Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 13 de 13
Filtrar
Mais filtros










Base de dados
Intervalo de ano de publicação
1.
Drug Metab Dispos ; 42(5): 918-31, 2014 May.
Artigo em Inglês | MEDLINE | ID: mdl-24608633

RESUMO

The disposition of a single oral dose of 5 mg (100 µCi) of [(14)C]axitinib was investigated in fasted healthy human subjects (N = 8). Axitinib was rapidly absorbed, with a median plasma Tmax of 2.2 hours and a geometric mean Cmax and half-life of 29.2 ng/ml and 10.6 hours, respectively. The plasma total radioactivity-time profile was similar to that of axitinib but the AUC was greater, suggesting the presence of metabolites. The major metabolites in human plasma (0-12 hours), identified as axitinib N-glucuronide (M7) and axitinib sulfoxide (M12), were pharmacologically inactive, and with axitinib comprised 50.4%, 16.2%, and 22.5% of the radioactivity, respectively. In excreta, the majority of radioactivity was recovered in most subjects by 48 hours postdose. The median radioactivity excreted in urine, feces, and total recovery was 22.7%, 37.0%, and 59.7%, respectively. The recovery from feces was variable across subjects (range, 2.5%-60.2%). The metabolites identified in urine were M5 (carboxylic acid), M12 (sulfoxide), M7 (N-glucuronide), M9 (sulfoxide/N-oxide), and M8a (methylhydroxy glucuronide), accounting for 5.7%, 3.5%, 2.6%, 1.7%, and 1.3% of the dose, respectively. The drug-related products identified in feces were unchanged axitinib, M14/15 (mono-oxidation/sulfone), M12a (epoxide), and an unidentified metabolite, comprising 12%, 5.7%, 5.1%, and 5.0% of the dose, respectively. The proposed mechanism to form M5 involved a carbon-carbon bond cleavage via M12a, followed by rearrangement to a ketone intermediate and subsequent Baeyer-Villiger rearrangement, possibly through a peroxide intermediate. In summary, the study characterized axitinib metabolites in circulation and primary elimination pathways of the drug, which were mainly oxidative in nature.


Assuntos
Imidazóis/farmacocinética , Indazóis/farmacocinética , Inibidores de Proteínas Quinases/farmacocinética , Proteínas Tirosina Quinases/antagonistas & inibidores , Receptores de Fatores de Crescimento do Endotélio Vascular/antagonistas & inibidores , Adulto , Axitinibe , Radioisótopos de Carbono , Cromatografia Líquida de Alta Pressão , Fezes/química , Humanos , Imidazóis/sangue , Imidazóis/metabolismo , Imidazóis/urina , Indazóis/sangue , Indazóis/metabolismo , Indazóis/urina , Espectroscopia de Ressonância Magnética , Masculino , Espectrometria de Massas , Pessoa de Meia-Idade , Estrutura Molecular , Inibidores de Proteínas Quinases/sangue , Inibidores de Proteínas Quinases/metabolismo , Inibidores de Proteínas Quinases/urina
2.
Drug Metab Dispos ; 40(3): 539-55, 2012 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-22180047

RESUMO

Sunitinib is an oral multitargeted tyrosine kinase inhibitor approved for the treatment of advanced renal cell carcinoma, imatinib-refractory gastrointestinal stromal tumor, and advanced pancreatic neuroendocrine tumors. The current studies were conducted to characterize the pharmacokinetics, distribution, and metabolism of sunitinib after intravenous and/or oral administrations of [(14)C]sunitinib in rats (5 mg/kg i.v., 15 mg/kg p.o.), monkeys (6 mg/kg p.o.), and humans (50 mg p.o.). After oral administration, plasma concentration of sunitinib and total radioactivity peaked from 3 to 8 h. Plasma terminal elimination half-lives of sunitinib were 8 h in rats, 17 h in monkeys, and 51 h in humans. The majority of radioactivity was excreted to the feces with a smaller fraction of radioactivity excreted to urine in all three species. The bioavailability in female rats was close to 100%, suggesting complete absorption of sunitinib. Whole-body autoradioluminography suggested radioactivity was distributed throughout rat tissues, with the majority of radioactivity cleared within 72 h. Radioactivity was eliminated more slowly from pigmented tissues. Sunitinib was extensively metabolized in all species. Many metabolites were detected both in urine and fecal extracts. The main metabolic pathways were N-de-ethylation and hydroxylation of indolylidene/dimethylpyrrole. N-Oxidation/hydroxylation/desaturation/deamination of N,N'-diethylamine and oxidative defluorination were the minor metabolic pathways. Des-ethyl metabolite M1 was the major circulating metabolite in all three species.


