RESUMEN
This study assessed the pharmacokinetics (PKs) and pharmacodynamics (PDs) of two antihypertensive drugs, nifedipine and captopril, by exploring their main (blood pressure [BP]) and secondary effects (heart rate [HR] and QT interval [QT]) in spontaneously hypertensive rats. This study aimed to assess the relationship between PKs and PDs. Using these PD parameters, BP, HR, and QT during coadministration were estimated. The coadministration of nifedipine and captopril resulted in an increase in nifedipine's total body clearance (CLtot) and a reduction in its mean residence time (MRT) with an increase in the terminal elimination half-life (t1/2) and volume of distribution at steady state (Vdss) of captopril. However, no significant PK interactions were observed. During monotherapy, BP reduced rapidly following nifedipine infusion. Subsequently, despite the increase in nifedipine plasma concentration, BP recovered, likely because of homeostasis. Similar results were observed with coadministration. Subsequently, BP demonstrated a sustained reduction that was greater than or equal to the additive effect estimated from each PK. Captopril exhibited a minimal effect on HR, except for a transient increase observed immediately after starting infusion, consistent with observations during coadministration. Subsequently, the HR reduction was nearly equal to that calculated from the nifedipine PK. QT prolongation was more rapid with captopril than with nifedipine. Although QT prolongation during the initial 60 min of coadministration was approximately the sum of both effects, the recovery period to baseline QT was faster than that in the simulation.
Asunto(s)
Antihipertensivos , Presión Sanguínea , Captopril , Frecuencia Cardíaca , Hipertensión , Nifedipino , Ratas Endogámicas SHR , Captopril/farmacocinética , Captopril/administración & dosificación , Captopril/farmacología , Nifedipino/farmacocinética , Nifedipino/administración & dosificación , Nifedipino/farmacología , Animales , Antihipertensivos/farmacocinética , Antihipertensivos/administración & dosificación , Antihipertensivos/farmacología , Masculino , Ratas , Presión Sanguínea/efectos de los fármacos , Hipertensión/tratamiento farmacológico , Hipertensión/inducido químicamente , Frecuencia Cardíaca/efectos de los fármacos , Interacciones Farmacológicas , Semivida , Quimioterapia CombinadaRESUMEN
This study aimed to investigate the effect of in vivo pH-responsive doxorubicin (DOX) release and the targetability of pilot molecules in folic acid (FA)-modified micelles using a pharmacokinetic-pharmacodynamic (PK-PD) model. The time profiles of intratumoral DOX concentrations in Walker256 tumor-bearing rats were monitored using a microdialysis probe, followed by compartmental analysis, to evaluate intratumoral tissue pharmacokinetics. Maximal DOX was released from micelles 350 min after the administration of pH-responsive DOX-releasing micelles. However, FA modification of the micelles shortened the time to peak drug concentration to 150 min. Additionally, FA modification resulted in a 27-fold increase in the tumor inflow rate constant. Walker256 tumor-bearing rats were subsequently treated with DOX, pH-responsive DOX-releasing micelles, and pH-responsive DOX-releasing FA-modified micelles to monitor the tumor growth-time profiles. An intratumoral threshold concentration of DOX (55-64 ng/g tumor) was introduced into the drug efficacy compartment to construct a PD model, followed by PK-PD analysis of the tumor growth-time profiles. Similar results of threshold concentration and drug potency of DOX were obtained across all three formulations. Cell proliferation was delayed as the drug delivery ability of DOX was improved. The PK model, which was developed using the microdialysis method, revealed the intratumoral pH-responsive DOX distribution profiles. This facilitated the estimation of intratumoral PK parameters. The PD model with threshold concentrations contributed to the estimation of PD parameters in the three formulations, with consistent mechanisms observed. We believe that our PK-PD model can objectively assess the contributions of pH-responsive release ability and pilot molecule targetability to pharmacological effects.
