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1.
J Pharmacol Exp Ther ; 362(1): 31-44, 2017 07.
Artigo em Inglês | MEDLINE | ID: mdl-28416568

RESUMO

Alzheimer's disease (AD) is characterized neuropathologically by an abundance of 1) neuritic plaques, which are primarily composed of a fibrillar 42-amino-acid amyloid-ß peptide (Aß), as well as 2) neurofibrillary tangles composed of aggregates of hyperphosporylated tau. Elevations in the concentrations of the Aß42 peptide in the brain, as a result of either increased production or decreased clearance, are postulated to initiate and drive the AD pathologic process. We initially introduced a novel class of bridged aromatics referred tγ-secretase modulatoro as γ-secretase modulators that inhibited the production of the Aß42 peptide and to a lesser degree the Aß40 peptide while concomitantly increasing the production of the carboxyl-truncated Aß38 and Aß37 peptides. These modulators potently lower Aß42 levels without inhibiting the γ-secretase-mediated proteolysis of Notch or causing accumulation of carboxyl-terminal fragments of APP. In this study, we report a large number of pharmacological studies and early assessment of toxicology characterizing a highly potent γ-secretase modulator (GSM), (S)-N-(1-(4-fluorophenyl)ethyl)-6-(6-methoxy-5-(4-methyl-1H-imidazol-1-yl)pyridin-2-yl)-4-methylpyridazin-3-amine (BPN-15606). BPN-15606 displayed the ability to significantly lower Aß42 levels in the central nervous system of rats and mice at doses as low as 5-10 mg/kg, significantly reduce Aß neuritic plaque load in an AD transgenic mouse model, and significantly reduce levels of insoluble Aß42 and pThr181 tau in a three-dimensional human neural cell culture model. Results from repeat-dose toxicity studies in rats and dose escalation/repeat-dose toxicity studies in nonhuman primates have designated this GSM for 28-day Investigational New Drug-enabling good laboratory practice studies and positioned it as a candidate for human clinical trials.


Assuntos
Secretases da Proteína Precursora do Amiloide/antagonistas & inibidores , Peptídeos beta-Amiloides/antagonistas & inibidores , Inibidores Enzimáticos/farmacologia , Inibidores Enzimáticos/toxicidade , Fragmentos de Peptídeos/antagonistas & inibidores , Fenetilaminas/farmacologia , Fenetilaminas/toxicidade , Piridazinas/farmacologia , Piridazinas/toxicidade , Doença de Alzheimer/tratamento farmacológico , Peptídeos beta-Amiloides/genética , Peptídeos beta-Amiloides/metabolismo , Precursor de Proteína beta-Amiloide/genética , Precursor de Proteína beta-Amiloide/metabolismo , Animais , Células Cultivadas , Sistema Nervoso Central/efeitos dos fármacos , Sistema Nervoso Central/metabolismo , Relação Dose-Resposta a Droga , Inibidores Enzimáticos/farmacocinética , Humanos , Macaca fascicularis , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Fragmentos de Peptídeos/genética , Fragmentos de Peptídeos/metabolismo , Placa Amiloide/tratamento farmacológico , Ratos , Ratos Sprague-Dawley , Proteínas tau/metabolismo
2.
J Exp Med ; 218(4)2021 04 05.
Artigo em Inglês | MEDLINE | ID: mdl-33651103

RESUMO

A potent γ-secretase modulator (GSM) has been developed to circumvent problems associated with γ-secretase inhibitors (GSIs) and to potentially enable use in primary prevention of early-onset familial Alzheimer's disease (EOFAD). Unlike GSIs, GSMs do not inhibit γ-secretase activity but rather allosterically modulate γ-secretase, reducing the net production of Aß42 and to a lesser extent Aß40, while concomitantly augmenting production of Aß38 and Aß37. This GSM demonstrated robust time- and dose-dependent efficacy in acute, subchronic, and chronic studies across multiple species, including primary and secondary prevention studies in a transgenic mouse model. The GSM displayed a >40-fold safety margin in rats based on a comparison of the systemic exposure (AUC) at the no observed adverse effect level (NOAEL) to the 50% effective AUC or AUCeffective, the systemic exposure required for reducing levels of Aß42 in rat brain by 50%.


