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1.
Drug Metab Dispos ; 52(2): 95-105, 2024 Jan 09.
Artigo em Inglês | MEDLINE | ID: mdl-38071533

RESUMO

To facilitate the design of drugs readily able to cross the blood brain barrier (BBB), a Madin-Darby canine kidney (MDCK) cell line was established that over expresses both P-glycoprotein (Pgp) and breast cancer resistance protein (BCRP), the main human efflux transporters of the BBB. Proteomics analyses indicate BCRP is expressed at a higher level than Pgp in this cell line. This cell line shows good activity for both transporters [BCRP substrate dantrolene efflux ratio (ER) 16.3 ± 0.9, Pgp substrate quinidine ER 27.5 ± 1.2], and use of selective transporter inhibitors enables an assessment of the relative contributions to overall ERs. The MDCKII-MDR1-BCRP ER negatively correlates with rat unbound brain/unbound plasma ratio, Kpuu Highly brain penetrant compounds with rat Kpuu ≥ 0.3 show ERs ≤ 2 in the MDCKII-MDR1-BCRP assay while compounds predominantly excluded from the brain, Kpuu ≤ 0.05, demonstrate ERs ≥ 20. A subset of compounds with MDCKII-MDR1-BCRP ER < 2 and rat Kpuu < 0.3 were shown to be substrates of rat Pgp using a rat transfected cell line, MDCKII-rMdr1a. These compounds also showed ERs > 2 in the human National Institutes of Health (NIH) MDCKI-MDR1 (high Pgp expression) cell line, which suggests that they are weak human Pgp substrates. Characterization of 37 drugs targeting the central nervous system in the MDCKII-MDR1-BCRP efflux assay show 36 have ERs < 2. In drug discovery, use of the MDCKII-MDR1-BCRP in parallel with the NIH MDCKI-MDR1 cell line is useful for identification of compounds with high brain penetration. SIGNIFICANCE STATEMENT: A single cell line that includes both the major human efflux transporters of the blood brain barrier (MDCKII-MDR1-BCRP) has been established facilitating the rapid identification of efflux substrates and enabling the design of brain penetrant molecules. Efflux ratios using this cell line demonstrate a clear relationship with brain penetration as defined by rat brain Kpuu.


Assuntos
Barreira Hematoencefálica , Proteínas de Neoplasias , Humanos , Animais , Cães , Ratos , Barreira Hematoencefálica/metabolismo , Membro 2 da Subfamília G de Transportadores de Cassetes de Ligação de ATP/metabolismo , Proteínas de Neoplasias/metabolismo , Proteínas de Membrana Transportadoras/metabolismo , Linhagem Celular , Membro 1 da Subfamília B de Cassetes de Ligação de ATP/metabolismo , Subfamília B de Transportador de Cassetes de Ligação de ATP/metabolismo
2.
CPT Pharmacometrics Syst Pharmacol ; 13(1): 5-22, 2024 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-37950388

RESUMO

Assessment of drug-induced effects on the cardiovascular (CV) system remains a critical component of the drug discovery process enabling refinement of the therapeutic index. Predicting potential drug-related unintended CV effects in the preclinical stage is necessary for first-in-human dose selection and preclusion of adverse CV effects in the clinical stage. According to the current guidelines for small molecules, nonclinical CV safety assessment conducted via telemetry analyses should be included in the safety pharmacology core battery studies. However, the manual for quantitative evaluation of the CV safety signals in animals is available only for electrocardiogram parameters (i.e., QT interval assessment), not for hemodynamic parameters (i.e., heart rate, blood pressure, etc.). Various model-based approaches, including empirical pharmacokinetic-toxicodynamic analyses and systems pharmacology modeling could be used in the framework of telemetry data evaluation. In this tutorial, we provide a comprehensive workflow for the analysis of nonclinical CV safety on hemodynamic parameters with a sequential approach, highlight the challenges associated with the data, and propose respective solutions, complemented with a reproducible example. The work is aimed at helping researchers conduct model-based analyses of the CV safety in animals with subsequent translation of the effect to humans seamlessly and efficiently.