Asunto(s)
Doxorrubicina , Ácido Fólico , Micelas , Doxorrubicina/farmacocinética , Doxorrubicina/farmacología , Doxorrubicina/administración & dosificación , Doxorrubicina/química , Animales , Ratas , Concentración de Iones de Hidrógeno , Ácido Fólico/química , Ácido Fólico/farmacocinética , Liberación de Fármacos , Proliferación Celular/efectos de los fármacos , Sistemas de Liberación de Medicamentos/métodos , Línea Celular Tumoral , Portadores de Fármacos/química , Femenino , Ratas Wistar , Humanos , Antibióticos Antineoplásicos/farmacocinética , Antibióticos Antineoplásicos/administración & dosificación , Antibióticos Antineoplásicos/farmacologíaRESUMEN
Hydrophobic ion pairing (HIP) is a drug encapsulation technology that uses electrostatic interactions between a drug and an additive. However, although polymeric micelles can encapsulate hydrophobic drugs in the core, the encapsulated drug often leaks. Therefore, we designed polymeric micelles with HIP functionalized in a hydrophobic inner core using three diblock copolymers comprising polypeptides with different ratios of polar and hydrophobic amino acids and polyethylene glycol (PEG) to encapsulate indomethacin (IND). The three IND-encapsulated HIP micelles showed different area under the curve (AUC) values as an index of blood retention after intravenous injection in mice. Despite having the same PEG shell, IND-PEG-poly(H/F)n showed a 1.56-fold higher AUC than IND-PEG-poly(D/F)n. PEG interface morphologies were evaluated to determine the differences in pharmacokinetic parameters caused by changes in inner core HIP patterns. The micellarized diblock copolymer was desorbed from IND-PEG-poly(D/F)n due to electrostatic repulsion between IND and the diblock copolymer comprising aspartic acid. Our results suggest that changes in the HIP patterns of the micelle inner core affected the PEG interface morphologies, such as PEG density and diblock copolymer desorption from micelles. These phenomena might lead to changes in the interaction of plasma proteins and drug dispositions.
Asunto(s)
Indometacina , Micelas , Ratones , Animales , Indometacina/química , Polímeros/química , Polietilenglicoles/química , Péptidos , Portadores de Fármacos/químicaRESUMEN
To investigate the relationship between the pharmacokinetics (PK) and pharmacodynamics (PD) of donepezil (Don), simultaneous examination of the PK of Don and the change in acetylcholine (ACh) in the cerebral hippocampus was analyzed using microdialysis in rats. Don plasma concentrations reached their maximum at the end of a 30-minute infusion. The maximum plasma concentrations (Cmaxs) of the major active metabolite, 6-O-desmethyl donepezil, were 9.38 and 13.3 ng/ml at 60 minutes after starting infusions at 1.25 and 2.5 mg/kg doses, respectively. The amount of ACh in the brain increased shortly after the start of the infusion and reached the maximum value at about 30 to 45 minutes, then decreased to the baseline with a slight delay from the transition of the Don concentration in plasma at a 2.5 mg/kg dose. However, the 1.25 mg/kg group showed little increase in ACh in the brain. The PK/PD models of Don, which were constructed using a general 2-compartment PK model with/without Michaelis-Menten metabolism and the suppressive effect of conversion of ACh to choline using an ordinary indirect response model, were able to effectively simulate Don's plasma and ACh profiles. The ACh profile in the cerebral hippocampus at a 1.25 mg/kg dose was effectively simulated using both constructed PK/PD models and parameters obtained at a 2.5 mg/kg dose by the PK/PD models and indicated that Don largely had no effect on ACh. When these models were used to simulate at 5 mg/kg, the Don PK were nearly linear, whereas the ACh transition had a different profile to lower doses. SIGNIFICANCE STATEMENT: Efficacy/safety of a drug and its pharmacokinetics (PK) are closely correlated. Therefore, it is important to understand the relationship between the drug's PK and its pharmacodynamics (PD). A quantitative procedure of achieving these goals is the PK/PD analysis. We constructed the PK/PD models of donepezil in rats. These models can predict the acetylcholine-time profiles from the PK. The modeling technique is a potential therapeutic application to predict the effect when changes in the PK are caused by pathological condition and co-administered drugs.