Assuntos
Doença de Alzheimer/enzimologia , Doença de Alzheimer/prevenção & controle , Secretases da Proteína Precursora do Amiloide/metabolismo , Fenetilaminas/administração & dosagem , Piridazinas/administração & dosagem , Transdução de Sinais/efeitos dos fármacos , Peptídeos beta-Amiloides/metabolismo , Animais , Linhagem Celular Tumoral , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Avaliação Pré-Clínica de Medicamentos/métodos , Feminino , Humanos , Macaca fascicularis , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Neuroblastoma/metabolismo , Neuroblastoma/patologia , Fragmentos de Peptídeos/metabolismo , Ratos , Ratos Sprague-Dawley , Resultado do Tratamento
3.
Curr Drug Metab ; 9(1): 46-59, 2008 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-18220571

RESUMO

For drugs that directly act on targets in the central nervous system (CNS), sufficient drug delivery into the brain is a prerequisite for drug action. Systemically administered drugs can reach CNS by passage across the endothelium of capillary vasculatures, the so-called blood-brain barrier (BBB). Literature data suggest that most marketed CNS drugs have good membrane permeability and relatively high plasma unbound fraction, but are not good P-glycoprotein (P-gp) substrates. Therefore, it is important to use the in vitro parameters of P-gp function activity, membrane permeability and plasma unbound fraction as key criteria for lead optimization during the early stage of drug discovery. Evidence from preclinical and clinical studies suggests that drug concentration in cerebrospinal fluid (CSF) appears to be reasonably accurate in predicting unbound drug concentration in the brain. Therefore, CSF can be used as a useful surrogate for in vivo assessment of CNS exposure and provides an important basis for the selection of drug candidates for entry into development. However, it is important to point out that CSF drug concentration is not always an accurate surrogate for predicting unbound drug concentration in the brain. Depending on the physicochemical properties of drugs and the site/timing of CSF sampling, the unbound drug concentration at the biophase within the brain could differ significantly from the corresponding CSF drug concentration.


Assuntos
Barreira Hematoencefálica/fisiologia , Preparações Farmacêuticas/sangue , Preparações Farmacêuticas/líquido cefalorraquidiano , Farmacocinética , Membro 1 da Subfamília B de Cassetes de Ligação de ATP/sangue , Membro 1 da Subfamília B de Cassetes de Ligação de ATP/líquido cefalorraquidiano , Animais , Proteínas Sanguíneas/metabolismo , Barreira Hematoencefálica/efeitos dos fármacos , Sistemas de Liberação de Medicamentos , Indústria Farmacêutica , Líquido Extracelular/metabolismo , Humanos , Preparações Farmacêuticas/metabolismo , Ligação Proteica , Distribuição Tecidual
4.
Curr Drug Metab ; 9(5): 419-38, 2008 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-18537578

RESUMO

Genetically modified mouse models in which a specific gene is removed or replaced have proven to be powerful tools for identification/validation of target gene and scientific understanding of molecular mechanisms underlying drug-induced toxicity through mechanistic studies. In spite of the advantage, there are significant limitations of genetically modified mouse models. Modification of a given gene does not always result in the anticipated phenotype. In some instances, phenotypes of targeted mouse mutants were not those predicted from the presumed function of the given genes, while other null mutants revealed no apparent defects. Furthermore, the phenotypic outcome can be influenced by many environmental and genetic factors. Therefore, interpretation of the significance of the findings from studies using genetically modified mouse models is not always as straightforward as one would expect, especially when desire is to extrapolate the findings to humans. Interestingly, many humanized mouse models have been generated for evaluating the function and regulation of cytochrome P450 (CYP) enzymes. Our fascination with humanized animals dates back to ancients. For example, the Great Sphinx of Giza, a large half-human and half-lion statue, is believed to have been built by Egyptians about 4500 years ago. Although the creation of humanized animals that carry a particular human CYP gene provides useful tools for scientific understanding of the function and regulation of the CYP enzyme, these humanized mouse models are not so useful in prediction of human pharmacokinetics in a quantitative sense. Accordingly, it is important to keep in mind that an animal engineered to express a human gene and its protein is still an animal.


Assuntos
Animais Geneticamente Modificados , Desenho de Fármacos , Camundongos Transgênicos , Farmacologia/tendências , Animais , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos , Camundongos , Preparações Farmacêuticas/metabolismo , Farmacocinética , Ratos , Medição de Risco
5.
Curr Drug Metab ; 8(2): 109-36, 2007 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-17305491

RESUMO

Patients vary considerably in their response to drug therapy. A drug that proves to be pharmacologically effective in some patients at a given dose may be ineffective or even toxic in others. The interindividual variability in drug response represents a major challenge in drug therapy, particularly for drugs with narrow therapeutic index. The intensity and duration of a drug action are determined not only by pharmacokinetic processes, but also by pharmacodynamic processes. Therefore, the variability in drug response is a result of the variability in either pharmacokinetic or pharmacodynamic processes, or a combination of both. The purpose of this paper is to review the sources that contribute to pharmacokinetic and pharmacodynamic variability. Although the main focus will be on the genetic variability, the impact of environmental factors on drug response will also be discussed. Finally, the application and limitation of the concept of personalized medicine will be briefly discussed.


