (2S)-(+)-5,5-dimethyl-2-morpholineacetic acid (SCH50911), and a specific GABA(A) receptor antagonist, bicuculline, were administered before GHB. The potential therapeutic strategies of receptor inhibition and monocarboxylate transporter (MCT) inhibition were assessed by inhibitor administration 5 min after GHB. The primary effect of GHB on respiration was a dose-dependent decrease in respiratory rate, accompanied by an increase in tidal volume, resulting in little change in minute volume. Pretreatment with 150 mg/kg SCH50911 completely prevented the decrease in respiratory rate, indicating agonism at GABA(B) receptors to be primarily responsible for GHB-induced respiratory depression. Administration of 50 mg/kg SCH50911 after GHB completely reversed the decrease in respiratory rate; lower doses had partial effects. Administration of the MCT inhibitor l-lactate increased GHB renal and total clearance, also improving respiratory rate. Administration of 5 mg/kg SCH50911 plus l-lactate further improved respiratory rate compared with the same dose of either agent alone, indicating that GABA(B) and MCT inhibitors, alone and in combination, represent potential treatment options for GHB-induced respiratory depression.


Assuntos
Receptores de Superfície Celular/antagonistas & inibidores , Insuficiência Respiratória/induzido quimicamente , Insuficiência Respiratória/tratamento farmacológico , Oxibato de Sódio/toxicidade , Animais , Bicuculina/farmacologia , Bicuculina/uso terapêutico , Relação Dose-Resposta a Droga , Overdose de Drogas , Masculino , Morfolinas/farmacologia , Morfolinas/uso terapêutico , Ratos , Ratos Sprague-Dawley , Receptores de Superfície Celular/fisiologia , Insuficiência Respiratória/metabolismo , Oxibato de Sódio/metabolismo , Resultado do Tratamento
19.
Drug Metab Dispos ; 40(1): 64-9, 2012 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-21976619

RESUMO

The drug of abuse γ-hydroxybutyrate (GHB) displays nonlinear renal clearance, which has been attributed to saturable renal reabsorption by monocarboxylate transporters (MCTs) present in the kidney. MCT1 is also present in red blood cells (RBCs); however, the significance of this transporter on the blood/plasma partitioning of GHB is unknown. The purpose of this research was to characterize the transport of GHB across the RBC membrane and assess GHB blood/plasma partitioning in vivo in the presence and absence of a competitive MCT inhibitor, l-lactate. In vitro experiments were performed using freshly isolated rat erythrocytes at pH values of 6.5 and 7.4. Inhibition with p-chloromercuribenzene sulfonate and 4,4'-diisothiocyanostilbene-2,2'-disulfonate were used to determine the contribution of MCT1 and band 3, respectively, on GHB uptake. For in vivo experiments, rats were administered GHB (400-1500 mg/kg) with and without l-lactate. In vitro experiments demonstrated that GHB is transported across the RBC membrane primarily by MCT1 at relevant in vivo concentrations. The K(m) for MCT1 was lower at pH 6.5 than that at pH 7.4, 2.2 versus 17.0 mM, respectively. The in vivo blood/plasma partitioning of GHB displayed linearity across all concentrations. l-Lactate coadministration increased GHB renal clearance but had no effect on the blood/plasma ratio. Unlike its MCT-mediated transport in the intestine and kidneys, GHB blood/plasma partitioning appears to be linear and is unaffected by l-lactate. These findings can be attributed, at least in part, to differences in physiologic pH at different sites of MCT-mediated transport.


Assuntos
Transportadores de Ácidos Monocarboxílicos/sangue , Oxibato de Sódio/sangue , Animais , Transporte Biológico Ativo/fisiologia , Eritrócitos/metabolismo , Concentração de Íons de Hidrogênio , Masculino , Ratos , Ratos Sprague-Dawley
20.
AAPS J ; 13(2): 240-54, 2011 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-21387146

RESUMO

γ-Hydroxybutyric acid (GHB), a drug of abuse, demonstrates complex toxicokinetics with capacity-limited metabolism and active renal reabsorption. The objectives of the present study were to conduct a local sensitivity analysis of a mechanistic model for the active renal reabsorption of GHB and to use the results to inform the design of future studies aimed at developing therapeutic strategies for treating GHB overdoses. A local sensitivity analysis was used to assess the influence of parameter perturbations on model outputs (plasma concentrations and urinary excretion of GHB). Further, a sensitivity index was calculated for each perturbed parameter to assess the specific segments of the time course that are critical to parameter estimation. Model outputs were simulated for rats dosed with 200, 400, 600, and 1,000 mg/kg GHB intravenously and individual parameters were perturbed by two-, five-, and tenfold higher and lower than the nominal value. Model outputs were sensitive to perturbations in clearance and volume parameters. In contrast, model outputs were found to be insensitive to changes in distributional parameters suggesting that additional tissue distribution data is required. Based on the sensitivity analysis the 1,000-mg/kg GHB dose can be eliminated from future studies as the parameters can be adequately estimated from the lower doses. To further validate the use of this model, dose-specific sampling schedules were designed based on model predictions for doses of 600 and 1,500 mg/kg. These sampling schedules were able to adequately capture the inflection point and terminal elimination phase of the plasma concentration-time profiles obtained.


Assuntos
Hidroxibutiratos/farmacocinética , Rim/metabolismo , Modelos Biológicos , Animais , Transporte Biológico , Relação Dose-Resposta a Droga , Hidroxibutiratos/administração & dosagem , Masculino , Ratos , Ratos Sprague-Dawley , Distribuição Tecidual
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA