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1.
Low Molecular Weight Proteins as Carriers for Renal Drug Targeting: Naproxen–Lysozyme 总被引:3,自引:0,他引:3
Franssen Eric J. F. van Amsterdam Ronald G. M. Visser Jan Moolenaar Frits de Zeeuw Dick Meijer Dirk K. F. 《Pharmaceutical research》1991,8(10):1223-1230
Low molecular weight proteins (LMWPs), such as lysozyme, may be suitable carriers to target drugs to the kidney. In this study the antiinflammatory drug naproxen was covalently bound to lysozyme (1:1). Pharmacokinetics of the conjugate, naproxen–lysozyme (nap-LYSO), were compared to that of an equimolar mixture of uncoupled naproxen with lysozyme in freely moving rats. Similar plasma kinetics and organ distribution for native lysozyme and the drug conjugate were observed (Clp = 1.2 and 1.1 ml/min;
= 85 and 75 min, respectively). In case of the uncoupled naproxen–lysozyme mixture, a monoexponential plasma disappearance of naproxen with a
of 2.8 hr was observed, coinciding with urinary excretion of naproxen metabolites (mainly 6-desmethylnaproxen sulfate; 6-DMN-S) between 2 and 8 hr after injection. Urinary recovery of total metabolites was 59% of the naproxen dose. In contrast, after injection of covalently bound naproxen, plasma levels of the parent drug were below the detection level, whereas naproxen was recovered as 6-DMN-S in urine over a period from 4 to 30 hr. However, only 8% of the administered dose was recovered as 6-DMN-S in urine, whereas 50% of the dose was recovered as naproxen metabolites in feces. Incubation experiments using purified renal tubular lysosomal lysates revealed that naproxen–lysozyme degradation ultimately results in a stable naproxen amino acid catabolite, naproxen–lysine (nap-lys). Hepatic uptake and biliary excretion of this catabolyte were demonstrated in isolated perfused rat livers. Further, an equipotent pharmacological activity relative to parent naproxen was observed. We conclude that LMWPs such as lysozyme are indeed suitable carriers for site-specific delivery of drugs to the kidney. Although naproxen covalently bound to lysozyme did not release the parent drug, it did result in renal release of a stable and active catabolite, naproxen–lysine. 相似文献
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3.
Integrated Population Pharmacokinetic Model of Both Cyclophosphamide and Thiotepa Suggesting a Mutual Drug–Drug Interaction 总被引:3,自引:0,他引:3
de Jonge ME Huitema AD Rodenhuis S Beijnen JH 《Journal of pharmacokinetics and pharmacodynamics》2004,31(2):135-156
PURPOSE/AIMS: Cyclophosphamide (CP) and thiotepa (TT) are frequently administered simultaneously in high-dose chemotherapy regimens. The prodrug CP shows strong autoinduction resulting in increased formation of its activated metabolite 4-hydroxycyclophosphamide (4OHCP). TT inhibits this bioactivation of CP. Previously, we successfully modelled CP bioactivation and the effect of TT on the autoinduction. Recently we suggested that CP may also induce the conversion of TT in to its metabolite tepa (T). The aim of the current study was to investigate whether the influence of CP on TT metabolism can be described with a population pharmacokinetic model and whether this interaction can be incorporated in an integrated model describing both CP and TT pharmacokinetics. METHODS: Plasma samples were collected from 49 patients receiving 86 courses of a combination of high-dose CP (4000 or 6000 mg/m2), TT (320 or 480 mg/m2) and carboplatin (1067 or 1600 mg/m2) given in short infusions during four consecutive days. For each patient, approximately 20 plasma samples were available per course. Concentrations of CP, 4OHCP, TT and T were determined using GC and HPLC. Kinetic data were processed using NONMEM. RESULTS: The pharmacokinetics of TT and T were described with a two-compartment model. TT was eliminated through a non-inducible and an inducible pathway, the latter resulting information of T (ClindTT = 12.4 l/hr, ClnonindTT = 17.0 l/hr). Induction of TT metabolism was mediated by a hypothetical amount of enzyme, different from that involved in CP induction, whose amount increased with time in the presence of CP. The amount of enzyme followed a zero-order formation and a decrease with a first-order elimination rate constant of 0.0343 hr(-1) (t1/2 = 20 hr). This model was significantly better than a model lacking the induction by CP. The model was successfully incorporated into the previously published pharmacokinetic model for CP, and resulted in comparable parameter estimates for this compound and its metabolite 4OHCP. CONCLUSION: The pharmacokinetics of TT, when administered in combination with CP, were successfully described. The model confirms induction of TT metabolism with time and it appears likely that CP is responsible for this phenomenon. The existence of a mutual pharmacokinetic interaction between CP and TT, as described in our integrated model, may be relevant in clinical practice. 相似文献
4.
