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1.
Eur J Drug Metab Pharmacokinet ; 45(2): 235-241, 2020 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-31782125

RESUMO

BACKGROUND AND OBJECTIVE: Dutasteride, an analog of testosterone, a 5α-reductase inhibitor is widely used in the treatment of moderate to severe symptomatic benign prostatic hyperplasia. The aim of this study was to compare the pharmacokinetic characteristics of dutasteride in beagle dogs after oral administration of a conventional soft gelatin capsule (Avodart®) and a novel solid-supersaturatable soft-microemulsifying drug delivery system (SMEDDS) tablet. METHODS: In this comparative dissolution study, the dissolution of dutasteride was pH-independent for both formulations. Noncompartmental analysis and modeling approaches were carried out to determine the pharmacokinetic parameters of dutasteride. RESULTS: Approximately 90% of the drug dissolved in all media within 15 min, indicating that there was little difference in the dissolution rate of the solid-supersaturatable SMEDDS tablets and that of the commercial soft gelatin capsules. Using t test analysis, no statistically significant difference was detected in the pharmacokinetic parameters of the two formulations. The test/reference geometric mean ratios were 1.087 (90% confidence intervals 0.8529-1.3854) for the area under the plasma concentration versus time curve from 0 to the last time point (48 h) with a measurable concentration and 1.094 (90% confidence intervals 0.8909-1.3454) for maximum plasma concentration. Unfortunately, the bioequivalent criterium (0.8-1.25) was not met due to the small sample size, but the results of this study suggest a possible bioequivalence of dutasteride in the two formulations. CONCLUSION: Based on the results of this study, the development of a tablet dosage form of dutasteride using a solid-supersaturatable SMEDDS should be considered for humans.


Assuntos
Inibidores de 5-alfa Redutase/farmacocinética , Sistemas de Liberação de Medicamentos , Dutasterida/farmacocinética , Inibidores de 5-alfa Redutase/administração & dosagem , Administração Oral , Animais , Cápsulas , Cães , Liberação Controlada de Fármacos , Dutasterida/administração & dosagem , Emulsões , Gelatina , Masculino , Comprimidos , Equivalência Terapêutica
2.
Drug Des Devel Ther ; 11: 1681-1692, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28652706

RESUMO

Finasteride (FIN) is a Class II candidate of the Biopharmaceutics Classification System (BCS). The lipophilic cavity of cyclodextrins (CyDs) enables it to construct a non-covalent inclusion complex with different insoluble drugs. Only ß-cyclodextrin (ß-CyD) and hydroxypropyl-ß-CyD (HP-ß-CyD) have been previously examined with FIN. This study aimed to investigate the consistence of FIN with different kinds of ß-CyDs, including dimethyl-ß-cyclodextrin (DM-ß-CyD), carboxymethyl-ß-cyclodextrin (CM-ß-CyD), HP-ß-CyD, sulfobutyl ether-ß-cyclodextrin (SBE-ß-CyD), and ß-CyD, by the coprecipitation method. The resultant inclusion systems were characterized by differential scanning calorimetry, infrared spectroscopy, X-ray diffractometry, and dissolution studies. Moreover, molecular docking for the selected inclusion systems was carried out to explore the suitable arrangements of FIN in the cavity of ß-CyD or its derivatives. The results suggested that the DM-ß-CyD inclusion system gave the higher complexation efficiency for improvement in solubility of FIN and hence enhancement of its bioavailability. Pharmacokinetic parameters displayed a higher absorption rate and higher area under the curve of the FIN/DM-ß-CyD inclusion complex when compared with the drug alone, which indicates an improvement in the absorption and bioavailability of FIN in the DM-ß-CyD inclusion system.


Assuntos
Inibidores de 5-alfa Redutase/farmacocinética , Finasterida/farmacocinética , Simulação de Acoplamento Molecular , beta-Ciclodextrinas/química , Inibidores de 5-alfa Redutase/administração & dosagem , Inibidores de 5-alfa Redutase/sangue , Inibidores de 5-alfa Redutase/química , Administração Oral , Animais , Área Sob a Curva , Disponibilidade Biológica , Varredura Diferencial de Calorimetria , Cristalografia por Raios X , Composição de Medicamentos , Liberação Controlada de Fármacos , Finasterida/administração & dosagem , Finasterida/sangue , Finasterida/química , Meia-Vida , Absorção Intestinal , Taxa de Depuração Metabólica , Modelos Biológicos , Difração de Pó , Coelhos , Solubilidade , Espectrofotometria Infravermelho
3.
J Pharm Sci ; 106(11): 3385-3394, 2017 11.
Artigo em Inglês | MEDLINE | ID: mdl-28652158