Assuntos
Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos , Animais , Humanos , Avaliação Pré-Clínica de Medicamentos , Pressão Sanguínea , Hemodinâmica , Frequência Cardíaca
3.
Curr Drug Metab ; 22(7): 523-531, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33397250

RESUMO

Membrane transporters play an important role in intestinal absorption, distribution and clearance of drugs. Additionally transporters along with enzymes regulate tissue exposures (e.g. liver, kidney and brain), which are important for safety and efficacy considerations. Early identification of transporters involved guides generation of in vitro and in vivo data needed to gain mechanistic understanding on the role of transporters in organ clearance, tissue exposures and enables development of physiological-based pharmacokinetic (PBPK) models. A lot of progress has been made in developing several in vitro assay systems and mechanistic in silico models to determine kinetic parameters for transporters, which are incorporated into PBPK models. Although, intrinsic clearance and inhibition data from in vitro systems generally tend to underpredict in vivo clearance and magnitude of drug-drug interactions (DDIs), empirical scaling factors derived from a sizable dataset are often used to offset underpredictions. PBPK models are increasing used to predict the impact of transporters on intestinal absorption, clearance, victim and perpetrator DDIs prior to first in human clinical trials. The models are often refined when clinical data is available and are used to predict pharmacokinetics in untested scenarios such as the impact of polymorphisms, ontogeny, ethnicity, disease states and DDIs with other perpetrator drugs. The aim of this review is to provide an overview of (i) regulatory requirements around transporters, (ii) in vitro systems and their limitations in predicting transporter mediated drug disposition and DDIs, (iii) PBPK modelling tactics and case studies used for internal decision making and/or for regulatory submissions.


Assuntos
Vias de Eliminação de Fármacos , Interações Medicamentosas , Absorção Intestinal , Proteínas de Membrana Transportadoras/metabolismo , Farmacocinética , Animais , Humanos , Proteínas de Membrana Transportadoras/efeitos dos fármacos , Modelos Biológicos
4.
AAPS J ; 23(1): 12, 2021 01 04.
Artigo em Inglês | MEDLINE | ID: mdl-33398593

RESUMO

Over the last 10 years, 40% of approved oral drugs exhibited a significant effect of food on their pharmacokinetics (PK) and currently the only method to characterize the effect of food on drug absorption, which is recognized by the authorities, is to conduct a clinical evaluation. Within the pharmaceutical industry, there is a significant effort to predict the mechanism and clinical relevance of a food effect. Physiologically based pharmacokinetic (PBPK) models combining both drug-specific and physiology-specific data have been used to predict the effect of food on absorption and to reveal the underlying mechanisms. This manuscript provides detailed descriptions of how a middle-out modeling approach, combining bottom-up in vitro-based predictions with limited top-down fitting of key model parameters for clinical data, can be successfully used to predict the magnitude and direction of food effect when it is predicted poorly by a bottom-up approach. For nefazodone, a mechanistic clearance for the gut and liver was added, for furosemide, an absorption window was introduced, and for aprepitant, the biorelevant solubility was refined using multiple solubility measurements. In all cases, these adjustments were supported by literature data and showcased a rational approach to assess the factors limiting absorption and exposure.


Assuntos
Interações Alimento-Droga , Mucosa Intestinal/metabolismo , Modelos Biológicos , Administração Oral , Aprepitanto/administração & dosagem , Aprepitanto/farmacocinética , Simulação por Computador , Liberação Controlada de Fármacos , Furosemida/administração & dosagem , Furosemida/farmacocinética , Eliminação Hepatobiliar , Humanos , Absorção Intestinal/fisiologia , Eliminação Intestinal , Permeabilidade , Piperazinas/administração & dosagem , Piperazinas/farmacocinética , Solubilidade , Triazóis/administração & dosagem , Triazóis/farmacocinética
6.
AAPS J ; 22(6): 123, 2020 09 27.
Artigo em Inglês | MEDLINE | ID: mdl-32981010

