RESUMEN
Because diagnostic tools for discriminating between hepatocellular carcinoma (HCC) and advanced cirrhosis are poor, HCC is often detected in a stage where transarterial chemoembolization (TACE) is the best treatment option, even though it provides a poor survival gain. Despite having been used worldwide for several decades, TACE still has many limitations. First, there is a vast heterogeneity in the cellular composition and metabolism of HCCs as well as in the patient population, which renders it difficult to identify patients who would benefit from TACE. Often the delivered drug does not penetrate sufficiently selectively and deeply into the tumour and the drug delivery system is not releasing the drug at an optimal clinical rate. In addition, therapeutic effectiveness is limited by the crosstalk between the tumour cells and components of the cirrhotic tumour microenvironment. To improve this widely used treatment of one of our most common and deadly cancers, we need to better understand the complex interactions between drug delivery, local pharmacology, tumour targeting mechanisms, liver pathophysiology, patient and tumour heterogeneity, and resistance mechanisms. This review provides a novel and important overview of clinical data and discusses the role of the tumour microenvironment and lymphatic system in the cirrhotic liver, its potential response to TACE, and current and possible novel DDSs for locoregional treatment.
Asunto(s)
Carcinoma Hepatocelular/terapia , Quimioembolización Terapéutica/métodos , Sistemas de Liberación de Medicamentos/métodos , Neoplasias Hepáticas/terapia , Animales , Antineoplásicos/administración & dosificación , Antineoplásicos/uso terapéutico , Carcinoma Hepatocelular/patología , Stents Liberadores de Fármacos , Aceite Etiodizado/administración & dosificación , Aceite Etiodizado/uso terapéutico , Humanos , Hidrogeles , Neoplasias Hepáticas/patología , Sistema Linfático/patología , Microambiente Tumoral/inmunologíaRESUMEN
It is important to be able to simulate and predict formulation effects on the pharmacokinetics of a drug in order to optimize effectivity in clinical practice and drug development. Two formulations containing doxorubicin are used in the treatment of hepatocellular carcinoma (HCC): a Lipiodol-based emulsion (LIPDOX) and a loadable microbead system (DEBDOX). Although equally effective, the formulations are vastly different, and little is known about the parameters affecting doxorubicin release in vivo. However, mathematical modeling can be used to predict doxorubicin release properties from these formulations and its in vivo pharmacokinetic (PK) profiles. A porcine semi-physiologically based pharmacokinetic (PBPK) model was scaled to a human physiologically based biopharmaceutical (PBBP) model that was altered to include HCC. DOX in vitro and in vivo release data from LIPDOX or DEBDOX were collected from the literature and combined with these in silico models. The simulated pharmacokinetic profiles were then compared with observed porcine and human HCC patient data. DOX pharmacokinetic profiles of LIPDOX-treated HCC patients were best predicted from release data sets acquired by in vitro methods that did not use a diffusion barrier. For the DEBDOX group, the best predictions were from the in vitro release method with a low ion concentration and a reduced loading dose. The in silico modeling combined with historical release data was effective in predicting in vivo plasma exposure. This can give useful insights into the release method properties necessary for correct in vivo predictions of pharmacokinetic profiles of HCC patients dosed with LIPDOX or DEBDOX.
Asunto(s)
Carcinoma Hepatocelular/terapia , Doxorrubicina/farmacocinética , Portadores de Fármacos/química , Liberación de Fármacos , Neoplasias Hepáticas/terapia , Animales , Quimioembolización Terapéutica/métodos , Simulación por Computador , Doxorrubicina/administración & dosificación , Emulsiones , Aceite Etiodizado/química , Humanos , Hígado/irrigación sanguínea , Hígado/patología , Neoplasias Hepáticas/patología , Microesferas , Modelos Biológicos , PorcinosRESUMEN
Currently, the screening of new drug candidates for intestinal permeation is typically based on in vitro models which give no information regarding regional differences along the gut. When evaluation of intestinal permeability by region is undertaken, two preclinical rat models are commonly used, the Ussing chamber method and single-pass intestinal perfusion (SPIP). To investigate the robustness of in vivo predictions of human intestinal permeability, a set of four model compounds was systematically investigated in both these models, using tissue specimens and segments from the jejunum, ileum, and colon of rats from the same genetic strain. The influence of luminal pH was also determined at two pH levels. Ketoprofen had high and enalaprilat had low effective (Peff) and apparent (Papp) permeability in all three regions and at both pH levels. Metoprolol had high Peff in all regions and at both pHs and high Papp at both pHs and in all regions except the jejunum, where Papp was low. Atenolol had low Peff in all regions and at both pHs, but had high Papp at pH 6.5 and low Papp at pH 7.4. There were good correlations between these rat in situ Peff (SPIP) and human in vivo Peff determined previously for the same compounds by both intestinal perfusion of the jejunum and regional intestinal dosing. The results of this study indicate that both investigated models are suitable for determining the regional permeability of the intestine; however, the SPIP model seems to be the more robust and accurate regional permeability model.