RESUMO

In this study, we developed positively charged liquid crystalline nanoparticles (LCN) coated with chitosan (CHI) to enhance the skin permeation and distribution of 5α-reductase inhibitors for the treatment of androgenetic alopecia. LCN and surface-modified LCN (CHI-LCN) were prepared by ultrasonication method, and their physicochemical properties were characterized. In vitro and in vivo skin permeation and retention were studied using porcine abdominal skin and mice skin using the Franz diffusion cell. Skin distribution and cellular uptake of LCN and CHI-LCN were also investigated. The particle size and surface charge were 244.9 ± 2.1 nm and -19.2 ± 1.1 mV, respectively, for LCNs and 300.0 ± 7.6 nm and 24.7 ± 2.4 mV, respectively, for CHI-LCN. The permeation of 5α-reductase inhibitors was significantly greater with CHI-LCN compared with LCN, whereas there was no significant difference observed in the skin distribution. In fluorescence studies, fluorescence intensity was higher for CHI-LCNs throughout the skin, whereas more intense fluorescence was seen only in the epidermis layer for LCN. CHI-LCN showed greater cellular uptake than LCN, resulting in internalization of 98.5 ± 1.9% of nanoparticles into human keratinocyte cells. In conclusion, surface modification of LCN with CHI is a promising strategy for increasing skin permeation of 5α-reductase inhibitors for topical delivery.


Assuntos
Inibidores de 5-alfa Redutase/administração & dosagem , Inibidores de 5-alfa Redutase/farmacocinética , Portadores de Fármacos/química , Cristais Líquidos/química , Nanopartículas/química , Absorção Cutânea , Animais , Linhagem Celular , Humanos , Queratinócitos/metabolismo , Camundongos , Camundongos Pelados , Tamanho da Partícula , Pele/metabolismo , Suínos
4.
Steroids ; 124: 29-34, 2017 08.
Artigo em Inglês | MEDLINE | ID: mdl-28549802

RESUMO

5α-Reductase is a key enzyme responsible for dihydrotestosterone biosynthesis and has been recognized as an important target for discovering new drugs against benign prostatic hyperplasia (BPH). In this study, a series of novel steroidal androst-3,5-diene-3-carboxylic acids have been designed and synthesized. Biological evaluations were performed on their 5α-reductase inhibitory activities by both in vitro enzyme inhibition assay and in vivo by prostate weighing method. Results showed that most of them displayed excellent 5α-reductase inhibitory potency. Detailed evaluation indicated that most of the compounds displayed slightly higher inhibition potency towards type 2 isozyme. Among all the compounds, 16a was found to be the most potential inhibitor with the IC50 of 0.25µM and 0.13µM against type 1 and 2 isozymes respectively. In vivo 5a-reductase inhibitory evaluation of 16a also showed a more significant reduction effect (p<0.001) in rat prostate weight than epristeride. Furthermore, the results of in silico ADME study indicated that compound 16a exhibited good pharmacokinetic properties. Thus, 16a could serve as promising lead candidates for further study.


Assuntos
Inibidores de 5-alfa Redutase/síntese química , Inibidores de 5-alfa Redutase/farmacologia , Ácidos Carboxílicos/síntese química , Ácidos Carboxílicos/farmacologia , Colestenona 5 alfa-Redutase/metabolismo , Desenho de Fármacos , Inibidores de 5-alfa Redutase/química , Inibidores de 5-alfa Redutase/farmacocinética , Animais , Ácidos Carboxílicos/química , Ácidos Carboxílicos/farmacocinética , Técnicas de Química Sintética , Simulação por Computador , Masculino , Ratos
6.
Curr Clin Pharmacol ; 12(1): 31-35, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28294070

RESUMO

BACKGROUND: Androgenetic alopecia is a common condition characterized by thinning of scalp hair. Conversion of testosterone to dihydrotestosterone, a more potent androgen, by the enzyme 5-α-reductase is responsible for underlying pathogenesis. Dutasteride, a synthetic 4-azasteroid, is a selective and competitive inhibitor of both type-1 and type-2 isoenzymes of 5-α-reductase. Finasteride and minoxidil are the only approved drugs for androgenetic alopecia. Dutasteride has been demonstrated to be effective in several randomized, double-blind, placebo controlled trials in androgenetic alopecia. In this review, after the pharmacology of dutasteride, the authors have discussed the status of dutasteride in androgenetic alopecia and have compared its efficacy with that of finasteride. OBJECTIVE: This article aims to review the current status of dutasteride in androgenetic alopecia. The structure, mechanism of action, pharmacokinetics and side effects are discussed along with its comparison with finasteride in androgenetic alopecia. METHOD: The main sources of our information were Medline Pubmed, Google scholar and Scopus including original articles and review articles. The keywords 'dutasteride', 'dutasteride in androgenetic alopecia' were used for search. CONCLUSION: Like finasteride, dutasteride is now becoming popular treatment option in AGA, due to its good response shown by various randomized control studies and meta-analysis. Also, in most of these studies, dutasteride was found to be better than finasteride with comparable adverse effects. Therefore, dutasteride could become a treatment of choice for AGA in near future.