RESUMO

The effect of food on pharmacokinetic properties of drugs is a commonly observed occurrence affecting about 40% of orally administered drugs. Within the pharmaceutical industry, significant resources are invested to predict and characterize a clinically relevant food effect. Here, the predictive performance of physiologically based pharmacokinetic (PBPK) food effect models was assessed via de novo mechanistic absorption models for 30 compounds using controlled, pre-defined in vitro, and modeling methodology. Compounds for which absorption was known to be limited by intestinal transporters were excluded in this analysis. A decision tree for model verification and optimization was followed, leading to high, moderate, or low food effect prediction confidence. High (within 0.8- to 1.25-fold) to moderate confidence (within 0.5- to 2-fold) was achieved for most of the compounds (15 and 8, respectively). While for 7 compounds, prediction confidence was found to be low (> 2-fold). There was no clear difference in prediction success for positive or negative food effects and no clear relationship to the BCS category of tested drug molecules. However, an association could be demonstrated when the food effect was mainly related to changes in the gastrointestinal luminal fluids or physiology, including fluid volume, motility, pH, micellar entrapment, and bile salts. Considering these findings, it is recommended that appropriately verified mechanistic PBPK modeling can be leveraged with high to moderate confidence as a key approach to predicting potential food effect, especially related to mechanisms highlighted here.


Assuntos
Interações Alimento-Droga , Absorção Intestinal/fisiologia , Modelos Biológicos , Administração Oral , Animais , Química Farmacêutica , Simulação por Computador , Cães , Liberação Controlada de Fármacos/fisiologia , Humanos , Concentração de Íons de Hidrogênio , Mucosa Intestinal/metabolismo , Células Madin Darby de Rim Canino , Permeabilidade , Solubilidade
7.
Expert Opin Drug Metab Toxicol ; 16(5): 387-401, 2020 May.
Artigo em Inglês | MEDLINE | ID: mdl-32228316

RESUMO

Introduction: Transporters and enzymes play an important role in absorption, distribution, clearance and elimination of drugs.Areas covered: This review provides an overview of the extended clearance concept and usefulness of extended clearance classification system (ECCS) in early identification of predominant clearance mechanisms. Clinical studies demonstrating transporter-enzyme interplay, challenges in scaling clearance from in vitro systems, utility of animal models and modeling approaches for evaluating hepatic clearance and drug-drug interactions are reviewed.Expert opinion: Clinical evidence exists supporting organic anion transporting peptide (OATP)1B and drug metabolizing enzymes involvement in clearance of ECCS class 1B drugs. Emerging evidence point toward contribution of organic cation transporter (OCT)1 to hepatic uptake of cationic drugs. Although, limited clinical evidence is presented, preclinical studies and modeling suggests organic anion transporter (OAT)2-enzyme interplay in clearance of class 1A drugs. Data from in vitro assays and preclinical models coupled with physiologically based modeling approaches are key for understanding transporter-enzyme interplay, enabling prediction of pharmacokinetics, tissue exposure and drug interactions. Current methodologies incur limitations and emphasis should be placed on the development of physiologically relevant in vitro models and characterize in vivo animal models to inform mechanistic modeling and improve confidence in prospective predictions.


Assuntos
Fígado/metabolismo , Proteínas de Membrana Transportadoras/metabolismo , Preparações Farmacêuticas/metabolismo , Animais , Vias de Eliminação de Fármacos , Interações Medicamentosas , Humanos , Transportadores de Ânions Orgânicos/metabolismo , Transportadores de Ânions Orgânicos Sódio-Independentes/metabolismo
8.
Genet Test Mol Biomarkers ; 15(5): 361-4, 2011 May.
Artigo em Inglês | MEDLINE | ID: mdl-21476899

RESUMO

AIM: Mitochondrial DNA (mtDNA) sequence variations are associated with a number of human diseases. The 9-bp repeat sequence, CCCCCTCTA, in the intergenic region of MTCO2 and MTTK genes of the mtDNA has been extensively used in phylogenic studies. The sequence has been reported to be polymorphic in south-east Asians in isolated cases of mt diseases. This is the first systemic study identifying the role of insertion-deletion polymorphism in human disease. RESULTS: A total of 241 patients including those with cardiomyopathy, ataxias, and idiopathic neurological disorders along with 100 controls were screened; 2.9% of patients showed a single repeat (deletion) and 4.14% had three repeats (insertion), whereas all the controls had two repeats (normal). CONCLUSION: This indicates that the 9-bp insertion-deletion repeat polymorphism plays a role in disease pathology, affecting the expression of the downstream genes of mtDNA and altering ATP generation.