Assuntos
Tratamento Farmacológico , Farmacocinética , Farmacologia , Relação Dose-Resposta a Droga , Variação Genética , Humanos
6.
Expert Opin Drug Metab Toxicol ; 3(1): 81-92, 2007 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-17269896

RESUMO

Although they are less frequently compared with the reported cases of CYP-mediated drug interactions, clinically significant transporter-mediated drug interactions, which are mainly based on efflux transporter or P-glycoprotein data, have been reported. Unlike the CYP-mediated drug interactions that can be readily defined by inhibition or induction of CYP enzymes, the evidence for the so-called transporter-mediated drug interactions is often less conclusive. The difficulty in defining transporter-mediated drug interactions is due mainly to the interplay between transporters and drug-metabolizing enzymes in drug disposition, and the lack of specific and potent inhibitors for each transporter and enzyme. An important lesson learned from animal studies is that transporter inhibition has a much greater impact on the tissue distribution of drugs than on the systemic exposure of drugs measured in plasma. The potential risk of transporter-mediated drug interactions might be underestimated if only plasma concentrations are monitored.


Assuntos
Interações Medicamentosas , Proteínas de Membrana Transportadoras/metabolismo , Preparações Farmacêuticas/metabolismo , Animais , Área Sob a Curva , Sistema Enzimático do Citocromo P-450/metabolismo , Humanos , Cetoconazol/administração & dosagem , Cetoconazol/metabolismo , Cetoconazol/farmacocinética , Midazolam/administração & dosagem , Midazolam/metabolismo , Midazolam/farmacocinética , Preparações Farmacêuticas/administração & dosagem , Rifampina/administração & dosagem , Rifampina/metabolismo , Rifampina/farmacocinética
7.
Curr Drug Metab ; 7(1): 39-65, 2006 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-16454692

RESUMO

With few exceptions, drugs exert their effects not within the plasma compartment, but in the defined target tissues. The process of drug distribution to the active site constitutes the "link-bridge" of the pharmacokinetic/pharmacodynamic (PK/PD) relationship. In spite of the importance of drug distribution as a key factor in determining pharmacologic response, research on drug distribution has historically received much less attention than that of absorption, metabolism, and excretion. The negligence of research on drug distribution is due mainly to the inaccessibility of the target tissues for obvious ethical reasons. In addition, lack of reliable experimental tools to assess the distribution process is also a major contributing factor. Because of this negligence, drug distribution has been referred to as "the forgotten relative in clinical pharmacokinetics." Although recent advances in molecular biology have led to the identification of many drug transporters, many of the processes of drug distribution are still not fully understood. The primary aim of this article is to provide new insight into the mechanisms of drug distribution, with an attempt to describe the relationship between the drug distribution and pharmacologic response. In addition, the factors that affect the processes of drug distribution will also be reviewed. Also, validity of some key assumptions that are used to relate the processes of tissue distribution with pharmacologic activity will be discussed.


Assuntos
Preparações Farmacêuticas/metabolismo , Distribuição Tecidual , Animais , Biotransformação , Humanos , Ligação Proteica , Fluxo Sanguíneo Regional
8.
Mol Cancer Ther ; 1(7): 451-9, 2002 May.
Artigo em Inglês | MEDLINE | ID: mdl-12479263

RESUMO

Currently, there is no therapy for men with androgen-refractory prostate cancer that substantially extends survival. This report characterizes by in vitro and in vivo techniques a new chemotherapeutic that is composed of desacetyl-vinblastine covalently linked to a peptide that contains a peptide bond that can be hydrolyzed by prostate-specific antigen (PSA). This compound (referred to as vinblastine-conjugate) is minimally toxic to cells in culture which do not express PSA. In the presence of PSA, the peptide moiety is hydrolyzed, generating several highly toxic metabolites that contain vinblastine. Animals bearing PSA-positive human prostate tumors that were treated with the vinblastine-conjugate experienced a >99% reduction in PSA serum level. In contrast, animals bearing PSA-positive human prostate tumors treated with the cytotoxic metabolites derived from the PSA hydrolysis of the vinblastine-conjugate showed a nonsignificant change in both PSA and tumor weight values. The cell killing activity of the vinblastine-conjugate is PSA dependent because animals bearing non-PSA-producing human tumor xenografts had a nonsignificant increase in tumor weight after vinblastine-conjugate treatment. Exploratory efficacy/toxicity studies in LNCaP tumor-bearing nude mice were conducted with animals treated for 5 consecutive days with various doses of either the vinblastine-conjugate or a PSA-generated toxic metabolite (desacetyl-vinblastine). The desacetyl-vinblastine treatment resulted in 10-70% mortality with a very slight effect on tumor growth. In contrast, vinblastine-conjugate treatments resulted in no mortality, good to excellent antitumor efficacy, very slight to slight peripheral neuropathy and myelopathy, and slight to severe testicular degeneration. Similar treatment of beagle dogs with the vinblastine-conjugate showed even less toxicity. These data support the use of the PSA-hydrolyzable vinblastine-conjugate as an experimental therapy for prostate cancer in man.