Asunto(s)
Absorción Fisiológica , Evaluación Preclínica de Medicamentos/métodos , Absorción Intestinal/fisiología , Modelos Animales , Ratas , Animales , Biofarmacia/métodos , Colon/metabolismo , Concentración de Iones de Hidrógeno , Íleon/metabolismo , Mucosa Intestinal/metabolismo , Yeyuno/metabolismo , Masculino , Perfusión/métodos , Permeabilidad , Ratas WistarRESUMEN
OBJECTIVES: In liver cancer treatment, lipiodol is used as a pharmaceutical excipient to improve delivery of the cytostatic drug doxorubicin (DOX). As DOX and its metabolite doxorubicinol (DOXol) cause serious off-target adverse effects, we investigated the effects of drug-free lipiodol or ciclosporin (CsA) on the tissue distribution (Kp ) of DOX and DOXol in relevant pig tissues. METHODS: Four treatment groups (TI-TIV) all received an intravenous DOX solution at 0 and 200 min. Before the second dose, the pigs received a portal vein infusion of saline (TI), lipiodol (TII), CsA (TIII) or lipiodol and CsA (TIV). After 6 h, the pigs were euthanised, and liver, kidney, heart and intestine samples were collected and analysed. KEY FINDINGS: The tissue DOX concentrations were highest in the kidney (TI-TIV). All the investigated tissues showed extensive DOX Kp . Lipiodol had no effect on the Kp of DOX to any of the tissues. However, the tissue concentrations of DOX were increased by CsA (in liver, kidney and intestine, P < 0.05). CONCLUSION: Lipiodol injected into the portal vein does not affect the tissue distribution of DOX and DOXol.
Asunto(s)
Doxorrubicina/farmacocinética , Aceite Etiodizado/farmacología , Animales , Ciclosporina/farmacología , Doxorrubicina/administración & dosificación , Doxorrubicina/análogos & derivados , Aceite Etiodizado/administración & dosificación , Excipientes/administración & dosificación , Excipientes/farmacología , Infusiones Intravenosas , Mucosa Intestinal/metabolismo , Riñón/metabolismo , Hígado/metabolismo , Miocardio/metabolismo , PorcinosRESUMEN
Predicting oral bioavailability (Foral) is of importance for estimating systemic exposure of orally administered drugs. Physiologically-based pharmacokinetic (PBPK) modelling and simulation have been applied extensively in biopharmaceutics recently. The Oral Biopharmaceutical Tools (OrBiTo) project (Innovative Medicines Initiative) aims to develop and improve upon biopharmaceutical tools, including PBPK absorption models. A large-scale evaluation of PBPK models may be considered the first step. Here we characterise the OrBiTo active pharmaceutical ingredient (API) database for use in a large-scale simulation study. The OrBiTo database comprised 83 APIs and 1475 study arms. The database displayed a median logP of 3.60 (2.40-4.58), human blood-to-plasma ratio of 0.62 (0.57-0.71), and fraction unbound in plasma of 0.05 (0.01-0.17). The database mainly consisted of basic compounds (48.19%) and Biopharmaceutics Classification System class II compounds (55.81%). Median human intravenous clearance was 16.9L/h (interquartile range: 11.6-43.6L/h; n=23), volume of distribution was 80.8L (54.5-239L; n=23). The majority of oral formulations were immediate release (IR: 87.6%). Human Foral displayed a median of 0.415 (0.203-0.724; n=22) for IR formulations. The OrBiTo database was found to be largely representative of previously published datasets. 43 of the APIs were found to satisfy the minimum inclusion criteria for the simulation exercise, and many of these have significant gaps of other key parameters, which could potentially impact the interpretability of the simulation outcome. However, the OrBiTo simulation exercise represents a unique opportunity to perform a large-scale evaluation of the PBPK approach to predicting oral biopharmaceutics.