Asunto(s)
Acetilcolina , Enfermedad de Alzheimer , Ratas , Animales , Donepezilo/metabolismo , Acetilcolina/metabolismo , Modelos Biológicos , Encéfalo/metabolismo , Relación Dosis-Respuesta a DrogaRESUMEN
The aim of this study was to develop a polyethylene glycol (PEG)-conjugated third-generation polyamidoamine dendrimer (PAMAM) with phosphorylated serine as an osteoid surface-targeting drug carrier for the treatment of bone diseases. We conjugated PAMAM backbones to l-serine and obtained Ser-PAMAM. Then, phosphoric acid and PEG were covalently bound to the Ser-PAMAM to generate PEGylated phosphorylated Ser-PAMAM (PEG-phosSer-PAMAM). Using osteoblast-like cells (MC3T3-E1 cells) cultured in 3D collagen gels, we showed that phosSer-PAMAM adsorbed both the hydroxyapatite and type I collagen components of the bone matrix. Fourier transform infrared spectroscopy analysis indicated that the phosphoryl side chains of phosSer-PAMAM formed electrostatic interactions and hydrogen bonds with the anionic amino acid residues of type I collagen. Mice were intravenously injected with the foregoing molecules, and a tissue distribution study disclosed that the lower limb bone took up about twice as much 111In-labeled PEG-phosSer-PAMAM as 111In-labeled nonphosphorylated PEG-Ser-PAMAM or unmodified PAMAM. An intrabone distribution experiment showed that fluorescein isothiocyanate (FITC)-labeled PEG-phosSer-PAMAM accumulated on the osteoid surfaces, which is associated with bone pathogenesis such as skeletal dysplasias and osteoporosis to a far greater extent than nonphosphorylated PEG-Ser-PAMAM. Our findings indicated that PEG-phosSer-PAMAM is a promising carrier for efficient drug targeting to osteoid surfaces.
Asunto(s)
Dendrímeros , Portadores de Fármacos , Animales , Matriz Ósea , Colágeno Tipo I , Dendrímeros/química , Portadores de Fármacos/química , Ratones , Poliaminas , Polietilenglicoles/química , SerinaRESUMEN
Bone-drug targeting therapies using nanoparticles based on targeting ligands remain challenging due to their uptake clearance at non-target sites such as the liver, kidney, and spleen. Furthermore, the distribution sites of nanoparticles in bones have not been fully investigated, thus halting the development of more effective bone metastasis treatment strategies. In this study, we developed nanoparticles self-assembled from cholesterol-terminated, polyethylene glycol-conjugated, aspartic acid (Asp)-modified polyamidoamine dendrimer (Asp-PAMAM-Micelles) with targeting to active bone turnover sites associated with bone metastasis pathogenesis. On analysis through whole-body single photon emission computed tomography/computed tomography (SPECT/CT) imaging, 111In-Asp-PAMAM-Micelles showed high specificity to active bone turnover sites (especially the joints in the lower limbs, shoulder, and pelvis) after intravenous injection in mice. The lower limb bone uptake clearance for 111In-Asp-PAMAM-Micelles encapsulating paclitaxel (PTX) was 3.5-fold higher than that for 111In-unmodified PAMAM-Micelles (PTX). 3H-PTX encapsulated Asp-PAMAM-Micelles effectively accumulated in the lower limb bones in a similar manner as the 111In-Asp-PAMAM-Micelles (PTX). In a bone metastatic tumor mouse model, the tumor growth in the lower limb bones was significantly inhibited by injection of Asp-PAMAM-Micelles (PTX) compared to unmodified PAMAM-Micelles (PTX). Our results demonstrate that Asp-PAMAM-Micelles are sophisticated drug delivery systems for highly potent targeting to active bone turnover sites.