Assuntos
Cardiomiopatia Dilatada/genética , DNA Mitocondrial/genética , Predisposição Genética para Doença , Doenças do Sistema Nervoso/genética , Polimorfismo Genético/genética , Ataxias Espinocerebelares/genética , Estudos de Casos e Controles , Complexo IV da Cadeia de Transporte de Elétrons/genética , Humanos , Mitocôndrias/genética , Mitocôndrias/patologia , Mutagênese Insercional , RNA de Transferência de Lisina/genética , Sequências Repetitivas de Ácido Nucleico , Deleção de Sequência
9.
Genet Test Mol Biomarkers ; 15(4): 257-61, 2011 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-21186995

RESUMO

Diabetes is gradually getting the status of a global epidemic, with India projected as the capital of type 2 diabetes mellitus (T2DM). Nephropathy is an important complication of diabetes and a major cause of end-stage renal disease. Studies from different parts of the world have given controversial results regarding the association of methylene tetrahydrofolate reductase (MTHFR) gene variation with T2DM and diabetic nephropathy (DN). This case-control study assessed the association of MTHFR C677T mutation in T2DM and DN cases. Genotyping of MTHFR was carried out for 236 T2DM cases with diabetes diagnosed for >8 years, having either normoalbuminuria (n=100) or established DN (n=136). One hundred age- and sex-matched healthy individuals with normal blood sugars and no family history of T2DM were selected as controls. This first report from India gives a highly significant odds ratio of 4.0423 (95% confidence interval=1.8753-8.7133), indicating that the MTHFR 677T allele confers a fourfold risk of developing DM in our population. The frequency of the T allele in both the DM and DN groups was similar (i.e., 0.16 and 0.11, respectively), showing no association with the initiation or progression of DN. Individuals with a family history of diabetes or with risk factors such as obesity, hypertension, and impaired glucose tolerance should be screened for MTHFR C677T mutation and may be prescribed folic acid, vitamin B6, and vitamin B12 to assess if this helps in delaying the onset of diabetes.


Assuntos
Diabetes Mellitus Tipo 2/genética , Nefropatias Diabéticas/genética , Metilenotetra-Hidrofolato Redutase (NADPH2)/genética , Polimorfismo Genético , Adulto , Idoso , Estudos de Casos e Controles , Diabetes Mellitus Tipo 2/complicações , Nefropatias Diabéticas/etiologia , Feminino , Frequência do Gene , Predisposição Genética para Doença , Genótipo , Humanos , Índia , Masculino , Pessoa de Meia-Idade , Mutação , Fatores de Risco
10.
J Diabetes Complications ; 21(4): 237-41, 2007.
Artigo em Inglês | MEDLINE | ID: mdl-17616353

RESUMO

OBJECTIVE: Diabetic nephropathy (DN) has become the leading cause of end-stage renal disease, but the pathogenesis of this condition is not exactly understood. Several studies from different parts of the world have examined angiotensin-converting enzyme (ACE) gene polymorphism as a candidate for DN. Two studies yielding controversial results have been reported from India. To rule out this discrepancy, we carried out a hospital-based study on a cohort from our population to determine whether ACE gene polymorphism is associated with DN. RESEARCH DESIGN AND METHODS: ACE gene polymorphism was analyzed by polymerase chain reaction in 460 individuals consisting of 174 cases of DN, 175 cases of Type 2 diabetes mellitus (DM), and 111 controls. The DN cases included in the study were Type 2 DM cases with serum creatinine >1.5 mg/dl and serum albumin >30 mg/dl in a 24-h urine sample. RESULTS: ACE insertion/deletion genotyping analysis showed DD genotype in 22.75% of DN cases, 15.42% of Type 2 DM cases, and 21.62% of controls. Chi-square test between the DN group and the control group did not show a significant difference in D allele. However, the difference was significant at P<.05 between the DN group and the DM group. The odds ratio was 2.0953 (95% confidence interval=1.35-3.2522), indicating a significant association of DD genotype and D allele with DN. CONCLUSION: Our data enable us to conclude that Asian Indians with D allele and Type 2 DM are at greater risk for developing DN.