Assuntos
Antineoplásicos Fitogênicos/uso terapêutico , Pró-Fármacos/uso terapêutico , Antígeno Prostático Específico/metabolismo , Neoplasias da Próstata/terapia , Vimblastina/uso terapêutico , Animais , Antineoplásicos/uso terapêutico , Antineoplásicos Fitogênicos/metabolismo , Cães , Doxorrubicina/uso terapêutico , Humanos , Masculino , Camundongos , Camundongos Nus , Modelos Químicos , Transplante de Neoplasias , Pró-Fármacos/metabolismo , Neoplasias da Próstata/patologia , Especificidade da Espécie , Distribuição Tecidual , Células Tumorais Cultivadas , Vimblastina/metabolismo
9.
Adv Drug Deliv Rev ; 55(1): 53-81, 2003 Jan 21.
Artigo em Inglês | MEDLINE | ID: mdl-12535574

RESUMO

P-glycoprotein (P-gp), the most extensively studied ATP-binding cassette transporter, functions as a biological barrier by extruding toxic substances and xenobiotics out of cells. In vitro and in vivo studies have demonstrated that P-gp plays a significant role in drug absorption and disposition. Like cytochrome P450 enzymes, inhibition and induction of P-gp have been reported as the causes of drug-drug interactions. Because many prototypic inhibitors and inducers affect both CYP3A4 and P-gp, many drug interactions caused by these inhibitors and inducers involve these two systems. Clinically, it is very difficult to quantitatively differentiate P-gp-mediated drug interactions versus CYP3A4-mediated drug interactions, unless their relative contributions can be accurately estimated. Therefore, care should be exercised when interpreting drug interaction data and exploring the underlying mechanisms of drug interactions.


Assuntos
Membro 1 da Subfamília B de Cassetes de Ligação de ATP/metabolismo , Interações Medicamentosas , Membro 1 da Subfamília B de Cassetes de Ligação de ATP/antagonistas & inibidores , Membro 1 da Subfamília B de Cassetes de Ligação de ATP/biossíntese , Barreira Hematoencefálica/fisiologia , Ensaios Clínicos como Assunto , Feminino , Humanos , Absorção Intestinal , Preparações Farmacêuticas/metabolismo , Farmacocinética , Placenta/metabolismo , Placenta/fisiologia , Gravidez , Distribuição Tecidual
10.
Curr Drug Metab ; 3(6): 623-46, 2002 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-12369890

RESUMO

Glucuronidation is responsible for the clearance of a diverse range of drug and chemicals whose topology confers properties that complicate in vitro-in vivo clearance correlations as compared to those possible for oxidative metabolism. The active site of the UGTs faces the inside of the luminal space of the endoplasmic reticulum, thus presenting diffusional barriers for substrates, the cosubstrate, UDPGA, and resultant glucuronide products. Transport processes for the cosubstrate UDPGA and glucuronidated products likely contribute to the well-known latency phenomena in which exogenous detergents or alamethicin are required for maximal UGT activity in microsomes. This complicates the extrapolation of results of in vitro clearance studies to the in vivo situation. Even with activation, the microsomal-based clearance values still underestimate the actual in vivo UGT-mediated clearance; therefore latency is not the only explanation for the poor correlation. Recent data indicate that hepatocytes are a promising in vitro system that can be used for the early evaluation of human clearance behavior of drug candidates. Both induction and inhibition of UGT-mediated clearance are a source of clinical drug-drug interactions. Emerging evidence indicates that the same mechanisms identified in the regulation of CYP enzymes also are involved in regulation of the UGTs, i.e., CAR, AH and probably PXR mediate regulation of UGT1A1, 1A6 and UGT2B7, respectively. In contrast to CYP-mediated interactions, with a few exceptions, the magnitude of UGT-mediated interactions are less than 2-fold because of the relatively high UGT Km values and substrate overlap among the multiple isozymes.


Assuntos
Glucuronosiltransferase/metabolismo , Uridina Difosfato Ácido Glucurônico/metabolismo , Animais , Transporte Biológico/fisiologia , Interações Medicamentosas/fisiologia , Glucuronosiltransferase/química , Humanos , Uridina Difosfato Ácido Glucurônico/química
11.
Curr Drug Metab ; 3(3): 257-73, 2002 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-12083320

RESUMO

The pharmacological effects of a drug are highly dependent on the absorption, metabolism, elimination, and distribution of the drug. In the past few years it has become apparent that transport proteins play a major role in regulating the distribution, elimination and metabolism of some drugs. As a consequence of our new understanding of the influence of transport proteins on the pharmacokinetic and pharmacodynamic behavior of drugs, increasing attention has been focused on the potential for drug-drug interactions arising from interactions with drug transport proteins. The efflux transporter P-glycoprotein (P-gp) has received the most attention with regard to its role in restricting drug absorption and distribution and as a potential source for variability in drug pharmacokinetics and pharmacodynamics. This review will focus on the evaluation of drug candidates to assess the potential for drug interactions at the level of P-gp. We will discuss the role of P-gp in drug disposition, the biochemistry of P-gp efflux as it relates to model systems to study drug interactions with P-gp, and the implementation of P-gp assay models within the drug discovery process.