Asunto(s)
Biofarmacia/métodos , Bases de Datos Factuales , Modelos Biológicos , Preparaciones Farmacéuticas/metabolismo , Administración Oral , Evaluación Preclínica de Medicamentos/métodos , Predicción , Humanos , Absorción Intestinal/efectos de los fármacos , Absorción Intestinal/fisiología , Preparaciones Farmacéuticas/administración & dosificaciónRESUMEN
Doxorubicin (DOX) delivered in a lipiodol-based emulsion (LIPDOX) or in drug-eluting beads (DEBDOX) is used as palliative treatment in patients with intermediate-stage hepatocellular carcinoma (HCC). The primary objective of this study was to evaluate the in vivo delivery performance of DOX from LIPDOX or DEBDOX in HCC patients using the local and systemic pharmacokinetics of DOX and its main metabolite doxorubicinol (DOXol). Urinary excretion of DOX and DOXol and their short-term safety and antitumor effects were also evaluated. In this open, prospective, nonrandomized multicenter study, LIPDOX (n = 13) or DEBDOX (n = 12) were injected into the feeding arteries of the tumor. Local (vena cava/hepatic vein orifice) and systemic (peripheral vein) plasma concentrations of DOX and DOXol were determined in samples obtained up to 6 h and 7 days after treatment. Tumor response was assessed using computed tomography or magnetic resonance imaging. The Cmax and AUC0-24 h for DOX were 5.6-fold and 2.4-fold higher in LIPDOX vs DEBDOX recipients, respectively (p < 0.001). After 6 h, the respective mean proportions of the dose remaining in the liver or drug-delivery system (DDS) were 49% for LIPDOX and 88% for DEBDOX. LIPDOX releases DOX faster than DEBDOX in HCC patients and provides more extensive local and systemic exposure (AUC) to DOX and DOXol initially (0-7 days). DEBDOX formulation has a release and distribution of DOX that is more restricted and rate controlled than LIPDOX.
Asunto(s)
Antibióticos Antineoplásicos/uso terapéutico , Carcinoma Hepatocelular/tratamiento farmacológico , Emulsiones/uso terapéutico , Aceite Etiodizado/uso terapéutico , Neoplasias Hepáticas/tratamiento farmacológico , Anciano , Anciano de 80 o más Años , Sistemas de Liberación de Medicamentos/métodos , Femenino , Humanos , Hígado/efectos de los fármacos , Masculino , Persona de Mediana Edad , Estudios ProspectivosRESUMEN
The biopharmaceutics risk assessment roadmap (BioRAM) optimizes drug product development and performance by using therapy-driven target drug delivery profiles as a framework to achieve the desired therapeutic outcome. Hence, clinical relevance is directly built into early formulation development. Biopharmaceutics tools are used to identify and address potential challenges to optimize the drug product for patient benefit. For illustration, BioRAM is applied to four relatively common therapy-driven drug delivery scenarios: rapid therapeutic onset, multiphasic delivery, delayed therapeutic onset, and maintenance of target exposure. BioRAM considers the therapeutic target with the drug substance characteristics and enables collection of critical knowledge for development of a dosage form that can perform consistently for meeting the patient's needs. Accordingly, the key factors are identified and in vitro, in vivo, and in silico modeling and simulation techniques are used to elucidate the optimal drug delivery rate and pattern. BioRAM enables (1) feasibility assessment for the dosage form, (2) development and conduct of appropriate "learning and confirming" studies, (3) transparency in decision-making, (4) assurance of drug product quality during lifecycle management, and (5) development of robust linkages between the desired clinical outcome and the necessary product quality attributes for inclusion in the quality target product profile.