Assuntos
Inibidores de 5-alfa Redutase/uso terapêutico , Alopecia/tratamento farmacológico , Dutasterida/uso terapêutico , Cabelo/efeitos dos fármacos , Inibidores de 5-alfa Redutase/efeitos adversos , Inibidores de 5-alfa Redutase/química , Inibidores de 5-alfa Redutase/farmacocinética , Alopecia/metabolismo , Alopecia/fisiopatologia , Animais , Di-Hidrotestosterona/metabolismo , Dutasterida/efeitos adversos , Dutasterida/química , Dutasterida/farmacocinética , Feminino , Finasterida/uso terapêutico , Cabelo/crescimento & desenvolvimento , Cabelo/metabolismo , Humanos , Masculino , Resultado do Tratamento
7.
Clin Drug Investig ; 36(9): 763-767, 2016 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-27356530

RESUMO

BACKGROUND AND OBJECTIVES: Dutasteride is currently marketed by GlaxoSmithKline (GSK), either as monotherapy or as a fixed-dose combination with tamsulosin. As part of the project to develop the fixed-dose combination product, alternative formulations of dutasteride were prepared by GSK, and their pharmacokinetic properties were investigated. METHODS: Two single-centre, open-label, active-comparator, randomised, three-period crossover studies were performed. The first study evaluated the relative bioavailability of dutasteride 0.5 mg soft gelatin capsule (marketed formulation, reference) versus a dutasteride 0.5 mg hard gelatin capsule and a dutasteride 0.5 mg tablet. The second assessed the relative bioavailability of dutasteride 0.5 mg from soft gelatin capsules containing 300 or 100 mg of mono- and diglycerides of caprylic acid/capric acid (MDC8, an emulsifying agent) versus the marketed formulation. RESULTS: In the first study (n = 36), compared with the marketed soft gelatin capsule formulation, the bioavailability (least squares [LS] means ratio) of the tablet formulation was 76 % (90 % CI 0.68-0.84), and that of the hard gelatin capsule was 73 % (90 % CI 0.66-0.82). Peak exposures were also lower for the tablet (73 %; 90 % CI 0.66-0.81) and hard capsule (71 %; 90 % CI 0.64-0.79) relative to the marketed soft gelatin capsule. In the second study (n = 37), compared with the marketed soft gelatin formulation, the bioavailability (LS means ratio) of the 300 mg MDC8 capsule formulation was 95 % (90 % CI 0.88-1.03), and that of the 100 mg MDC8 capsule formulation was 93 % (90 % CI 0.86-1.00). Peak exposures were also lower for the 300 mg MDC8 (90 %; 90 % CI 0.81-0.99) and 100 mg MDC8 (87 %; 90 % CI 0.79-0.96) formulations. CONCLUSIONS: The bioavailability of, and peak exposure to, dutasteride are influenced by the formulation of the administered medication. These studies demonstrate the importance of formulation for obtaining the optimal pharmacokinetic properties of dutasteride.


Assuntos
Inibidores de 5-alfa Redutase/farmacocinética , Dutasterida/farmacocinética , Inibidores de 5-alfa Redutase/administração & dosagem , Adolescente , Adulto , Disponibilidade Biológica , Cápsulas , Estudos Cross-Over , Composição de Medicamentos , Dutasterida/administração & dosagem , Feminino , Gelatina , Humanos , Masculino , Pessoa de Meia-Idade , Comprimidos , Adulto Jovem
8.
Drug Des Devel Ther ; 9: 3231-8, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-26150696

RESUMO

In this study, a gelatin microparticle-containing self-microemulsifying formulation (SMF) was developed using a spray-drying method to enhance the oral delivery of the poorly water-soluble therapeutic dutasteride. The effect of the amount of gelatin and the type and amount of hydrophilic additives, namely, Gelucire(®) 44/14, poloxamer 407, sodium lauryl sulfate, Soluplus(®), Solutol™ HS15, and D-α-tocopheryl polyethylene glycol 1000 succinate, on the droplet size, dissolution, and oral absorption of dutasteride from the SMF was investigated. Upon dispersion of the gelatin microparticle-containing SMF in water after spray-drying, the mean droplet size of the aqueous dispersion was in the range of 110-137 nm. The in vitro dissolution and recrystallization results showed that gelatin could be used as a solid carrier and recrystallization inhibitor for the SMF of dutasteride. Furthermore, combination of the gelatin microparticle-containing SMF and Soluplus enhanced the dissolution properties and oral absorption of dutasteride. The results of our study suggest that the gelatin microparticle-containing SMF in combination with Soluplus could be useful to enhance the oral absorption of dutasteride.