Assuntos
Diabetes Mellitus Tipo 2/complicações , Diabetes Mellitus Tipo 2/genética , Nefropatias Diabéticas/genética , Predisposição Genética para Doença/genética , Peptidil Dipeptidase A/genética , Polimorfismo Genético/genética , Adulto , Alelos , Ásia/etnologia , Diabetes Mellitus Tipo 2/enzimologia , Diabetes Mellitus Tipo 2/epidemiologia , Nefropatias Diabéticas/enzimologia , Nefropatias Diabéticas/epidemiologia , Feminino , Genótipo , Humanos , Índia/epidemiologia , Masculino , Pessoa de Meia-Idade , Peptidil Dipeptidase A/metabolismo
11.
Mol Cells ; 24(3): 338-42, 2007 Dec 31.
Artigo em Inglês | MEDLINE | ID: mdl-18182848

RESUMO

Spinocerebellar ataxias (SCAs) are caused by expansion of (CAG)n triplet repeats. These repeats occur as polymorphic forms in general population; however, beyond a threshold size they become pathogenic. The sizes and distributions of repeats at the SCA1, SCA2, SCA3, SCA7 and DRPLA loci were assessed by molecular analysis of 124 unrelated ataxia patients and 44 controls, and the association of larger normal (LN) alleles with disease prevalence was evaluated. Triplet repeat expansions in the disease range were detected in 8% (10/124) of the cases, with the majority having expansion at the SCA1 locus. Normal allele ranges in the cohort studied were similar to the Caucasian and North Indian populations but differed from the Korean and Japanese populations at various loci. The percentage of individuals with LN alleles at the SCA1 and SCA2 loci was higher than reported in Indians, Japanese and Caucasians. LN alleles showed a good correlation with the incidence of SCA1, indicating that SCA1 is the most prevalent ataxia in our population. The majority of cases with clinical symptoms of SCA could not be diagnosed by established CAG repeat criteria, suggesting that there may be an alternative basis for disease pathogenesis: (i) Repeats lower than the normal range may also result in abnormal phenotypes (ii) LN alleles at different loci in the same individual may contribute to symptoms (iii) Exogenous factors may play a role in triggering disease symptoms in individuals with LN alleles (iv) Triplet repeats may reach the disease range in the brain but not in the blood.


Assuntos
Ataxias Espinocerebelares/genética , Repetições de Trinucleotídeos/genética , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Criança , Pré-Escolar , Feminino , Frequência do Gene , Humanos , Índia/epidemiologia , Masculino , Pessoa de Meia-Idade , Ataxias Espinocerebelares/epidemiologia , Expansão das Repetições de Trinucleotídeos/genética
12.
J Mol Neurosci ; 29(1): 29-33, 2006.
Artigo em Inglês | MEDLINE | ID: mdl-16757807

RESUMO

The pathological expansion of unstable trinucleotide repeats is known to cause neurodegenerative diseases. Trinucleotide repeat expansions might prove to be pathological through a variety of mechanisms, including alteration of DNA structure, transcription, RNA-protein interaction, and altered protein conformations/interactions. Deamidation of human proteins have been shown to regulate some time-dependent biological processes such as development and aging. In this paper we hypothesize the possible role of glutamine deamidation as a signaling event in the pathogenesis of neurodegenerative diseases associated with triplet repeat expansion.


Assuntos
Amidas/química , Glutamina/química , Doenças Neurodegenerativas , Expansão das Repetições de Trinucleotídeos , Diagnóstico Diferencial , Humanos , Doenças Neurodegenerativas/classificação , Doenças Neurodegenerativas/genética , Doenças Neurodegenerativas/metabolismo , Doenças Neurodegenerativas/fisiopatologia , Neurônios/metabolismo , Transdução de Sinais/fisiologia
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