Asunto(s)
Biofarmacia , Descubrimiento de Drogas/métodos , Efectos Colaterales y Reacciones Adversas Relacionados con Medicamentos/prevención & control , Preparaciones Farmacéuticas/química , Animales , Biofarmacia/normas , Química Farmacéutica , Simulación por Computador , Preparaciones de Acción Retardada , Portadores de Fármacos , Descubrimiento de Drogas/normas , Evaluación Preclínica de Medicamentos , Efectos Colaterales y Reacciones Adversas Relacionados con Medicamentos/etiología , Humanos , Modelos Teóricos , Preparaciones Farmacéuticas/administración & dosificación , Farmacocinética , Control de Calidad , Medición de Riesgo , Factores de Riesgo , Pruebas de ToxicidadRESUMEN
The biopharmaceutical properties of doxorubicin delivered via two drug-delivery systems (DDSs) for the palliative treatment of unresectable hepatocellular carcinoma were reviewed with relation to the associated liver and tumor (patho)physiology. These two DDSs, doxorubicin emulsified with Lipiodol(®) and doxorubicin loaded into DC Bead(®) are different regarding tumor delivery, release rate, local bioavailability, if and how they can be given repeatedly, biodegradability, length of embolization and safety profile. There have been few direct head-to-head comparisons of these DDSs, and in-depth investigations into their in vitro and in vivo performance is warranted.
Asunto(s)
Antibióticos Antineoplásicos/administración & dosificación , Carcinoma Hepatocelular/tratamiento farmacológico , Doxorrubicina/administración & dosificación , Portadores de Fármacos , Aceite Etiodizado/química , Neoplasias Hepáticas/tratamiento farmacológico , Alcohol Polivinílico/química , Animales , Antibióticos Antineoplásicos/química , Antibióticos Antineoplásicos/metabolismo , Antibióticos Antineoplásicos/farmacocinética , Disponibilidad Biológica , Carcinoma Hepatocelular/metabolismo , Carcinoma Hepatocelular/patología , Doxorrubicina/química , Doxorrubicina/metabolismo , Doxorrubicina/farmacocinética , Estabilidad de Medicamentos , Humanos , Neoplasias Hepáticas/metabolismo , Neoplasias Hepáticas/patología , Estadificación de Neoplasias , Solubilidad , Distribución TisularRESUMEN
Doxorubicin (DOX) emulsified in Lipiodol (LIP) is used as local palliative treatment for unresectable intermediate stage hepatocellular carcinoma. The objective of this study was to examine the poorly understood effects of the main excipient in the drug delivery system, LIP, alone or together with cyclosporin A (CsA), on the in vivo liver disposition of DOX and its active metabolite doxorubicinol (DOXol). The advanced, multi-sampling-site, acute pig model was used; samples were collected from three blood vessels (v. portae, v. hepatica and v. femoralis), bile and urine. The four treatment groups (TI-TIV) all received two intravenous 5 min infusions of DOX into an ear vein: at 0 and 200 min. Before the second dose, the pigs received a portal vein infusion of saline (TI), LIP (TII), CsA (TIII) or LIP and CsA (TIV). Concentrations of DOX and DOXol were analyzed using UPLC-MS/MS. The developed multicompartment model described the distribution of DOX and DOXol in plasma, bile and urine. LIP did not affect the pharmacokinetics of DOX or DOXol. CsA (TIII and TIV) had no effect on the plasma pharmacokinetics of DOX, but a 2-fold increase in exposure to DOXol and a significant decrease in hepatobiliary clearance of DOX and DOXol were observed. Model simulations supported that CsA inhibits 99% of canalicular biliary secretion of both DOX and DOXol, but does not affect the metabolism of DOX to DOXol. In conclusion, LIP did not directly interact with transporters, enzymes and/or biological membranes important for the hepatobiliary disposition of DOX.