Assuntos
Inibidores de 5-alfa Redutase/química , Inibidores de 5-alfa Redutase/farmacocinética , Portadores de Fármacos , Dutasterida/química , Dutasterida/farmacocinética , Gelatina/química , Inibidores de 5-alfa Redutase/administração & dosagem , Inibidores de 5-alfa Redutase/sangue , Administração Oral , Animais , Disponibilidade Biológica , Química Farmacêutica , Dutasterida/administração & dosagem , Dutasterida/sangue , Emulsões , Excipientes/química , Interações Hidrofóbicas e Hidrofílicas , Masculino , Tamanho da Partícula , Polietilenoglicóis/química , Polivinil/química , Ratos Sprague-Dawley , Solubilidade
9.
Drug Res (Stuttg) ; 65(9): 449-56, 2015 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-25919644

RESUMO

A specific, fast and sensitive LC-MS/MS assay was developed for the determination of finasteride in human plasma using betamethsone dipropionate as the internal standard (IS). The limit of quantification was 1.0 ng/ml and the method was linear in the range of 1.0-25.0 ng/ml. The retention times were 0.75 min for finasteride and 0.85 min for IS. Method intra-batch precision and accuracy ranged from 3.6 to 7.1%, and 96.6 to 103.9%, respectively. Inter-batch precision ranged from 2.5 to 3.4%, while Inter-batch accuracy ranged from 100.3 to 103.5%. The analytical method was applied to evaluate the pharmacokinetic and relative bioavailability of 2 different pharmaceutical formulations containing 1.0 mg of finasteride. This study evaluated 38 volunteers in a randomized, 2-period crossover study with 7 days washout period between doses. The geometric mean and respective 90% CI of finasteride test/reference percent ratios were 95.68% (91.2 - 104.6%) for Cmax, 97.5% (92.1-103.3%) for AUC0-t and 98.1 (92.67-103.8) for AUC0-inf. Based on the 90% confidence interval of the individual ratios (test formulation/reference formulation) for Cmax and AUC0-inf, it was concluded that the test formulation is bioequivalent to the reference one with respect to the rate and extent of absorption of finasteride.


Assuntos
Finasterida/sangue , Finasterida/farmacocinética , Inibidores de 5-alfa Redutase/sangue , Inibidores de 5-alfa Redutase/farmacocinética , Adolescente , Adulto , Betametasona/análogos & derivados , Betametasona/sangue , Betametasona/farmacocinética , Disponibilidade Biológica , Cromatografia Líquida de Alta Pressão , Estudos Cross-Over , Humanos , Limite de Detecção , Masculino , Pessoa de Meia-Idade , Espectrometria de Massas por Ionização por Electrospray , Espectrometria de Massas em Tandem , Equivalência Terapêutica , Adulto Jovem
10.
Clin Pharmacol Drug Dev ; 4(6): 427-33, 2015 11.
Artigo em Inglês | MEDLINE | ID: mdl-27137714

RESUMO

The purpose of this study was to evaluate the effect of tamsulosin (0.2 mg) on the pharmacokinetics of dutasteride (0.5 mg) in a group of healthy Chinese male volunteers. This was an open-label, single-sequence, 3-period, drug-drug interaction phase 1 study. Twenty-four healthy Chinese male volunteers were enrolled and administered a single dose of 0.5 mg dutasteride and, following a 28- to 30-day washout period, 0.2 mg tamsulosin once daily for 7 days. On day 5, subjects received 0.2 mg tamsulosin coadministered with 0.5 mg dutasteride. Serum dutasteride and tamsulosin concentrations were monitored. In the presence or absence of tamsulosin, there were no apparent changes in dutasteride AUC and Cmax . Adverse events reported were mild to moderate in intensity and resolved by the end of the study. In healthy Chinese male volunteers, tamsulosin 0.2 mg at steady state had no apparent effect on dutasteride pharmacokinetics. Dutasteride and tamsulosin when administered alone or in combination were well tolerated.