Assuntos
Membro 1 da Subfamília B de Cassetes de Ligação de ATP/metabolismo , Interações Medicamentosas , Preparações Farmacêuticas/metabolismo , Administração Oral , Animais , Bioensaio , Transporte Biológico , Carbapenêmicos/metabolismo , Células Cultivadas , Desenho de Fármacos , Técnicas In Vitro , Especificidade da Espécie , Relação Estrutura-Atividade , Distribuição Tecidual
12.
J Med Chem ; 45(21): 4706-15, 2002 Oct 10.
Artigo em Inglês | MEDLINE | ID: mdl-12361397

RESUMO

Chemotherapy of prostate cancer with antimitotic agents such as vinblastine and doxorubicin is only marginally effective, due to dose-limiting systemic toxicity. Herein we report the development of peptidyl conjugate 5 of the cytotoxic agent vinblastine (1), along with the results of its in vitro and in vivo evaluation as a pro-drug targeted at prostate cancer cells. Prostate-derived tumors are known to produce significant amounts of prostate specific antigen (PSA), a serine protease with chymotrypsin-like properties. Earlier work in these laboratories established that an appropriately engineered peptidyl pro-drug will release active cytotoxic agent strictly within the microenvironment of the tumor tissue (Garsky, V. M., et al. J. Med.Chem. 2001, 44, 4216-4224). Conjugate 5, which features an octapeptide segment attached by an ester linkage at the 4-position of vinblastine (1), undergoes rapid cleavage by PSA (T(1/2) = 12 min) between the Gln and Ser residues. In nude mouse xenograft studies, 5 reduced circulating PSA levels by 99% and tumor weight by 85% at a dose just below its MTD. By contrast, the putative end-point metabolite, the cytotoxic agent des-acetyl vinblastine (1b), was ineffective in reducing PSA levels and tumor burden at its maximum tolerated doses. Additional data from metabolism studies on 5 support the supervention of a novel in vivo processing mechanism, the spontaneous release of 1b from a dipeptidyl intermediate driven by favorable diketopiperazine formation.


Assuntos
Antineoplásicos/síntese química , Oligopeptídeos/síntese química , Pró-Fármacos/síntese química , Neoplasias da Próstata/tratamento farmacológico , Vimblastina/análogos & derivados , Vimblastina/síntese química , Animais , Antineoplásicos/farmacologia , Antineoplásicos/toxicidade , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Masculino , Camundongos , Camundongos Nus , Transplante de Neoplasias , Oligopeptídeos/farmacologia , Oligopeptídeos/toxicidade , Pró-Fármacos/farmacologia , Pró-Fármacos/toxicidade , Neoplasias da Próstata/patologia , Relação Estrutura-Atividade , Células Tumorais Cultivadas , Vimblastina/farmacologia , Vimblastina/toxicidade
13.
Clin Pharmacokinet ; 42(1): 59-98, 2003.
Artigo em Inglês | MEDLINE | ID: mdl-12489979

RESUMO

P-glycoprotein, the most extensively studied ATP-binding cassette (ABC) transporter, functions as a biological barrier by extruding toxins and xenobiotics out of cells. In vitro and in vivo studies have demonstrated that P-glycoprotein plays a significant role in drug absorption and disposition. Because of its localisation, P-glycoprotein appears to have a greater impact on limiting cellular uptake of drugs from blood circulation into brain and from intestinal lumen into epithelial cells than on enhancing the excretion of drugs out of hepatocytes and renal tubules into the adjacent luminal space. However, the relative contribution of intestinal P-glycoprotein to overall drug absorption is unlikely to be quantitatively important unless a very small oral dose is given, or the dissolution and diffusion rates of the drug are very slow. This is because P-glycoprotein transport activity becomes saturated by high concentrations of drug in the intestinal lumen. Because of its importance in pharmacokinetics, P-glycoprotein transport screening has been incorporated into the drug discovery process, aided by the availability of transgenic mdr knockout mice and in vitro cell systems. When applying in vitro and in vivo screening models to study P-glycoprotein function, there are two fundamental questions: (i) can in vitro data be accurately extrapolated to the in vivo situation; and (ii) can animal data be directly scaled up to humans? Current information from our laboratory suggests that in vivo P-glycoprotein activity for a given drug can be extrapolated reasonably well from in vitro data. On the other hand, there are significant species differences in P-glycoprotein transport activity between humans and animals, and the species differences appear to be substrate-dependent. Inhibition and induction of P-glycoprotein have been reported as the causes of drug-drug interactions. The potential risk of P-glycoprotein-mediated drug interactions may be greatly underestimated if only plasma concentration is monitored. From animal studies, it is clear that P-glycoprotein inhibition always has a much greater impact on tissue distribution, particularly with regard to the brain, than on plasma concentrations. Therefore, the potential risk of P-glycoprotein-mediated drug interactions should be assessed carefully. Because of overlapping substrate specificity between cytochrome P450 (CYP) 3A4 and P-glycoprotein, and because of similarities in P-glycoprotein and CYP3A4 inhibitors and inducers, many drug interactions involve both P-glycoprotein and CYP3A4. Unless the relative contribution of P-glycoprotein and CYP3A4 to drug interactions can be quantitatively estimated, care should be taken when exploring the underlying mechanism of such interactions.