Biodegradable polymers provided the opportunity to explore beyond conventional drug delivery and turned out to be the focus of current drug delivery. In spite of availability of diverse class of polymers, several of these polymers lack important physicochemical and biological properties, limiting their widespread application in pharmaceutical drug delivery. However, most polymers in the form of blends, copolymers and functionally modified polymers have exhibited their applicability to overcome specific limitations and to produce novel and/or functionalized formulations for drug delivery as well as tissue engineering. This review aims to provide the need of polymeric modification, approaches adopted to modify and their scope. Special emphasis has been given to synthetic polyester PCL, as it is widely demonstrated in its modified form to overcome its problem of hydrophobicity and much slower degradation over the past decade. Past studies show a significantly higher utility of modified form of PCL in comparison to its native form. From the statistical analysis of these modifications and the formulations prepared, we present a basic understanding of the impact of selective modifications on the formulation design. In conclusion, we remark that a thorough understanding of the polymer and its modification has a huge potential to be the future trend for drug delivery and tissue engineering applications. 相似文献
5.
《Journal of pharmaceutical sciences》2022,111(5):1522-1530
Capecitabine and irinotecan (CPT-11) combination regimen (XELIRI) is used for colorectal cancer treatment. Capecitabine is metabolized to 5-fluorouracil (5-FU) by three enzymes, including carboxylesterase (CES). CES can also convert CPT-11 to 7-ethyl-10-hydroxycamptotecin (SN-38). CES is involved in the metabolic activation of both capecitabine and CPT-11, and it is possible that drug–drug interactions occur in XELIRI. Here, a physiologically based pharmacokinetic (PBPK) model was developed to evaluate drug–drug interactions. Capecitabine (180 mg/kg) and CPT-11 (180 mg/m2) were administered to rats, and blood (250 μL) was collected from the jugular vein nine times after administration. Metabolic enzyme activities and Ki values were calculated through in vitro experiments. The plasma concentration of 5-FU in XELIRI was significantly decreased compared to capecitabine monotherapy, and metabolism of capecitabine by CES was inhibited by CPT-11. A PBPK model was developed based on the in vivo and in vitro results. Furthermore, a PBPK model-based simulation was performed with the capecitabin dose ranging from 0 to 1000mol/kg in XELIRI, and it was found that an approximately 1.7-fold dosage of capecitabine was required in XELIRI for comparable 5-FU exposure with capecitabine monotherapy. PBPK model-based simulation will contribute to the optimization of colorectal cancer chemotherapy using XELIRI. 相似文献
6.
《Expert opinion on therapeutic targets》2013,17(10):1351-1360
Introduction: α-Synuclein, a neuronal protein, plays a central role in the pathophysiology of Parkinson’s disease (PD), the second most prevalent neurodegenerative disorder. Cases of PD have increased tremendously over the past decade necessitating the identification of new therapeutic targets to reduce patient morbidity and to improve PD patients’ quality of life.Areas covered: The purpose of this article is to provide an update on the role of α-synuclein in fibrils formation and review its role as an effective immunotherapeutic target for PD. The rapidly expanding evidence for the contribution of α-synuclein to the pathogenesis of PD led to the development of antibodies against the C terminus of α-synuclein and other molecules involved in the inflammatory signaling pathways that were found to contribute significantly to initiation and progression of the disease.Expert opinion: The readers will obtain new insights on the mechanisms by which α-synuclein can trigger the development of PD and other related degenerative disorders along with the potential role of active and passive antibodies targeted against specific form of α-synuclein aggregates to clear neurotoxicity, stop the propagation of the prion-like behavior of these oligomers and reverse neuronal degeneration associated with PD. 相似文献
7.