Assuntos
Inibidores de 5-alfa Redutase/farmacocinética , Antagonistas de Receptores Adrenérgicos alfa 1/administração & dosagem , Dutasterida/farmacocinética , Sulfonamidas/administração & dosagem , Inibidores de 5-alfa Redutase/administração & dosagem , Inibidores de 5-alfa Redutase/efeitos adversos , Administração Oral , Adolescente , Antagonistas de Receptores Adrenérgicos alfa 1/efeitos adversos , Adulto , Área Sob a Curva , China , Esquema de Medicação , Interações Medicamentosas , Dutasterida/administração & dosagem , Dutasterida/efeitos adversos , Meia-Vida , Voluntários Saudáveis , Humanos , Masculino , Taxa de Depuração Metabólica , Pessoa de Meia-Idade , Modelos Biológicos , Dinâmica não Linear , Sulfonamidas/efeitos adversos , Tansulosina , Adulto Jovem
11.
Talanta ; 131: 728-35, 2015 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-25281165

RESUMO

Benign prostatic hyperplasia and prostate cancer can be treated with the 5α-reductase inhibitors, finasteride and dutasteride, when pharmacodynamic biomarkers are useful in assessing response. A novel method was developed to measure the substrates and products of 5α-reductases (testosterone, 5α-dihydrotestosterone (DHT), androstenedione) and finasteride and dutasteride simultaneously by liquid chromatography tandem mass spectrometry, using an ABSciex QTRAP(®) 5500, with a Waters Acquity™ UPLC. Analytes were extracted from serum (500 µL) via solid-phase extraction (Oasis(®) HLB), with (13)C3-labelled androgens and d9-finasteride included as internal standards. Analytes were separated on a Kinetex C18 column (150 × 3 mm, 2.6 µm), using a gradient run of 19 min. Temporal resolution of analytes from naturally occurring isomers and mass +2 isotopomers was ensured. Protonated molecular ions were detected in atmospheric pressure chemical ionisation mode and source conditions optimised for DHT, the least abundant analyte. Multiple reaction monitoring was performed as follows: testosterone (m/z 289 → 97), DHT (m/z 291 → 255), androstenedione (m/z 287 → 97), dutasteride (m/z 529 → 461), finasteride (m/z 373 → 317). Validation parameters (intra- and inter-assay precision and accuracy, linearity, limits of quantitation) were within acceptable ranges and biological extracts were stable for 28 days. Finally the method was employed in men treated with finasteride or dutasteride; levels of DHT were lowered by both drugs and furthermore the substrate concentrations increased.


Assuntos
Inibidores de 5-alfa Redutase/sangue , Androgênios/sangue , Cromatografia Líquida/métodos , Neoplasias da Próstata/sangue , Espectrometria de Massas em Tandem/métodos , Inibidores de 5-alfa Redutase/farmacocinética , Inibidores de 5-alfa Redutase/farmacologia , Androgênios/farmacocinética , Androgênios/farmacologia , Androstenodiona/sangue , Androstenodiona/farmacocinética , Androstenodiona/farmacologia , Azasteroides/sangue , Azasteroides/farmacocinética , Azasteroides/farmacologia , Di-Hidrotestosterona/sangue , Di-Hidrotestosterona/farmacocinética , Di-Hidrotestosterona/farmacologia , Dutasterida , Finasterida/sangue , Finasterida/farmacocinética , Finasterida/farmacologia , Humanos , Masculino , Neoplasias da Próstata/tratamento farmacológico , Extração em Fase Sólida/métodos , Testosterona/sangue , Testosterona/farmacocinética , Testosterona/farmacologia , Distribuição Tecidual
12.
Int J Pharm ; 478(1): 341-347, 2015 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-25437113

RESUMO

A novel supersaturable self-emulsifying drug delivery system (S-SEDDS) was formulated to improve the oral absorption of dutasteride (DTS), a 5α-reductase inhibitor that is poorly water-soluble. A supersaturable system was prepared by employing Soluplus(®) (polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer) as a precipitation inhibitor with a conventional SEDDS vehicle consisted of Capryol™ 90, Cremophor(®) EL and Transcutol(®) HP (DTS:SEDDS vehicle:Soluplus(®)=1.0:67.6:10.0 w/v/w). In an in vitro dissolution test in a non-sink condition, the drug dissolution rate from SEDDS was rapidly increased to 72% for an initial period of 5min, but underwent rapid drug precipitation within 2h, decreasing the amount of drug dissolved to one-seventh of its original amount. On the other hand, S-SEDDS resulted in a slower crystallization of DTS by virtue of a precipitation inhibitor, maintaining a 3 times greater dissolution rate after 2h compared to SEDDS. In an in vivo pharmacokinetic study in rats, the S-SEDDS formulation exhibited 3.9-fold greater area-under-curve value than that of the drug suspension and 1.3-fold greater than that of SEDDS. The maximum plasma concentration of S-SEDDS was 5.6- and 2.0-fold higher compared to drug suspension and SEDDS, respectively. The results of this study suggest that the novel supersaturable system may be a promising tool for improving the physicochemical property and oral absorption of the 5α-reductase inhibitor.