Assuntos
Membro 1 da Subfamília B de Cassetes de Ligação de ATP/metabolismo , Farmacocinética , Membro 1 da Subfamília B de Cassetes de Ligação de ATP/biossíntese , Membro 1 da Subfamília B de Cassetes de Ligação de ATP/genética , Animais , Transporte Biológico Ativo , Biotransformação , Interações Medicamentosas , Humanos , Absorção Intestinal , Especificidade da Espécie , Distribuição Tecidual
14.
J Pharm Sci ; 93(10): 2488-96, 2004 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-15349958

RESUMO

Cytochromes P450 (CYPs) and p-glycoproteins (Pgps) are believed to play important roles in drug absorption, metabolism, and elimination. Numerous drugs and environmental chemicals can modulate expression of these two classes of genes in different species. The present study investigated the effect of dexamethasone (Dex) on gene expression on both message and protein levels of mdr1a, mdr1b, CYP3A1, and CYP3A2 in small intestine, colon, liver, kidney, and brain microvessels of the rats treated orally with Dex at 1 or 20 mg/kg/day for 3 days. The basal expression of mdr1a mRNA was highest in the brain microvessels followed by colon, small intestine, liver, and kidney, and mdr1b mRNA was highest in the brain microvessels followed by kidney, liver, colon, and small intestine. After Dex treatment, mdr1a mRNA was increased by 5.5- and 10.7-fold in the small intestine, decreased extensively by 85-90% in the liver, and showed little or no change in the colon, kidney, and brain microvessels compared to the control rats. A similar pattern was observed for mdr1b mRNA. CYP3A1 mRNA was increased in all tissues examined. CYP3A2 mRNA was not significantly changed with the exception that at 20 mg/kg CYP3A2 mRNA was increased 5- and 30-fold in the colon and kidney. In general, Western blot analyses were consistent with mRNA changes. CYP3A protein expression was increased in all tissues examined. The disparity of the impact of Dex on the CYP 3A and Pgp expression in these studies suggest that the regulation of Pgp expression is very complex and is difficult to predict solely based on the PXR response to xenobiotics.


Assuntos
Subfamília B de Transportador de Cassetes de Ligação de ATP/biossíntese , Transportadores de Cassetes de Ligação de ATP/biossíntese , Hidrocarboneto de Aril Hidroxilases/biossíntese , Dexametasona/farmacologia , Proteínas de Membrana/biossíntese , Subfamília B de Transportador de Cassetes de Ligação de ATP/genética , Transportadores de Cassetes de Ligação de ATP/genética , Administração Oral , Animais , Hidrocarboneto de Aril Hidroxilases/genética , Western Blotting , Encéfalo/irrigação sanguínea , Colo/metabolismo , Citocromo P-450 CYP3A , Immunoblotting , Intestino Delgado/metabolismo , Rim/metabolismo , Fígado/metabolismo , Masculino , Proteínas de Membrana/genética , Microcirculação , Reação em Cadeia da Polimerase , RNA Mensageiro/biossíntese , Ratos , Ratos Sprague-Dawley , Membro 4 da Subfamília B de Transportadores de Cassetes de Ligação de ATP
15.
J Pharm Anal ; 4(4): 270-278, 2014 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-29403890

RESUMO

An efficient screening assay was developed and validated for simultaneous assessment of compound-mediated inhibition of six major human cytochrome P450 (CYP) enzymes. This method employed a cocktail of six probe substrates (i.e., phenacetin, amodiaquine, diclofenac, S-mephenytoin, dextromethorphan and midazolam for CYP1A2, 2C8, 2C9, 2C19, 2D6 and 3A4, respectively) as well as individual prototypical inhibitors of the six CYP enzymes in human liver microsomes under optimized incubation conditions. The corresponding marker metabolites (i.e., acetaminophen, N-desethylamodiaquine, 4-OH-diclofenac, 4-OH-S-mephenytoin, dextrorphan and 1-OH-midazolam) in the incubates were quantified using LC-MS/MS methods either by an internal standard (IS) calibration curve or a simplified analyte-to-IS peak area ratio approach. The results showed that the IC50 values determined by the cocktail approach were in good agreement with those obtained by the individual substrate approach as well as those reported in the literature. Besides, no remarkable difference was observed between the two quantification approaches. In conclusion, this new cocktail assay can be used for reliable screening of compound-mediated CYP inhibition.