Asunto(s)
Antibióticos Antineoplásicos/farmacocinética , Bilis/metabolismo , Ciclosporina/farmacología , Doxorrubicina/farmacocinética , Aceite Etiodizado/farmacología , Hígado/metabolismo , Animales , Masculino , PorcinosRESUMEN
Unresectable, intermediate stage hepatocellular carcinoma (HCC) is often treated palliatively in humans by doxorubicin (DOX). The drug is administered either as a drug-emulsified-in-Lipiodol (DLIP) or as drug loaded into drug eluting beads (DEB), and both formulations are administered intrahepatically. However, several aspects of their in vivo performance in the liver are still not well-understood. In this study, DLIP and DEB were investigated regarding the local and systemic pharmacokinetics (PK) of DOX and its primary metabolite doxorubicinol (DOXol). An advanced PK-multisampling site acute in vivo pig model was used for simultaneous sampling in the portal, hepatic, and femoral veins and the bile duct. The study had a randomized, parallel design with four treatment groups (TI-TIV). TI (n = 4) was used as control and received an intravenous (i.v.) infusion of DOX as a solution. TII and TIII were given a local injection in the hepatic artery with DLIP (n = 4) or DEB (n = 4), respectively. TIV (n = 2) received local injections of DLIP in the hepatic artery and bile duct simultaneously. All samples were analyzed for concentrations of DOX and DOXol with UPLC-MS/MS. Compared to DLIP, the systemic exposure for DOX with DEB was reduced (p < 0.05), in agreement with a slower in vivo release. The approximated intracellular bioavailability of DOX during 6 h appeared to be lower for DEB than DLIP. Following i.v. infusion (55 min), DOX had a liver extraction of 41 (28-53)%, and the fraction of the dose eliminated in bile of DOX and DOXol was 20 (15-22)% and 4.2 (3.2-5.2)%, respectively. The AUCbile/AUCVP for DOX and DOXol was 640 (580-660) and 5000 (3900-5400), respectively. In conclusion, DLIP might initially deliver a higher hepatocellular concentration of DOX than DEB as a consequence of its higher in vivo release rate. Thus, DLIP delivery results in higher intracellular peak concentrations that might correlate with better anticancer effects, but also higher systemic drug exposure and safety issues.
Asunto(s)
Antibióticos Antineoplásicos/farmacocinética , Conductos Biliares/efectos de los fármacos , Doxorrubicina/análogos & derivados , Doxorrubicina/farmacocinética , Sistemas de Liberación de Medicamentos , Arteria Hepática/efectos de los fármacos , Infusiones Intraarteriales , Animales , Antibióticos Antineoplásicos/química , Conductos Biliares/metabolismo , Conductos Biliares/cirugía , Cromatografía Líquida de Alta Presión , Relación Dosis-Respuesta a Droga , Doxorrubicina/administración & dosificación , Doxorrubicina/química , Aceite Etiodizado/química , Arteria Hepática/metabolismo , Arteria Hepática/cirugía , Masculino , Porcinos , Espectrometría de Masas en Tándem , Distribución TisularRESUMEN
BACKGROUND: Given the growing prevalence of overweight and obesity, weight-management strategies could be developed based on the effect of specific food ingredients on the gastrointestinal system to reduce food intake. OBJECTIVE: The aim of this study was to investigate the mechanisms by which a vegetable-oil emulsion may exert its effect on satiety by applying a multilumen tube to investigate digestion and absorption of lipids in the stomach and proximal jejunum. DESIGN: We gave 16 healthy, normal-weight subjects (in a double-blind, placebo-controlled crossover design) a test product (yogurt with a vegetable-oil emulsion) or an equal-calorie control by intragastric administration on 2 separate occasions. Gastric and intestinal samples were collected from the proximal jejunum during 180 min. RESULTS: We observed almost double amounts (P < 0.05) of total lipids, mainly as free fatty acids, from the test product (450 +/- 119 mg) in the proximal jejunum compared with amounts of total lipids from the control product (230 +/- 50 mg), and an over-time difference of free fatty acid concentrations was observed between the products (P < 0.05). To our knowledge, a novel and unexpected finding was the appearance of needle-shaped crystals in the jejunal samples that originated from the vegetable-oil emulsion and consisted of saturated fatty acids. Crystals were only rarely seen in the control samples. CONCLUSION: The higher amount of lipids in the proximal jejunum and the recovery of crystals in the intestinal samples after test-product infusion provide a plausible physiologic explanation for the ileal brake mechanism that leads to the increased satiety observed for this test product.