Assuntos
Inibidores de 5-alfa Redutase/administração & dosagem , Sistemas de Liberação de Medicamentos , Dutasterida/administração & dosagem , Polietilenoglicóis/administração & dosagem , Polivinil/administração & dosagem , Inibidores de 5-alfa Redutase/sangue , Inibidores de 5-alfa Redutase/química , Inibidores de 5-alfa Redutase/farmacocinética , Administração Oral , Animais , Dutasterida/sangue , Dutasterida/química , Dutasterida/farmacocinética , Emulsões , Absorção Intestinal , Masculino , Polietilenoglicóis/química , Polietilenoglicóis/farmacocinética , Polivinil/química , Polivinil/farmacocinética , Ratos Sprague-Dawley , Solubilidade
13.
Arch Pharm Res ; 38(4): 534-42, 2015 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-25085659

RESUMO

The objective of this study is to enhance skin permeation of finasteride and dutasteride for the treatment of androgenetic alopecia using surface-modified liquid crystalline nanoparticle (sm-LCN) dispersion. LCN entrapped with the drugs was prepared by using monoolein as a liquid crystal former, and surface modification was performed by treatment of the LCN dispersion with same volume of 1 % v/v acetic acid solution containing chitosan. Physicochemical properties of the LCN's were studied with regard to particle size, polydispersity index, zeta potential, and release of the drugs. Skin permeation of drugs entrapped into the LCN and sm-LCN was investigated with porcine abdominal skin using Franz diffusion cell. Cytotoxicity of the LCN's was also studied using human skin keratinocytes. The particle size and zeta potential of the LCN were 197.9 ± 2.5 nm and -20.2 ± 1.9 mV, respectively, and sm-LCN showed slightly bigger size and positive zeta potential due to the presence of thin coating on the surface of the nanoparticles. Compared to LCN, sm-LCN resulted in significantly enhanced skin permeation of the drugs whereas in vitro release was significantly reduced. Cell viability as a measure of cytotoxicity was above 80 % up to 20 µg/ml concentration of both LCN and sm-LCN. In conclusion, sm-LCN may provide a strategy to maximize therapeutic efficacy minimizing unwanted systemic side effects associated with the use of the drugs for the treatment of androgenetic alopecia.


Assuntos
Inibidores de 5-alfa Redutase/farmacocinética , Cristais Líquidos , Nanopartículas/metabolismo , Absorção Cutânea/fisiologia , Inibidores de 5-alfa Redutase/química , Animais , Sobrevivência Celular/efeitos dos fármacos , Sobrevivência Celular/fisiologia , Humanos , Queratinócitos/efeitos dos fármacos , Queratinócitos/metabolismo , Cristais Líquidos/química , Nanopartículas/química , Técnicas de Cultura de Órgãos , Absorção Cutânea/efeitos dos fármacos , Propriedades de Superfície , Suínos
14.
J Pharm Sci ; 103(8): 2307-14, 2014 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-24942358

RESUMO

In hair follicle (Hf) cells, the type-2 5-α-reductase enzyme, implicated in androgenetic alopecia, is selectively inhibited by finasteride (FNS). Because an effective topical formulation to deliver FNS to Hf is currently unavailable, this investigation aimed at evaluating in vitro FNS skin permeation and retention through and into hairless rat and human abdominal skin. Four hydroxypropyl chitosan (HPCH)-based formulations (P-08-012, P-08-016, P-08-063, and P-08-064) and one anhydrous formulation without HPCH (P-10-008) were tested. The pharmacokinetics in plasma and skin after application of P-08-016 or P-10-008 on dorsal rat skin with single and repeated doses was investigated. P-08-016 performed the best in driving FNS to the reticular dermis without producing a high transdermal flux. Neither the in vivo single nor the repeated dose experiments produced plasma levels of FNS and no differences were found between formulations concerning skin retention. No increase in the amount of drug retained in the skin was obtained with the repeated dose experiment. In conclusion, the HPCH-based formulation P-08-016 might represent an alternative to systemic therapy for its ability to promote a cutaneous depot of FNS in the region of hair bulbs, minimizing systemic absorption even after repeated treatments.