Asunto(s)
Antineoplásicos Fitogénicos/administración & dosificación , Neoplasias Óseas/tratamiento farmacológico , Dendrímeros/química , Portadores de Fármacos , Melanoma Experimental/tratamiento farmacológico , Paclitaxel/administración & dosificación , Animales , Antineoplásicos Fitogénicos/química , Antineoplásicos Fitogénicos/farmacocinética , Ácido Aspártico/química , Neoplasias Óseas/diagnóstico por imagen , Neoplasias Óseas/secundario , Línea Celular Tumoral , Colesterol/química , Composición de Medicamentos , Femenino , Inyecciones Intravenosas , Masculino , Melanoma Experimental/diagnóstico por imagen , Melanoma Experimental/secundario , Ratones Endogámicos C57BL , Micelas , Nanopartículas , Paclitaxel/química , Paclitaxel/farmacocinética , Polietilenglicoles/química , Ratas Wistar , Tomografía Computarizada por Tomografía Computarizada de Emisión de Fotón Único , Distribución TisularRESUMEN
Bone metastases can cause high morbidity and mortality, often developing as they advance, especially in patients with prostate and breast cancers. Most drugs are rarely distributed to the bone and are hence pharmacologically ineffective in treating bone metastases. The development of drug targeting technologies is required for the efficient treatment of bone metastases. To date, numerous bone-targeting ligands, including tetracyclines, bisphosphonates, aspartic acid, and aptamers have been developed and used for bone-targeted delivery of anti-tumor drugs, peptide/protein drugs, nucleic acid drugs, and diagnostic imaging agents. The conjugates of drugs with bone-targeting ligands were first developed in the field of bone drug targeting systems; macromolecular carriers and nanoparticles modified with these bone-targeting ligands have also been developed. Additionally, antibodies to prostate-specific membrane antigen (PSMA) and human epidermal growth factor receptor 2 (HER2) are used in active targeting bone metastatic prostate cancer and breast cancer, respectively. Some conjugates using antibodies to PSMA and HER2 were developed and used in clinical trials. In this review, recent challenges in the development of bone-targeted delivery systems and strategies for the treatment of bone metastasis have been summarized. Future development of novel drug formulations in order to optimize targeted drug delivery in the treatment of bone metastasis have also been discussed.
Asunto(s)
Antineoplásicos/farmacología , Neoplasias Óseas/tratamiento farmacológico , Neoplasias Óseas/secundario , Sistemas de Liberación de Medicamentos , Animales , Antígenos de Superficie/metabolismo , Antineoplásicos/química , Neoplasias Óseas/metabolismo , Glutamato Carboxipeptidasa II/antagonistas & inhibidores , Glutamato Carboxipeptidasa II/metabolismo , Humanos , Ligandos , Estructura Molecular , Receptor ErbB-2/antagonistas & inhibidores , Receptor ErbB-2/metabolismoRESUMEN
Breast cancer resistance protein transporter (ABCG2/BCRP) is highly expressed on the intestinal epithelial membrane and has a significant impact on the oral absorption of topotecan. In this study, we examined 6 pharmaceutical excipients including BL-9EX, Brij97, Cremophor EL, Labrasol, Pluronic F68, and Tween 20 for their BCRP inhibitory effects. A bidirectional transport study using Caco-2 cells demonstrated that Tween 20 and Cremophor EL significantly increased the absorptive transport of topotecan, while simultaneously decreasing secretory transport. Interestingly, Labrasol selectively increased absorptive transport, whereas Pluronic F68 selectively decreased the secretory transport, of topotecan. Further investigation using an in situ closed loop experiment showed that 0.05% (w/v) Tween 20 and Cremophor EL significantly increased the intestinal absorption of topotecan in rats. An LDH assay demonstrated that 0.05% (w/v) Tween 20 and Cremophor EL did not cause significant damage to intestinal epithelial membranes. Furthermore, we examined the absorption-enhancing mechanisms of these excipients and found that Cremophor EL, Tween 20, and Labrasol increased the membrane fluidity of the inner lipid bilayers of the intestine. Therefore, this might be one of the most important mechanisms for inhibition of BCRP function by these excipients in the intestine.