Assuntos
Indóis/metabolismo , Indóis/farmacocinética , Pirróis/metabolismo , Pirróis/farmacocinética , Absorção/fisiologia , Administração Oral , Adulto , Animais , Disponibilidade Biológica , Isótopos de Carbono/administração & dosagem , Isótopos de Carbono/metabolismo , Isótopos de Carbono/urina , Radioisótopos de Carbono , Fezes/química , Feminino , Meia-Vida , Humanos , Indóis/administração & dosagem , Indóis/urina , Injeções Intravenosas/métodos , Macaca fascicularis , Masculino , Pessoa de Meia-Idade , Pirróis/administração & dosagem , Pirróis/urina , Ratos , Ratos Sprague-Dawley , Sunitinibe , Distribuição Tecidual , Adulto Jovem
3.
Drug Metab Dispos ; 37(5): 992-8, 2009 May.
Artigo em Inglês | MEDLINE | ID: mdl-19220984

RESUMO

The recently introduced Clonetics human corneal epithelium (cHCE) cell line is considered a promising in vitro permeability model, replacing excised animal cornea to predict corneal permeability of topically administered compounds. The purpose of this study was to further characterize cHCE as a corneal permeability model from both drug metabolism and transport aspects. First, good correlation was found in the permeability values (P(app)) obtained from cHCE and rabbit corneas for various ophthalmic drugs and permeability markers. Second, a previously established real-time quantitative polymerase chain reaction method was used to profile mRNA expression of drug-metabolizing enzymes (major cytochromes P450 and UDP glucuronosyltransferase 1A1) and transporters in cHCE in comparison with human cornea. Findings indicated that 1) the mRNA expression of most metabolizing enzymes tested was lower in cHCE than in excised human cornea, 2) the mRNA expression of efflux transporters [multidrug resistant-associated protein (MRP) 1, MRP2, MRP3, and breast cancer resistance protein], peptide transporters (PEPT1 and PEPT2), and organic cation transporters (OCTN1, OCTN2, OCT1, and OCT3) could be detected in cHCE as in human cornea. However, multidrug resistance (MDR) 1 and organic anion transporting polypeptide 2B1 was not detected in cHCE; 3) cHCE was demonstrated to possess both esterase and ketone reductase activities known to be present in human cornea; and 4) transport studies using probe substrates suggested that both active efflux and uptake transport may be limited in cHCE. As the first detailed report to delineate drug metabolism and transport characteristics of cHCE, this work shed light on the usefulness and potential limitations of cHCE in predicting the corneal permeability of ophthalmic drugs, including ester prodrugs, and transporter substrates.


Assuntos
Córnea/citologia , Córnea/metabolismo , Células Epiteliais/metabolismo , Oxirredutases do Álcool/metabolismo , Animais , Linhagem Celular , Cromatografia Líquida de Alta Pressão , Córnea/enzimologia , DNA Complementar/biossíntese , DNA Complementar/genética , Digoxina/metabolismo , Células Epiteliais/enzimologia , Esterases/metabolismo , Humanos , Indinavir/metabolismo , Espectrometria de Massas , Permeabilidade , RNA Mensageiro/biossíntese , RNA Mensageiro/genética , Coelhos , Reação em Cadeia da Polimerase Via Transcriptase Reversa
4.
Cancer Chemother Pharmacol ; 64(4): 691-706, 2009 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-19169880