16.
Curr Drug Metab ; 10(7): 661-91, 2009 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-19702530

RESUMO

With the advances in recombinant DNA biotechnology, molecular biology and immunology, the number of biotech drugs, including peptides, proteins and monoclonal antibodies, available for clinical use has dramatically increased in recent years. Although pharmacokinetic principles are equally applicable to the large molecule drugs and conventional small molecule drugs, the underlying mechanisms for the processes of absorption, distribution, metabolism and excretion (ADME) of large molecule drugs are often very different from that of small molecule drugs. Therefore, a good understanding of the ADME processes of large molecule drugs is essential in support of the development of therapeutic biologics. The purpose of this article is to review the current knowledge of the ADME processes that govern the pharmacokinetics of biotech drugs. The challenges encountered by orally administered peptide and protein drugs, and the nature of lymphatic absorption after subcutaneous administration will be discussed. In addition, molecular mechanisms of biodistribution, metabolism and renal excretion of biotech drugs will also be discussed. Finally, approaches used for prediction of human pharmacokinetics of protein drugs will be briefly discussed.


Assuntos
Anticorpos Monoclonais/farmacocinética , Peptídeos/farmacocinética , Proteínas/farmacocinética , Animais , Anticorpos Monoclonais/administração & dosagem , Biotecnologia/métodos , DNA Recombinante , Desenho de Fármacos , Humanos , Peptídeos/administração & dosagem , Proteínas/administração & dosagem
17.
Pharm Res ; 23(6): 1089-116, 2006 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-16718615

RESUMO

Cytochrome P450 (CYP) induction-mediated interaction is one of the major concerns in clinical practice and for the pharmaceutical industry. There are two major issues associated with CYP induction: a reduction in therapeutic efficacy of comedications and an induction in reactive metabolite-induced toxicity. Because CYP induction is a metabolic liability in drug therapy, it is highly desirable to develop new drug candidates that are not potent CYP inducer to avoid the potential of CYP induction-mediated drug interactions. For this reason, today, many drug companies routinely include the assessment of CYP induction at the stage of drug discovery as part of the selection processes of new drug candidates for further clinical development. The purpose of this article is to review the molecular mechanisms of CYP induction and the clinical implications, including pharmacokinetic and pharmacodynamic consequences. In addition, factors that affect the degree of CYP induction and extrapolation of in vitro CYP induction data to in vivo situations will also be discussed. Finally, assessment of the potential of CYP induction at the drug discovery and development stage will be discussed.


Assuntos
Citocromo P-450 CYP2B1/biossíntese , Citocromo P-450 CYP2E1/biossíntese , Citocromo P-450 CYP3A/biossíntese , Interações Medicamentosas , Indução Enzimática/efeitos dos fármacos , Farmacocinética , Farmacologia , Receptores Citoplasmáticos e Nucleares/metabolismo , Animais , Receptor Constitutivo de Androstano , Citocromo P-450 CYP2B1/genética , Citocromo P-450 CYP2E1/genética , Citocromo P-450 CYP3A/genética , Desenho de Fármacos , Indução Enzimática/genética , Variação Genética , Humanos , Fígado/efeitos dos fármacos , Fígado/enzimologia , Receptor de Pregnano X , Receptor Cross-Talk , Receptores de Hidrocarboneto Arílico/metabolismo , Receptores Citoplasmáticos e Nucleares/genética , Receptores de Esteroides/metabolismo , Especificidade da Espécie , Fatores de Transcrição/metabolismo
18.
Toxicol Appl Pharmacol ; 217(2): 143-52, 2006 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-17055014

RESUMO

This paper aims to provide a scientifically based perspective on issues surrounding the proposed toxicology testing of synthetic drug metabolites as a means of ensuring adequate nonclinical safety evaluation of drug candidates that generate metabolites considered either to be unique to humans or are present at much higher levels in humans than in preclinical species. We put forward a number of theoretical considerations and present several specific examples where the kinetic behavior of a preformed metabolite given to animals or humans differs from that of the corresponding metabolite generated endogenously from its parent. The potential ramifications of this phenomenon are that the results of toxicity testing of the preformed metabolite may be misleading and fail to characterize the true toxicological contribution of the metabolite when formed from the parent. It is anticipated that such complications would be evident in situations where (a) differences exist in the accumulation of the preformed versus generated metabolites in specific tissues, and (b) the metabolite undergoes sequential metabolism to a downstream product that is toxic, leading to differences in tissue-specific toxicity. Owing to the complex nature of this subject, there is a need to treat drug metabolite issues in safety assessment on a case-by-case basis, in which a knowledge of metabolite kinetics is employed to validate experimental paradigms that entail administration of preformed metabolites to animal models.