Asunto(s)
Transportador de Casetes de Unión a ATP, Subfamilia G, Miembro 2/metabolismo , Excipientes/farmacología , Absorción Intestinal/efectos de los fármacos , Proteínas de Neoplasias/metabolismo , Topotecan/farmacocinética , Transportador de Casetes de Unión a ATP, Subfamilia G, Miembro 2/antagonistas & inhibidores , Administración Oral , Animales , Disponibilidad Biológica , Células CACO-2 , Excipientes/química , Glicéridos/química , Glicéridos/farmacología , Glicerol/análogos & derivados , Glicerol/química , Glicerol/farmacología , Humanos , Membrana Dobles de Lípidos/metabolismo , Masculino , Proteínas de Neoplasias/antagonistas & inhibidores , Poloxámero/química , Poloxámero/farmacología , Polisorbatos/química , Polisorbatos/farmacología , Ratas , Topotecan/químicaRESUMEN
We developed a bone-targeting dendrimer for the delivery of anti-tumour agents and effective treatment of bone metastasis, in which alendronate (ALN), a bone-targeting moiety, is covalently bonded to a polyethylene glycol (PEG)-conjugated polyamidoamine (PAMAM) dendrimer (PEG-PAMAM-ALN). Approximately 7.0 and 21.9% of the administered doses of [111In]PAMAM and PEG-PAMAM-ALN accumulated in the bones within 180 min after intravenous injection in mice, respectively. [3H]-labelled methotrexate (MTX) rapidly disappeared from the blood, and bone distribution was found to be only 1.1% of the administered dose at 180 min. In contrast, 21.5% of the administered dose of [3H]MTX-loaded PEG-PAMAM-ALN accumulated in the bones at 180 min after intravenous injection in mice, which was approximately 20-fold higher than that of [3H]MTX. In a bone metastatic tumour mouse model, in which B16-BL6/Luc cells were injected into the left ventricle of female C57BL/6 mice, the growth of metastatic tumour in the bones was significantly inhibited by intravenous injection of MTX-loaded PEG-PAMAM-ALN. These findings indicate that PEG-PAMAM-ALN is a promising bone-targeting carrier for the delivery of anti-tumour agents and treatment of bone metastasis.
Asunto(s)
Antimetabolitos Antineoplásicos/uso terapéutico , Neoplasias Óseas/tratamiento farmacológico , Dendrímeros/uso terapéutico , Metotrexato/uso terapéutico , Animales , Antimetabolitos Antineoplásicos/farmacocinética , Femenino , Masculino , Metotrexato/farmacocinética , Ratones , Ratones Endogámicos C57BL , Distribución TisularRESUMEN
To prevent bone metastasis, we developed polyethylene glycol (PEG)-conjugated aspartic acid (Asp)-modified liposomes (PEG-Asp-Lipo) as a bone-targeting carrier of paclitaxel (PTX) by using Asp-modified 1,2-dipalmitoyl-sn-glycero-3-phosphoethanolamine (DPPE-Asp). The affinity of Asp-modified liposomes to hydroxyapatite increased as the concentration of DPPE-Asp increased. The bone accumulation of [3H]-labeled PEG(2)-Asp(33)-Lipo was approximately 24.6% 360 min after intravenous injection in mice, in contrast to 5.4% and 6.7% of [3H]-labeled normal Lipo and PEG(2)-Lipo, respectively. Similarly, [14C]-labeled PTX encapsulated into PEG(2)-Asp(33)-Lipo predominantly accumulated in the bone. Furthermore, using an in situ imaging experiment, we observed that near-infrared fluorescence-labeled PEG(2)-Asp(33)-Lipo selectively accumulated in the bone near the joint after intravenous injection in mice. We also found that FITC-labeled PEG(2)-Asp(33)-Lipo predominantly accumulated on eroded and quiescent bone surfaces. In a bone metastatic tumor mouse model, in which B16-BL6/Luc cells were injected into the left ventricle of female C57BL/6 mice, metastatic bone tumor growth was significantly inhibited by an intravenous injection of PEG(2)-Asp(33)-liposomal PTX. In contrast, PEGylated liposomal PTX hardly affected the growth of metastatic bone tumors. These findings indicate that PEG(2)-Asp(33)-Lipo is a promising bone-targeting carrier for the delivery of PTX and treatment of bone metastasis.