Asunto(s)
Grasas de la Dieta/administración & dosificación , Ácidos Grasos no Esterificados/metabolismo , Yeyuno/metabolismo , Metabolismo de los Lípidos , Aceites de Plantas/metabolismo , Saciedad/fisiología , Adulto , Estudios Cruzados , Cristalización , Digestión , Método Doble Ciego , Emulsiones , Ácidos Grasos/metabolismo , Femenino , Tránsito Gastrointestinal/fisiología , Humanos , Absorción Intestinal , Masculino , Obesidad/prevención & control , Aceites de Plantas/farmacología , Valores de Referencia , Saciedad/efectos de los fármacos , Yogur , Adulto JovenRESUMEN
The aim of this study was to investigate what the consequences of induced drug metabolism, caused by St. John's wort (SJW, Hypericum perforatum) treatment, would have on the plasma, biliary and urinary pharmacokinetics of finasteride and its two previously identified phase I metabolites (hydroxy-finasteride and carboxy-finasteride). Twelve healthy men were administered 5mg finasteride directly to the intestine via a catheter with a multi-channel tubing system, Loc-I-Gut, before and after 14 days SJW (300mg b.i.d, hyperforin 4%) treatment. Bile samples were withdrawn via the Loc-I-Gut device from the proximal jejunum. LC-ESI-MS/MS was used to analyze finasteride and its metabolites in plasma, bile and urine. HPLC-UV was used to analyze hyperforin in plasma. The herbal treatment significantly reduced the peak plasma concentration (C(max)), the area under the plasma concentration-time curve (AUC(0-24h)) and the elimination half-life (t(1/2)) of finasteride. The geometric mean ratios (90% CI) were 0.42 (0.36-0.49), 0.66 (0.56-0.79) and 0.54 (0.48-0.61), respectively. Finasteride was excreted unchanged to a minor extent into bile and urine. Hydroxy-finasteride was not detected in plasma, bile or urine. Carboxy-finasteride was quantified in all three compartments and its plasma pharmacokinetics was significantly affected by SJW treatment. Hyperforin concentration in plasma was 21+/-7ng/ml approximately 12h after the last dose of the 14 days SJW treatment. In conclusion, SJW treatment for 2 weeks induced the metabolism of finasteride and caused a reduced plasma exposure of the drug. New knowledge was gained about the biliary and urinary excretion or the drug and its metabolites.
Asunto(s)
Sistema Biliar/metabolismo , Inhibidores Enzimáticos/farmacocinética , Finasterida/farmacocinética , Hypericum , Adulto , Compuestos Bicíclicos con Puentes/sangre , Cromatografía Líquida de Alta Presión , Inhibidores Enzimáticos/sangre , Inhibidores Enzimáticos/orina , Finasterida/sangre , Finasterida/orina , Semivida , Humanos , Masculino , Floroglucinol/análogos & derivados , Floroglucinol/sangre , Valores de Referencia , Espectrometría de Masa por Ionización de Electrospray , Espectrofotometría Ultravioleta , Espectrometría de Masas en Tándem , Terpenos/sangreRESUMEN
Data on folate absorption from food from validated human studies using physiological folate doses are still needed to estimate dietary requirements and to formulate recommendations. The aim of the present work was to study the effects from fortified and processed foods on folate absorption in ileostomy volunteers (n 9) using the area under the plasma concentration curve (AUC) and kinetic modelling. Using a standardized single-dose protocol, dairy products fortified with a candidate fortificant (6S)-5-methyltetrahydrofolate ((6S)-5-CH3-H4folate), folic acid-fortified bread and a dessert crème containing natural yeast folate polyglutamates were compared with folate supplements. Absorbed folate was estimated by AUC and a kinetic model, and non-absorbed folate by ileostomal folate excretion. Median apparent absorption from test foods ranged from 55 to 86 %. Added folate-binding proteins (FBP) significantly reduced folate absorption from dairy products, as in the absence of FBP, AUC-dose-corrected ratios were increased and ileal folate excretion decreased. After in vivo gastrointestinal passage of dairy products containing FBP, up to 43 % of the ingested FBP was found in ileostomal effluent. Folate absorption was similar for (6S)-5-CH3-H4folate fortificant from fermented milk and for folic acid from fortified bread. Folic acid, ingested as food fortificant in bread, was significantly less absorbed compared with an isolated supplement. We conclude that all tested foods were suitable matrices for folate fortification. However, dairy products, fortified with the new candidate fortificant (6S)-5-CH3-H4folate, are suitable if no active FBP is present.