RESUMO

PURPOSE: The purpose of these extensive non-clinical studies was to assess pharmacokinetics and dispositional properties of sunitinib and its primary active metabolite (SU12662). METHODS: Sunitinib was administered in single and repeat oral doses in mice, rats, and monkeys. Assessments were made using liquid-chromatography-tandem mass spectrometric methods, radioactive assays, and quantitative whole body autoradiography. RESULTS: Sunitinib was readily absorbed with good oral bioavailability and linear kinetics at clinically-relevant doses. SU12662 plasma levels were less than those of sunitinib in mice and monkeys, but greater in rats. Sunitinib was extensively distributed with moderate-to-high systemic clearance and eliminated primarily into feces. Single- and repeat-dosing kinetics were similar. A prolonged half-life allowed once-daily dosing, enabling adequate systemic exposure with limited-to-moderate accumulation. In multiple-dose studies with cyclic dosing, drug plasma concentrations cleared from one cycle to the next. CONCLUSIONS: Sunitinib exhibited advantageous pharmacokinetic and dispositional properties in non-clinical species, translating into favorable properties in humans.


Assuntos
Antineoplásicos/farmacocinética , Indóis/farmacocinética , Inibidores de Proteínas Quinases/farmacocinética , Pirróis/farmacocinética , Receptores Proteína Tirosina Quinases/antagonistas & inibidores , Animais , Antineoplásicos/sangue , Área Sob a Curva , Cromatografia Líquida de Alta Pressão , Feminino , Indóis/administração & dosagem , Indóis/sangue , Macaca fascicularis , Masculino , Camundongos , Inibidores de Proteínas Quinases/administração & dosagem , Inibidores de Proteínas Quinases/sangue , Pirróis/administração & dosagem , Pirróis/sangue , Ratos , Ratos Sprague-Dawley , Sunitinibe , Espectrometria de Massas em Tandem
5.
Clin Cancer Res ; 14(22): 7272-83, 2008 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-19010843

RESUMO

PURPOSE: Axitinib (AG-013736) is a potent and selective inhibitor of vascular endothelial growth factor (VEGF) receptor tyrosine kinases 1 to 3 that is in clinical development for the treatment of solid tumors. We provide a comprehensive description of its in vitro characteristics and activities, in vivo antiangiogenesis, and antitumor efficacy and translational pharmacology data. EXPERIMENTAL DESIGN: The potency, kinase selectivity, pharmacologic activity, and antitumor efficacy of axitinib were assessed in various nonclinical models. RESULTS: Axitinib inhibits cellular autophosphorylation of VEGF receptors (VEGFR) with picomolar IC(50) values. Counterscreening across multiple kinase and protein panels shows it is selective for VEGFRs. Axitinib blocks VEGF-mediated endothelial cell survival, tube formation, and downstream signaling through endothelial nitric oxide synthase, Akt and extracellular signal-regulated kinase. Following twice daily oral administration, axitinib produces consistent and dose-dependent antitumor efficacy that is associated with blocking VEGFR-2 phosphorylation, vascular permeability, angiogenesis, and concomitant induction of tumor cell apoptosis. Axitinib in combination with chemotherapeutic or targeted agents enhances antitumor efficacy in many tumor models compared with single agent alone. Dose scheduling studies in a human pancreatic tumor xenograft model show that simultaneous administration of axitinib and gemcitabine without prolonged dose interruption or truncation of axitinib produces the greatest antitumor efficacy. The efficacious drug concentrations predicted in nonclinical studies are consistent with the range achieved in the clinic. Although axitinib inhibits platelet-derived growth factor receptors and KIT with nanomolar in vitro potencies, based on pharmacokinetic/pharmacodynamic analysis, axitinib acts primarily as a VEGFR tyrosine kinase inhibitor at the current clinical exposure. CONCLUSIONS: The selectivity, potency for VEGFRs, and robust nonclinical activity may afford broad opportunities for axitinib to improve cancer therapy.