Assuntos
Inibidores de 5-alfa Redutase/farmacocinética , Finasterida/farmacocinética , Absorção Cutânea , Inibidores de 5-alfa Redutase/administração & dosagem , Inibidores de 5-alfa Redutase/sangue , Administração Cutânea , Alopecia/tratamento farmacológico , Animais , Finasterida/administração & dosagem , Finasterida/sangue , Humanos , Masculino , Ratos , Ratos Pelados , Pele/metabolismo
15.
J Pharm Sci ; 103(8): 2323-9, 2014 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-24916447

RESUMO

The differential stripping technique consists of a tape-stripping phase followed by a cyanoacrylate biopsy. This technique not only allows the quantification of drug retained in the stratum corneum (SC) and in the hair follicles but also differentiates transepidermal from transfollicular penetration. Our study aimed at both validating the differential stripping procedure on hairless rat skin and assessing the role of the hair follicle in the cutaneous penetration of finasteride (FNS) after application of two experimental formulations for 6 or 24 h: P-08-016, a hydroxypropyl chitosan (HPCH)-based formulation and P-10-008, an anhydrous formulation devoid of HPCH. Microscopic and histological evaluation showed that after 15 tape strips both the SC and the viable epidermis were completely removed. A subsequent cyanoacrylate skin surface biopsy led to the removal of the infundibula content. The largest amounts of FNS were found in the epidermis and in the appendages after application of P-08-016, regardless of the time from application. In contrast, smaller and statistically significant amounts of FNS were recovered with P-10-008 6 h after application, compared with that at 24 h. In conclusion, the differential stripping technique allowed determination of the amount of FNS localized in different skin districts, focusing particularly on the follicular contribution.


Assuntos
Inibidores de 5-alfa Redutase/farmacocinética , Finasterida/farmacocinética , Folículo Piloso/metabolismo , Absorção Cutânea , Inibidores de 5-alfa Redutase/administração & dosagem , Administração Cutânea , Animais , Finasterida/administração & dosagem , Folículo Piloso/ultraestrutura , Masculino , Ratos , Ratos Pelados , Pele/metabolismo , Pele/ultraestrutura
16.
J Pharm Sci ; 102(11): 4057-64, 2013 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-23983168

RESUMO

The treatment of benign prostatic hyperplasia can be accomplished by the use of different drugs including, doxazosin, an α-1 adrenergic antagonist, and finasteride (FIN), a 5-α reductase inhibitor. Traditionally, treatments using these drugs have been administered as either a mono or combination therapy by the oral route. A transdermal delivery system optimized for doxazosin and FIN combination therapy would provide increased patient adherence and facilitate dose adjustment. Doxazosin base (DB) was prepared from doxazosin mesylate and characterized together with FIN, by X-ray powder diffraction (XRD), differential scanning calorimetry (DSC), and nuclear magnetic resonance (NMR). The permeation enhancers, azone and lauric acid, and the gelling agents, hydroxypropyl cellulose (HPC) and Poloxamer 407 (P407), were evaluated to determine their ability to promote in vitro permeation of drugs through the pig ear epidermis. Successful preparation of DB was confirmed by evaluating the XRD, DSC, and NMR patterns and in vitro studies revealed that 3% (w/w) azone was the best permeation enhancer. When P407 gel was compared with HPC gel, it showed reduced lag time and promoted higher permeation of both drugs. This may be because of the interactions of the former with the stratum corneum, which disorganizes the lipid structure and consequently promotes higher drug permeation.


Assuntos
Inibidores de 5-alfa Redutase/administração & dosagem , Antagonistas de Receptores Adrenérgicos alfa 1/administração & dosagem , Doxazossina/administração & dosagem , Finasterida/administração & dosagem , Veículos Farmacêuticos/metabolismo , Inibidores de 5-alfa Redutase/farmacocinética , Administração Cutânea , Antagonistas de Receptores Adrenérgicos alfa 1/farmacocinética , Animais , Azepinas/metabolismo , Doxazossina/farmacocinética , Finasterida/farmacocinética , Humanos , Ácidos Láuricos/metabolismo , Masculino , Permeabilidade , Hiperplasia Prostática/tratamento farmacológico , Absorção Cutânea , Suínos
18.
Eur J Drug Metab Pharmacokinet ; 35(3-4): 137-46, 2011 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-21302041

RESUMO

In this study, an attempt was made to describe and validate liquid chromatography-electrospray ionization tandem mass spectrometry as a fast, sensitive and reproducible method for determining finasteride in human plasma. Finasteride and internal standard (pantoprazole) were extracted by liquid-liquid extraction using methyl tert-butyl ether. Separation was performed by using a flow rate gradient on a reverse phase C18 column at 25°C. The mobile phase consisted of methanol-water (70:30, v/v) containing 0.5% anhydrous formic acid. The protonated analytes were quantitated in positive ionization by multiple reaction monitoring in mass spectrometry. The mass transitions are m/z 373.4→305.3 and 384.1→200.0 for finasteride and pantoprazole, respectively. The method had a run time of 3.6 min and a linear calibration curve at a range of 0.2-100 ng mL(-1) (r2=0.9958). The lower limit of quantification was 0.2 ng mL(-1). The extraction recoveries of finasteride from the biological matrix were more than 82.7%, and the intra- and inter-day precision of the assay at four concentrations were 2.4-8.0% with an accuracy of 94.3-105.8%. The developed method requires less plasma (0.1 mL), but has high sensitivity. The validated method has been successfully used to analyze human plasma samples in pharmacokinetic or bioequivalence studies.