Asunto(s)
Ácido Fólico/farmacocinética , Manipulación de Alimentos/métodos , Alimentos Fortificados , Absorción , Anciano , Área Bajo la Curva , Pan , Productos Lácteos , Dieta , Proteínas en la Dieta/metabolismo , Femenino , Ácido Fólico/sangre , Ácido Fólico/orina , Humanos , Ileostomía , Masculino , Persona de Mediana Edad , Modelos Biológicos , Ácidos Pteroilpoliglutámicos/metabolismo , Tetrahidrofolatos/administración & dosificación , Tetrahidrofolatos/farmacocinéticaAsunto(s)
Evaluación Preclínica de Medicamentos/métodos , Proteínas de Transporte de Membrana/metabolismo , Preparaciones Farmacéuticas/metabolismo , Farmacocinética , Subfamilia B de Transportador de Casetes de Unión a ATP/genética , Subfamilia B de Transportador de Casetes de Unión a ATP/metabolismo , Animales , Barrera Hematoencefálica/metabolismo , Células Cultivadas , Interacciones Farmacológicas , Humanos , Absorción Intestinal , Riñón/metabolismo , Hígado/metabolismo , Proteínas de Transporte de Membrana/genética , Modelos Biológicos , Transportadores de Anión Orgánico/metabolismo , Placenta , Especificidad de la Especie , Especificidad por SustratoRESUMEN
Bioavailability (BA) and bioequivalence (BE) play a central role in pharmaceutical product development and BE studies are presently being conducted for New Drug Applications (NDAs) of new compounds, in supplementary NDAs for new medical indications and product line extensions, in Abbreviated New Drug Applications (ANDAs) of generic products and in applications for scale-up and post-approval changes. The Biopharmaceutics Classification System (BCS) has been developed to provide a scientific approach for classifying drug compounds based on solubility as related to dose and intestinal permeability in combination with the dissolution properties of the oral immediaterelease (IR) dosage form. The aim of the BCS is to provide a regulatory tool for replacing certain BE studies by accurate in-vitro dissolution tests. The aim of this review is to present the status of the BCS and discuss its future application in pharmaceutical product development. The future application of the BCS is most likely increasingly important when the present framework gains increased recognition, which will probably be the case if the BCS borders for certain class II and III drugs are extended. The future revision of the BCS guidelines by the regulatory agencies in communication with academic and industrial scientists is exciting and will hopefully result in an increased applicability in drug development. Finally, we emphasize the great use of the BCS as a simple tool in early drug development to determine the rate-limiting step in the oral absorption process, which has facilitated the information between different experts involved in the overall drug development process. This increased awareness of a proper biopharmaceutical characterization of new drugs may in the future result in drug molecules with a sufficiently high permeability, solubility and dissolution rate, and that will automatically increase the importance of the BCS as a regulatory tool over time.
Asunto(s)
Biofarmacia/clasificación , Disponibilidad Biológica , Biofarmacia/legislación & jurisprudencia , Aprobación de Drogas/legislación & jurisprudencia , Evaluación Preclínica de Medicamentos/métodos , Interacciones Alimento-Droga , Guías como Asunto , Humanos , Absorción Intestinal , Solubilidad , Tecnología Farmacéutica/legislación & jurisprudenciaRESUMEN
OBJECTIVE: Our objective was to investigate the inducing effect of repeated oral administration of St John's wort on the jejunal transport and presystemic extraction of R- and S-verapamil in humans. METHODS: Jejunal single-pass perfusion experiments with 120-mg/L (244 micromol/L) R-/S-verapamil were performed in 8 healthy male volunteers for 100 minutes before and after 14 days of oral treatment with St John's wort (300 mg 3 times a day). The enantiomers of verapamil and the cytochrome P450 (CYP) 3A4-formed metabolite norverapamil in perfusate and plasma were quantified by chiral HPLC with fluorescence and tandem mass spectrometry detection, respectively. RESULTS: St John's wort did not affect the jejunal permeability or the fraction absorbed of either R- or S-verapamil. The values for area under the plasma concentration-time curve (AUC) for R- and S-verapamil decreased by 78% and 80%, respectively (P <.0001). The corresponding decreases in the maximum concentration were 76% and 78%, respectively (P <.0001), whereas the terminal half-life did not change significantly for any of the enantiomers. The AUC for R-verapamil was 6 times higher than that for S-verapamil in the control phase, and St John's wort did not change this ratio. The AUC values for R- and S-norverapamil decreased by 51% (P <.01) and 63% (P <.0001), respectively. CONCLUSIONS: Repeated administration of St John's wort significantly decreased the bioavailability of R- and S-verapamil. This effect is caused by induction of first-pass CYP3A4 metabolism, most likely in the gut, because the jejunal permeability and the terminal half-life were unchanged for both enantiomers.