Assuntos
Inibidores da Angiogênese/farmacologia , Imidazóis/farmacologia , Indazóis/farmacologia , Neoplasias Experimentais/tratamento farmacológico , Neovascularização Patológica/tratamento farmacológico , Receptores de Fatores de Crescimento do Endotélio Vascular/antagonistas & inibidores , Transdução de Sinais/efeitos dos fármacos , Animais , Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Axitinibe , Western Blotting , Linhagem Celular Tumoral , Sinergismo Farmacológico , Feminino , Humanos , Imuno-Histoquímica , Imunoprecipitação , Camundongos , Camundongos Nus , Inibidores de Proteínas Quinases/farmacologia , Receptores de Fatores de Crescimento do Endotélio Vascular/efeitos dos fármacos , Ensaios Antitumorais Modelo de Xenoenxerto
6.
Drug Metab Dispos ; 36(7): 1300-7, 2008 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-18411399

RESUMO

Studies were designed to quantitatively assess the mRNA expression of 1) 10 cytochrome P450 (P450) enzymes in human cornea, iris-ciliary body (ICB), and retina/choroid relative to their levels in the liver, and of 2) 21 drug transporters in these tissues relative to their levels in human small intestine, liver, or kidney. Potential species differences in mRNA expression of PEPT1, PEPT2, and MDR1 were also assessed in these ocular tissues from rabbit, dog, monkey, and human. P450 expression was either absent or marginal in human cornea, ICB, and retina/choroid, suggesting a limited role for P450-mediated metabolism in ocular drug disposition. In contrast, among 21 key drug efflux and uptake transporters, many exhibited relative expression levels in ocular tissues comparable with those observed in small intestine, liver, or kidney. This robust ocular transporter presence strongly suggests a significant role that transporters may play in ocular barrier function and ocular pharmacokinetics. The highly expressed efflux transporter MRP1 and uptake transporters PEPT2, OCT1, OCTN1, and OCTN2 may be particularly important in absorption, distribution, and clearance of their drug substrates in the eye. Evidence of cross-species ocular transporter expression differences noted in these studies supports the conclusion that transporter expression variability, along with anatomic and physiological differences, should be taken into consideration to better understand animal ocular pharmacokinetic and pharmacodynamic data and the scalability to human for ocular drugs.


Assuntos
Sistema Enzimático do Citocromo P-450/genética , Olho/metabolismo , Preparações Farmacêuticas/metabolismo , RNA Mensageiro/genética , Animais , Sequência de Bases , Primers do DNA , Cães , Feminino , Haplorrinos , Humanos , Masculino , Farmacocinética , Reação em Cadeia da Polimerase , Coelhos
7.
Drug Metab Dispos ; 35(9): 1593-602, 2007 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-17567732

RESUMO

Metabolism of [(14)C]capravirine was studied via both in vitro and in vivo means in rats and dogs. Mass balance was achieved in rats and dogs, with mean total recovery of radioactivity >86% for each species. Capravirine was well absorbed in rats but only moderately so in dogs. The very low levels of recovered unchanged capravirine and the large number of metabolites observed in rats and dogs indicate that capravirine was eliminated predominantly by metabolism in both species. Capravirine underwent extensive metabolism via oxygenation reactions (predominant pathways in both species), depicolylation and carboxylation in rats, and decarbamation in dogs. The major circulating metabolites of capravirine were two depicolylated products in rats and three decarbamated products in dogs. However, none of the five metabolites was observed in humans, indicating significant species differences in terms of identities and relative abundances of circulating capravirine metabolites. Because the majority of in vivo oxygenated metabolites of capravirine were observed in liver microsomal incubations, the in vitro models provided good insight into the in vivo oxygenation pathways. In conclusion, the diversity (i.e., hydroxylation, sulfoxidation, sulfone formation, and N-oxidation), multiplicity (i.e., mono-, di-, tri-, and tetraoxygenations), and high enzymatic specificity (>90% contribution by CYP3A4 in humans, CYP3A1/2 in rats, and CYP3A12 in dogs) of the capravirine oxygenation reactions observed in humans, rats, and dogs in vivo and in vitro suggest that capravirine can be a useful CYP3A substrate for probing catalytic mechanisms and kinetics of CYP3A enzymes in humans and animal species.