Assuntos
Inibidores de 5-alfa Redutase/sangue , Cromatografia Líquida/métodos , Finasterida/sangue , Espectrometria de Massas por Ionização por Electrospray/métodos , Inibidores de 5-alfa Redutase/farmacocinética , Administração Oral , Adulto , Finasterida/farmacocinética , Humanos , Masculino , Reprodutibilidade dos Testes , Espectrometria de Massas em Tandem/métodos , Equivalência Terapêutica , Adulto Jovem
19.
Drug Metab Dispos ; 39(5): 847-57, 2011 May.
Artigo em Inglês | MEDLINE | ID: mdl-21317368

RESUMO

The overall aim of this detailed investigation of the pharmacokinetics (PK) and metabolism of finasteride in pigs was to improve understanding of in vivo PK for this drug and its metabolites. Specific aims were to examine the effects of ketoconazole coadministration on the PK in three plasma compartments (the portal, hepatic, and femoral veins), bile, and urine and to use these data to study in detail the intestinal absorption and the liver extraction ratio and apply a semiphysiological based PK model to the data. The pigs received an intrajejunal dose of finasteride (0.8 mg/kg) either alone (n = 5) or together with ketoconazole (10 mg/kg) (n = 5) or an intravenous dose (0.2 mg/kg) (n = 3). Plasma, bile, and urine (collected from 0 to 6 h) were analyzed with ultraperformance liquid chromatography-tandem mass spectrometry. Ketoconazole increased the bioavailability of finasteride from 0.36 ± 0.23 to 0.91 ± 0.1 (p < 0.05) and the terminal half-life from 1.6 ± 0.4 to 4.0 ± 1.1 h (p < 0.05). From deconvolution, it was found that the absorption rate from the intestine to the portal vein was rapid, and the product of the fraction absorbed and the fraction that escaped gut wall metabolism was high (f(a) · F(G) ∼ 1). Interestingly, the apparent absorption rate constant (k(a)) to the femoral vein was lower than that to the portal vein, probably because of binding and distribution within the liver. The liver extraction ratio was time-dependent and varied with the two routes of administration. After intrajejunal administration, from 1 to 6 h, the liver extraction ratio was significantly (p < 0.05) reduced by ketoconazole treatment from intermediate (0.41 ± 0.21) to low (0.21 ± 0.10).


Assuntos
Inibidores de 14-alfa Desmetilase/metabolismo , Inibidores de 5-alfa Redutase/metabolismo , Bile/metabolismo , Finasterida/metabolismo , Absorção Intestinal , Cetoconazol/farmacologia , Fígado/metabolismo , Inibidores de 14-alfa Desmetilase/farmacologia , Inibidores de 5-alfa Redutase/administração & dosagem , Inibidores de 5-alfa Redutase/sangue , Inibidores de 5-alfa Redutase/farmacocinética , Animais , Interações Medicamentosas , Finasterida/administração & dosagem , Finasterida/farmacocinética , Finasterida/farmacologia , Meia-Vida , Injeções Intravenosas , Absorção Intestinal/efeitos dos fármacos , Cetoconazol/administração & dosagem , Fígado/efeitos dos fármacos , Masculino , Neoplasias da Próstata/prevenção & controle , Suínos
20.
Future Oncol ; 6(12): 1897-913, 2010 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-21142863

RESUMO

Incidences of prostate cancer in most countries are increasing owing to better detection methods; however, prevention with the use of finasteride, a very effective steroid 5α-reductase type II inhibitor, has been met with mixed success. A wide interindividual variation in response exists and is thought to be due to heritable factors. This article summarizes the literature that attempts to elucidate the molecular mechanisms of finasteride in terms of its metabolism, excretion and interaction with endogenous steroid molecules. We describe previously reported genetic variations of steroid-metabolizing genes and their potential association with finasteride efficacy. Based on the literature, we outline directions of research that may contribute to understanding the interindividual variation in finasteride prevention and to the future development of personalized medicine.


Assuntos
Inibidores de 5-alfa Redutase/metabolismo , Finasterida/metabolismo , Neoplasias da Próstata/prevenção & controle , 3-Oxo-5-alfa-Esteroide 4-Desidrogenase/genética , Inibidores de 5-alfa Redutase/farmacocinética , Citocromo P-450 CYP3A/genética , Finasterida/farmacocinética , Variação Genética , Glucuronosiltransferase/genética , Humanos , Masculino , Medicina de Precisão , Neoplasias da Próstata/tratamento farmacológico , Neoplasias da Próstata/genética , Testosterona/metabolismo
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