Qin Liu Xiangfan Yin Lucia R. Languino Dario C. Altieri 《Statistics In Biopharmaceutical Research》2018,10(2):112-122
To test the anticancer effect of combining two drugs targeting different biological pathways, the popular way to show synergistic effect of drug combination is a heat map or surface plot based on the percent excess the Bliss prediction using the average response measures at each combination dose. Such graphs, however, are inefficient in the drug screening process and it does not give a statistical inference on synergistic effect. To make a statistically rigorous and robust conclusion for drug combination effect, we present a two-stage Bliss independence response surface model to estimate an overall interaction index (τ) with 95% confidence interval (CI). By taking into all data points account, the overall τ with 95% CI can be applied to determine if the drug combination effect is synergistic overall. Using some example data, the two-stage model was compared to a couple of classic models following Bliss rule. The data analysis results obtained from our model reflect the pattern shown from other models. The application of overall τ helps investigators to make decision easier and accelerate the preclinical drug screening. 相似文献
8.
The inactivation of freeze-dried -galactosidase during storage was studied, focusing on the effect of water mobility as measured by the spin-lattice relaxation time, T
1, of water using 17O NMR. Inactivation of -galactosidase lyophilized from phosphate buffer solution was studied as a function of water content, which in turn affected the T
l of water. An increase in the water content of freeze-dried -galactosidase brought about an increase in the T
l of water, as well as a rise in pH. For the freeze-dried enzyme with sufficient water content to be dissolved, the inactivation rate was related to the T
l of water rather than to the pH change. It is suggested that as the water content increases, the mobility of water around the enzyme increases, resulting in enhanced enzyme inactivation. The freeze-dried samples with limited moisture showed inactivation rates faster than those expected from the pH and water mobility, suggesting that the inactivation mechanism is different from that for the freeze-dried enzyme with a larger amount of water. Inactivation of -galactosidase in solutions was also studied as a function of phosphate buffer and sodium chloride concentrations, which in turn affected the T
l of water. Because the inactivation rate increased with increasing salt concentrations and the rate extrapolated to zero concentration was negligible, inactivation of the freeze-dried enzyme was apparently induced by the salts used as additives for lyophilization. The enhancing effect of phosphate buffer components, however, was reduced at higher concentrations, an effect related to the decrease in the T
l of water. This result may be ascribed to the decrease in water mobility caused by phosphate buffer components and is consistent with the observation that the inactivation rate of the freeze-dried enzyme with a relatively large amount of water decreased with decreasing T
1 of water. 相似文献
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10.
The Liposome as a Model Membrane in Correlations of Partitioning with α-Adrenoceptor Agonist Activities 总被引:1,自引:0,他引:1
The apparent partition coefficients of a group of imidazoline -adrenoceptor agonists in liposome/buffer systems (Km) and in the n-octanol/buffer system (P) have been compared in quantitative structure–activity relationships (QSAR) employing biological activities and receptor binding affinities. A parabolic relationship between log K
m
and log P was found, and log K
m
was greater than log P for all liposome compositions. In liposomes, log K
m
decreased in the order, negatively charged > neutral > positively charged. Overall, hyper- and hypotensive activities of these drugs correlated better with log K
m
than with log P; however, poor correlations were obtained between partition coefficients and in vitro binding affinities. Linear correlations of log K
m
with hypotensive activities were obtained with negatively charged liposomes, whereas correlations with hypertensive activities were obtained using positively charged liposomes. Multiple regressions of biological activities with binding affinities showed positive correlations with hypotensive but not hypertensive activities with or without the inclusion of log K
m
or log P. Thus, the liposome represents a more selective model membrane system than a bulk oil phase for predicting the biological activities of imidazoline -adrenoceptor agonists. 相似文献
11.