Assuntos
Fármacos Anti-HIV/farmacocinética , Citocromo P-450 CYP3A/metabolismo , Imidazóis/farmacocinética , Compostos de Enxofre/farmacocinética , Animais , Fármacos Anti-HIV/farmacologia , Anticorpos Bloqueadores/farmacologia , Biotransformação , Cromatografia Líquida , Inibidores do Citocromo P-450 CYP3A , Cães , Técnicas In Vitro , Masculino , Espectrometria de Massas , Microssomos Hepáticos/efeitos dos fármacos , Microssomos Hepáticos/metabolismo , Ratos , Ratos Sprague-Dawley , Proteínas Recombinantes/metabolismo , Ritonavir/farmacologia , Especificidade da Espécie , Especificidade por Substrato
8.
Drug Metab Lett ; 1(1): 61-5, 2007 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-19356020

RESUMO

Six tetra- and two penta-oxygenated capravirine metabolites observed in rats, dogs and humans represent the maximum numbers of isomers that can be predicted since oxygenations are restricted at the pyridinyl nitrogen (N-oxidation), sulfur (sulfoxidation), and isopropyl group (hydroxylation), exemplifying a unique case that is very unusual for sequential drug metabolism.


Assuntos
Fármacos Anti-HIV/farmacocinética , Imidazóis/farmacocinética , Oxigênio/metabolismo , Compostos de Enxofre/farmacocinética , Administração Oral , Animais , Cromatografia Líquida de Alta Pressão , Cães , Humanos , Isomerismo , Espectrometria de Massas , Ratos , Ratos Sprague-Dawley , Especificidade da Espécie
9.
Drug Metab Dispos ; 34(11): 1798-802, 2006 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-16914510

RESUMO

Capravirine, a new non-nucleoside reverse transcriptase inhibitor, undergoes extensive oxygenation reactions, including N-oxidation, sulfoxidation, sulfonation, and hydroxylation in humans. Numerous primary (mono-oxygenated) and sequential (di-, tri-, and tetraoxygenated) metabolites of capravirine are formed via the individual or combined oxygenation pathways. In this study, cytochrome P450 enzymes responsible for the primary and sequential oxygenation reactions of capravirine in human liver microsomes were identified at the specific pathway level. The total oxygenation of capravirine is mediated predominantly (>90%) by CYP3A4 and marginally (<10%) by CYP2C8, 2C9, and 2C19 in humans. Specifically, each of the two major mono-oxygenated metabolites C23 (sulfoxide) and C26 (N-oxide), is mediated predominantly (>90%) by CYP3A4 and slightly (<10%) by CYP2C8, the minor tertiary hydroxylated metabolite C19 by CYP3A4, 2C8, and 2C19, and the minor primary hydroxylated metabolite C20 by CYP3A4, 2C8, and 2C9. However, all sequential oxygenation reactions are mediated exclusively by CYP3A4. Due to their relatively insignificant contributions of C19 and C20 to total capravirine metabolism, no attempt was made to determine relative contributions of cytochrome P450 enzymes to the formation of the two minor metabolites.


Assuntos
Fármacos Anti-HIV/farmacocinética , Sistema Enzimático do Citocromo P-450/metabolismo , Imidazóis/farmacocinética , Microssomos Hepáticos/enzimologia , Compostos de Enxofre/farmacocinética , Biotransformação , Humanos , Técnicas In Vitro , Microssomos Hepáticos/metabolismo , Estrutura Molecular , Oxirredução
10.
Birth Defects Res B Dev Reprod Toxicol ; 77(2): 95-103, 2006 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-16607633

RESUMO

BACKGROUND: Matrix metalloproteinases (MMPs) play key roles in remodeling of the extracellular matrix during embryogenesis and fetal development. The objective of this study was to determine the effects of prinomastat, a potent selective MMP inhibitor, on fetal growth and development. METHODS: Prinomastat (25, 100, 250 mg/kg/day, p.o.) was administered to pregnant female Sprague-Dawley rats on gestational days (GD) 6-17. A Cesarian section was carried out on GD 20 and the fetuses were evaluated for viability and skeletal and soft tissue abnormalities. RESULTS: Prinomastat treatment at the 250 mg/kg/day dose produced a decrease in body weight and food consumption in the dams. A dose-dependent increase in post-implantation loss was observed in the 100 and 250 mg/kg/day-dose groups, resulting in only 22% of the dams having viable litters for evaluation at the 250 mg/kg/day dose. Fetal skeletal tissue variations and malformations were present in all prinomastat treated groups and their frequency increased with dose. Variations and malformation in fetal soft tissue were also increased at the 100 and 250 mg/kg/day doses. Prinomastat also interfered with fetal growth of rat embryo cultures in vitro. CONCLUSIONS: These data confirm that MMP inhibition has a profound effect on fetal growth and development in vivo and in vitro.