Asunto(s)
Interacciones Farmacológicas , Hypericum , Absorción Intestinal/efectos de los fármacos , Fitoterapia , Preparaciones de Plantas/administración & dosificación , Verapamilo/farmacocinética , Administración Oral , Adulto , Análisis de Varianza , Área Bajo la Curva , Disponibilidad Biológica , Relación Dosis-Respuesta a Droga , Esquema de Medicación , Semivida , Humanos , Yeyuno/efectos de los fármacos , Yeyuno/fisiología , Masculino , Perfusión , Sensibilidad y Especificidad , Verapamilo/administración & dosificaciónRESUMEN
Dose-response effects of fluorouracil, paclitaxel, doxorubicin, cisplatin, methotrexate, cyclophosphamide and etoposide on VEGF165/164-mediated angiogenesis using the rat mesenteric-window angiogenesis assay are reported. VEGF is a pivotal pro-angiogenic factor in most tumors. Microvessel spatial extension, density, pattern formation and segment length were assessed quantitatively and objectively. A single i.v. injection of each drug was given at a low, intermediate or high dose, 7 days before sacrifice. All the drugs elicited significant responses in terms of one or more measured variables. Only paclitaxel, doxorubicin and cyclophosphamide significantly suppressed the overall angiogenic response (p < or = 0.0001, p < or = 0.0002 and p < or = 0.05, respectively), however. Taking toxicity into account, paclitaxel was more potent in inhibition of angiogenesis than the other agents. No clear correlation was found between drug half-life, the degree of toxic effects (in terms ofbody weight changes) and the antiangiogenic effect. The antiangiogenic effects were distinctly drug specific.
Asunto(s)
Antineoplásicos/farmacología , Mesenterio/irrigación sanguínea , Neovascularización Fisiológica/efectos de los fármacos , Animales , Antineoplásicos/administración & dosificación , Cisplatino/administración & dosificación , Cisplatino/farmacología , Ciclofosfamida/administración & dosificación , Ciclofosfamida/farmacología , Relación Dosis-Respuesta a Droga , Doxorrubicina/administración & dosificación , Doxorrubicina/farmacología , Factores de Crecimiento Endotelial/farmacología , Etopósido/administración & dosificación , Etopósido/farmacología , Fluorouracilo/administración & dosificación , Fluorouracilo/farmacología , Humanos , Inyecciones Intravenosas , Péptidos y Proteínas de Señalización Intercelular/farmacología , Linfocinas/farmacología , Masculino , Mesenterio/efectos de los fármacos , Metotrexato/administración & dosificación , Metotrexato/farmacología , Paclitaxel/administración & dosificación , Paclitaxel/farmacología , Ratas , Ratas Sprague-Dawley , Factor A de Crecimiento Endotelial Vascular , Factores de Crecimiento Endotelial Vascular , Aumento de Peso/efectos de los fármacosRESUMEN
For the first time the human intestinal effective permeability, estimated from the luminal disappearance and intestinal metabolism of phytochemicals, sulforaphane and quercetin-3,4'-glucoside, as well as the simultaneous changes in gene expression in vivo in enterocytes, has been studied in the human jejunum in vivo (Loc-I-Gut). Both compounds as components of an onion and broccoli extract could readily permeate the enterocytes in the perfused jejunal segment. At the physiologically relevant, dietary concentration tested, the average effective jejunal permeability (Peff) and percentage absorbed (+/- S.D.) were 18.7 +/- 12.6 x 10-4 cm/s and 74 +/- 29% for sulforaphane and 8.9 +/- 7.1 x 10-4 cm/s and 60 +/- 31% for quercetin-3,4'-diglucoside, respectively. Furthermore, a proportion of each compound was conjugated and excreted back into the lumen as sulforaphane-glutathione and quercetin-3'-glucuronide. The capacity of the isolated segment to deconjugate quercetin from quercetin-3,4'-diglucoside during the perfusion was much higher than the beta-glucosidase activity of the preperfusion jejunal contents, indicating that the majority (79-100%) of the beta-glucosidase capacity derives from the enterocytes in situ. Simultaneously, we determined short-term changes in gene expression in exfoliated enterocytes, which showed 2.0 +/- 0.4-fold induction of glutathione transferase A1 (GSTA1) mRNA (p < 0.002) and 2.4 +/- 1.2-fold induction of UDP-glucuronosyl transferase 1A1 (UGT1A1) mRNA (p < 0.02). The changes in gene expression were also seen in differentiated Caco-2 cells, where sulforaphane was responsible for induction of GSTA1 and quercetin for induction of UGT1A1. These results show that food components have the potential to modify drug metabolism in the human enterocyte in vivo very rapidly.