Assuntos
Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos , Preparações Farmacêuticas/metabolismo , Farmacocinética , Animais , Biotransformação , Humanos , Medição de Risco , Distribuição Tecidual
19.
Drug Metab Dispos ; 34(9): 1546-55, 2006 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-16782766

RESUMO

In this study, induction and inhibition of rhesus monkey CYP3A64 versus human CYP3A4 were characterized in vitro, and the corresponding pharmacokinetic consequences were evaluated in rhesus monkeys. In monkey hepatocytes, rifampin markedly induced CYP3A64 mRNA (EC50 = 0.5 microM; Emax = 6-fold) and midazolam (MDZ) 1'-hydroxylase activity (EC50 = 0.2 microM; Emax = 2-fold). Compound A (N-[2(R)-hydroxy-1(S)-indanyl-5-[2(S)-(1,1-dimethylethylaminocarbonyl)-4-[(furo[2,3-b]pyridin-5-yl)-methyl]piperazin-1-yl]-4(S)-hydroxy-2(R)-phenylmethylpentanamide), a known potent and mechanism-based inhibitor of CYP3A4, strongly inhibited the formation of 1'-hydroxy MDZ by recombinant CYP3A64 in a concentration- and time-dependent manner (KI = 0.25 microM; k(inact) = 0.4 min(-1)). Similar corresponding results also were obtained with human CYP3A4 in the presence of rifampin or compound A. In rhesus monkeys, MDZ exhibited a relatively high metabolic clearance (primarily via 1'-hydroxylation followed by glucuronidation) and a low hepatic availability (Fh = 16%). Consistent with the induction of hepatic metabolism of a high-clearance compound, pretreatment with rifampin (18 mg/kg p.o. for 5 days) did not significantly affect the i.v. kinetics of MDZ, but caused a pronounced reduction (approximately 10-fold) in the systemic exposure to MDZ and, consequently, its Fh following intrahepatic portal vein administration (i.pv.) of MDZ. A comparable extent of the pharmacokinetic interaction also was obtained after a 1.8 mg/kg rifampin dose. Also consistent with the in vitro CYP3A64 inhibition finding, compound A (6 mg/kg i.v.) markedly increased (10-fold) the i.pv. administered MDZ exposure. At the doses studied, plasma concentrations of rifampin or compound A reached or exceeded their respective in vitro EC50 or KI values. These findings suggest the potential applicability of the in vitro-in vivo relationship approach in rhesus monkeys for studying CYP3A-mediated interactions in humans.


Assuntos
Citocromo P-450 CYP3A/biossíntese , Sistema Enzimático do Citocromo P-450/biossíntese , Avaliação Pré-Clínica de Medicamentos , Hepatócitos/enzimologia , Adolescente , Adulto , Idoso , Animais , Células Cultivadas , Citocromo P-450 CYP3A/genética , Inibidores do Citocromo P-450 CYP3A , Inibidores das Enzimas do Citocromo P-450 , Sistema Enzimático do Citocromo P-450/genética , Avaliação Pré-Clínica de Medicamentos/métodos , Interações Medicamentosas , Indução Enzimática , Inibidores Enzimáticos/farmacocinética , Inibidores Enzimáticos/farmacologia , Éteres/farmacocinética , Éteres/farmacologia , Feminino , Hepatócitos/efeitos dos fármacos , Humanos , Hidrocarbonetos Fluorados/farmacocinética , Hidrocarbonetos Fluorados/farmacologia , Hidroxilação , Infusões Intravenosas , Isoenzimas/antagonistas & inibidores , Isoenzimas/biossíntese , Isoenzimas/genética , Macaca mulatta , Masculino , Midazolam/administração & dosagem , Midazolam/farmacocinética , Pessoa de Meia-Idade , Modelos Animais , RNA Mensageiro/biossíntese , Proteínas Recombinantes/antagonistas & inibidores , Proteínas Recombinantes/metabolismo , Rifampina/farmacocinética , Rifampina/farmacologia
20.
Drug Metab Dispos ; 33(5): 603-13, 2005 May.
Artigo em Inglês | MEDLINE | ID: mdl-15673596

RESUMO

Individual variability in cytochrome P450 (P450) induction comprises an important component contributing to the difficulties in assessing and predicting metabolism-based drug-drug interactions in humans. In this article, we outline the major factors responsible for the individual variability in P450 induction, including variable transporter activity and metabolism of inducers in vivo, genetic variations of P450 genes and their regulatory regions, genetic variations of receptors and regulatory proteins required for induction, and different physiological and environmental elements. With a better understanding of the major determinants in P450 induction and a profile of the phenotypes of these determinants in each individual, it is believed that the individual variability in induction-mediated drug-drug interactions can be adequately evaluated.


Assuntos
Sistema Enzimático do Citocromo P-450/biossíntese , Sistema Enzimático do Citocromo P-450/genética , Interações Medicamentosas , Preparações Farmacêuticas/metabolismo , Animais , Indução Enzimática/fisiologia , Variação Genética , Humanos
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