Assuntos
Inibidores Enzimáticos/toxicidade , Feto/anormalidades , Inibidores de Metaloproteinases de Matriz , Compostos Orgânicos/toxicidade , Animais , Peso Corporal/efeitos dos fármacos , Osso e Ossos/anormalidades , Ingestão de Alimentos/efeitos dos fármacos , Técnicas de Cultura Embrionária , Perda do Embrião/induzido quimicamente , Embrião de Mamíferos/anormalidades , Embrião de Mamíferos/efeitos dos fármacos , Inibidores Enzimáticos/farmacocinética , Feminino , Feto/efeitos dos fármacos , Feto/enzimologia , Tamanho do Órgão/efeitos dos fármacos , Compostos Orgânicos/farmacocinética , Gravidez , Ratos , Ratos Sprague-Dawley , Útero/anatomia & histologia , Útero/efeitos dos fármacos
11.
Drug Metab Dispos ; 33(10): 1438-45, 2005 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-16006566

RESUMO

Capravirine, a non-nucleoside reverse transcriptase inhibitor for the treatment of human immunodeficiency virus type 1, undergoes extensive oxygenations to numerous sequential metabolites in humans. Because several possible oxygenation pathways may be involved in the formation and/or sequential metabolism of a single metabolite, it is very difficult or even impossible to determine the definitive pathways and their relative contributions to the overall metabolism of capravirine using conventional approaches. For this reason, a human liver microsome-based "sequential incubation" method has been developed to deconvolute the complicated sequential metabolism of capravirine. In brief, the method includes three fundamental steps: 1) 30-min primary incubation of [(14)C]capravirine, 2) isolation of (14)C metabolites from the primary incubate, and 3) 30-min sequential incubation of each isolated (14)C metabolite supplemented with an ongoing (30 min) microsomal incubation with nonlabeled capravirine. Based on the extent of both the disappearance of the isolated precursor (14)C metabolites and the formation of sequential (14)C metabolites, definitive oxygenation pathways of capravirine were assigned. In addition, the percentage contribution of a precursor metabolite to the formation of each of its sequential metabolites (called sequential contribution) and the percentage contribution of a sequential metabolite formed from each of its precursor metabolites (called precursor contribution) were determined. An advantage of this system is that the sequential metabolism of each isolated (14)C metabolite can be monitored selectively by radioactivity in the presence of all relevant metabolic components (i.e., nonlabeled parent and its other metabolites). This methodology should be applicable to mechanistic studies of other compounds involving complicated sequential metabolic reactions when radiolabeled materials are available.


Assuntos
Imidazóis/metabolismo , Microssomos Hepáticos/metabolismo , Inibidores da Transcriptase Reversa/metabolismo , Biotransformação , Radioisótopos de Carbono , Humanos , Imidazóis/química , Técnicas In Vitro , Métodos , Compostos de Enxofre
12.
Drug Metab Dispos ; 32(7): 689-98, 2004 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-15205383