Asunto(s)
Ácido Aspártico/química , Neoplasias Óseas/tratamiento farmacológico , Neoplasias Óseas/secundario , Huesos/efectos de los fármacos , Sistemas de Liberación de Medicamentos , Paclitaxel/uso terapéutico , Polietilenglicoles/química , Animales , Apoptosis/efectos de los fármacos , Ácido Aspártico/sangre , Ácido Aspártico/farmacocinética , Línea Celular Tumoral , Durapatita/metabolismo , Femenino , Citometría de Flujo , Colorantes Fluorescentes/metabolismo , Liposomas , Masculino , Ratones Endogámicos C57BL , Osteoclastos/efectos de los fármacos , Osteoclastos/metabolismo , Paclitaxel/farmacología , Factores de Tiempo , Distribución Tisular , TritioRESUMEN
In this study, we aimed to develop a polyethylene glycol (PEG)-conjugated third generation polyamidoamine (PAMAM) dendrimer with multiple carboxylic acids as a bone-targeting carrier for the treatment of bone diseases. We conjugated PAMAM backbones to various carboxylic acids [aspartic acid (Asp), glutamic acid (Glu), succinic acid (Suc), or aconitic acid (Aco)] to obtain four different types of carboxylic acid-modified PAMAMs. PEG was covalently bound to carboxylic acid-modified PAMAMs to obtain PEGylated carboxylic acid-modified PAMAMs. In a tissue distribution study, the amount of 111In-labeled unmodified PAMAM taken up by the bone after intravenous injection in mice was 11.3%. In contrast, the dose of 111In-labeled PEG(5)-Asp-PAMAM, PEG(5)-Glu-PAMAM, PEG(5)-Suc-PAMAM, or PEG(5)-Aco-PAMAM that accumulated in the bone after injection was approximately 46.0, 15.6, 22.6, and 24.5%, respectively. The bone clearance rates of 111In-labeled PEGylated carboxylic acid-modified PAMAMs were proportional to their affinities to hydroxyapatite and Ca2+. An intra-bone distribution study showed that fluorescein isothiocyanate-labeled PEG(5)-Asp-PAMAM predominantly accumulated on eroded and quiescent surfaces, a pattern associated with the pathogenesis of bone diseases, such as rheumatoid arthritis and osteoporosis. Our findings indicate that PEG(5)-Asp-PAMAM is a promising drug carrier for efficient drug targeting to the bones.
Asunto(s)
Huesos/metabolismo , Ácidos Carboxílicos/administración & dosificación , Dendrímeros/administración & dosificación , Portadores de Fármacos/administración & dosificación , Polietilenglicoles/administración & dosificación , Animales , Enfermedades Óseas/tratamiento farmacológico , Ácidos Carboxílicos/química , Ácidos Carboxílicos/farmacocinética , Ácidos Carboxílicos/uso terapéutico , Dendrímeros/química , Dendrímeros/farmacocinética , Dendrímeros/uso terapéutico , Portadores de Fármacos/química , Portadores de Fármacos/farmacocinética , Portadores de Fármacos/uso terapéutico , Masculino , Ratones , Polietilenglicoles/química , Polietilenglicoles/farmacocinética , Polietilenglicoles/uso terapéuticoRESUMEN
Reactive oxygen species (ROS) are involved in the pathophysiology of ischemia/reperfusion injury. To protect mouse hepatocytes from ischemia/reperfusion injury, we prepared two different sizes of citric acid-protected platinum nanoparticles (Pt-NPs), which exhibited ROS-scavenging activities and selective delivery to a specific type of liver cell. Small Pt-NPs (30 nm) reduced the superoxide anion, hydrogen peroxide, and hydroxyl radical levels in solution to a greater extent than did large Pt-NPs (106 nm). Large and small Pt-NPs predominantly accumulated in hepatic nonparenchymal cells after intravenous injection into mice. In a mouse model of ischemia/reperfusion injury, in which hepatic injury was induced by occluding the portal vein for 15 min followed by 6 h reperfusion, the increase in plasma alanine aminotransferase (ALT) and aspartate aminotransferase (AST) activities was inhibited by a bolus intravenous injection of either large or small Pt-NPs. However, small Pt-NPs inhibited the increase in these markers of hepatic injury to a greater extent than did large Pt-NPs. These results indicate that Pt-NPs can be used to prevent hepatic ischemia/reperfusion injury. To our knowledge, this is the first report demonstrating the pharmacokinetics and efficacy of Pt-NPs to prevent hepatic ischemia/reperfusion injury.