RESUMO

Metabolism and disposition of capravirine, a new non-nucleoside reverse transcriptase inhibitor, were studied in healthy male volunteers who were randomly divided into two groups (A and B) with five subjects in each group. Group A received a single oral dose of [(14)C]capravirine (1400 mg) and group B received multiple oral doses of ritonavir (100 mg), followed by a single oral dose of [(14)C]capravirine (1400 mg). Mean total recoveries of radioactivity for groups A and B were 86.3% and 79.0%, respectively, with a mean cumulative recovery in urine comparable with that in feces for both groups. Excretion of unchanged capravirine was negligible in urine and low in feces for both groups. The results suggest that capravirine was well absorbed, with metabolism as the principal mechanism of clearance. Capravirine underwent extensive metabolism to a variety of metabolites via oxygenations (mono-, di-, tri-, and tetra-) representing the predominant pathway, glucuronidation, and sulfation in humans. No useful plasma profiles of group A were obtained due to extremely low levels of plasma radioactivity. Analysis of group B plasma indicated that unchanged capravirine was the major radiochemical component, with three monooxygenated products and a glucuronide of capravirine as the major circulating metabolites. Nineteen metabolites were identified using liquid chromatography-multistage ion-trap mass spectrometry methodologies. In summary, coadministration of low-dose ritonavir (a potent CYP3A4 inhibitor) drastically decreased the levels of sequential oxygenated metabolites and markedly increased the levels of the parent drug and primary oxygenated metabolites overall in plasma, urine, and feces.


Assuntos
Fármacos Anti-HIV/metabolismo , Inibidores das Enzimas do Citocromo P-450 , Inibidores da Transcriptase Reversa/metabolismo , Ritonavir/farmacologia , Administração Oral , Fármacos Anti-HIV/sangue , Radioisótopos de Carbono , Cromatografia Líquida de Alta Pressão , Citocromo P-450 CYP3A , Interações Medicamentosas , Fezes/química , Humanos , Imidazóis , Masculino , Inibidores da Transcriptase Reversa/sangue , Espectrometria de Massas por Ionização por Electrospray , Compostos de Enxofre , Fatores de Tempo
13.
J Med Chem ; 46(21): 4572-85, 2003 Oct 09.
Artigo em Inglês | MEDLINE | ID: mdl-14521419

RESUMO

The optimization of the pharmacokinetic performance of various 2-pyridone-containing human rhinovirus (HRV) 3C protease (3CP) inhibitors following oral administration to either beagle dogs or CM-monkeys is described. The molecules described in this work are composed of a 2-pyridone-containing peptidomimetic binding determinant and an alpha,beta-unsaturated ester Michael acceptor moiety which forms an irreversible covalent adduct with the active site cysteine residue of the 3C enzyme. Modification of the ester contained within these compounds is detailed along with alteration of the P(2) substituent present in the peptidomimetic portion of the inhibitors. The pharmacokinetics of several inhibitors in both dogs and monkeys are described (7 h plasma concentrations after oral administration) along with their human plasma stabilities, stabilities in incubations with human, dog, and monkey microsomes and hepatocytes, Caco-2 permeabilities, and aqueous solubilities. Compounds containing an alpha,beta-unsaturated ethyl ester fragment and either an ethyl or propargyl P(2) moiety displayed the most promising combination of 3C enzyme inhibition (k(obs)/[I] 170 000-223 000 M(-1) s(-1)), antiviral activity (EC(50) = 0.047-0.058 microM, mean vs seven HRV serotypes), and pharmacokinetics following oral administration (7 h dog plasma levels = 0.248-0.682 microM; 7 h CM-monkey plasma levels = 0.057-0.896 microM).


Assuntos
Antivirais/síntese química , Antivirais/farmacologia , Cisteína Endopeptidases/metabolismo , Inibidores de Proteases/síntese química , Inibidores de Proteases/farmacologia , Piridonas/síntese química , Piridonas/farmacologia , Rhinovirus/enzimologia , Proteínas Virais/metabolismo , Proteases Virais 3C , Animais , Antivirais/farmacocinética , Disponibilidade Biológica , Proteínas Sanguíneas/metabolismo , Células CACO-2 , Cães , Desenho de Fármacos , Meia-Vida , Hepatócitos/metabolismo , Humanos , Técnicas In Vitro , Indicadores e Reagentes , Macaca fascicularis , Espectroscopia de Ressonância Magnética , Masculino , Microssomos Hepáticos/metabolismo , Inibidores de Proteases/farmacocinética , Ligação Proteica , Rhinovirus/efeitos dos fármacos , Solubilidade , Relação Estrutura-Atividade
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA
...