《Expert opinion on therapeutic targets》2013,17(3):265-273
Importance of the field: Cerebral aneurysms (CAs) are the main cause of life-threatening subarachnoid hemorrhage. Given its prevalence and endpoint, CA treatment is a public health issue. Effective medical treatment of CAs is lacking because the detailed mechanisms of CA formation are incompletely understood.Areas covered in this review: The aim of this contribution is to review recent articles about CA formation, to suggest the underlying mechanisms of CA formation, and to discuss potential therapeutic targets for treatment. Articles were collected by an internet search of PubMed using the keywords ‘intracranial’ or ‘cerebral aneurysm’.What the readers will gain: A review of articles about the pathogenesis of CA formation focusing on inflammation. Recent articles demonstrate that inflammation-related-molecule induction and inflammatory cell infiltration in CA walls and the close relationship between inflammatory responses and CA formation. From studies in experimental models, chronic inflammation triggered primarily by NF-κB activation in endothelial cells and subsequent macrophage infiltration have critical roles in CA formation. Inhibition of inflammation-related molecules in CA walls results in the decreased incidence of CA formation.Take-home message: Agents with anti-inflammatory activity (particularly anti- NF-κB effects) have potential as therapeutic drugs for CAs. 相似文献
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《Statistics In Biopharmaceutical Research》2013,5(2):148-159
As part of a series of articles celebrating the American Statistical Association's 175th anniversary in 2014, this article provides a historical perspective of key statistical contributions to pharmacometrics (the design, modeling, and analysis of experiments involving complex dynamic systems) as well as a commentary on the author's career as a pharmaceutical industry statistician and pharmacometrician. Individuals with training in various academic disciplines including pharmacokinetics, pharmacology, engineering, and statistics, to name a few, have pursued careers as pharmacometricians. While pharmacometrics has benefitted greatly from advances in statistical methodology, there continues to be tension and skepticism between biostatisticians and pharmacometricians as they apply their expertise to drug development problems. This article explores some of the root causes for this tension and provides some suggestions for improving collaborations between statisticians and pharmacometricians. The article concludes with a plea for more statisticians to consider careers as pharmacometrics practitioners. 相似文献
15.
Shi-Xiang Wang Kai Luo Jing Liang Fei Fan Hua Li Jian-Bin Zheng Xiao-Hui Zheng 《Medicinal chemistry research》2011,20(1):16-22
A metabolomic method was established to investigate the plasma metabolic difference between healthy rabbits and rabbits with
Qi-stagnancy and blood stasis. All rabbits were administrated with an extraction of Salvia miltiorrhiza and S. miltiorrhiza coupled with Lignum dalbergiae odoriferae. The main compounds in plasma samples were detected by high-performance liquid chromatography/diode array detector/electrospray-mass
spectrometry (HPLC/DAD/ESI-MS). The data were analyzed by principal component analysis (PCA). The results showed that Qi-stagnancy
and blood stasis had a close relationship with dopamine. In addition, the results also indicated that the major plasma metabolic
difference between rabbits administrated with S. miltiorrhiza and S. miltiorrhiza coupled with Lignum dalbergiae odoriferae were 4-methylbenzamide, Danshensu and β-(3,4-dihydroxybenzene)-α-hydroxyl propanoic acid isopropyl ester. The above results could provide experimental evidence for the theory of traditional
Chinese medicine. 相似文献
16.
Masanori Ookubo Miyuki Sadamatsu Atsushi Yoshimura Satoru Suzuki Nobumasa Kato Hideto Kojima Naoto Yamada Hirohiko Kanai 《The international journal of neuropsychopharmacology / official scientific journal of the Collegium Internationale Neuropsychopharmacologicum (CINP)》2015,18(7)
Background:
Thyroid hormone receptors are divided into 2 functional types: TRα and TRβ. Thyroid hormone receptors play pivotal roles in the developing brain, and disruption of thyroid hormone receptors can produce permanent behavioral abnormality in animal models and humans.Methods:
Here we examined behavioralchanges, regional monoamine metabolism, and expression of epigenetic modulatory proteins, including acetylated histone H3 and histone deacetylase, in the developing brain of TRα-disrupted (TRα0/0) and TRβ-deficient (TRβ−/−) mice. Tissue concentrations of dopamine, serotonin (5-hydroxytryptamine) and their metabolites in the mesocorticolimbic pathway were measured.Results:
TRβ−/− mice, a model of attention-deficit/hyperactivity disorder, showed significantly high exploratory activity and reduced habituation, whereas TRα0/0 mice showed normal exploratory activity. The biochemical profiles of dopamine and 5-hydroxytryptamine showed significantly low dopamine metabolic rates in the caudate putamen and nucleus accumbens and overall low 5-hydroxytryptamine metabolic rates in TRβ−/− mice, but not in TRα0/0 mice. Furthermore, the expression of acetylated histone H3 was low in the dorsal raphe of TRβ−/− mice, and histone deacetylase 2/3 proteins were widely increased in the mesolimbic system.Conclusions:
These findings suggest that TRβ deficiency causes dysfunction of the monoaminergic system, accompanied by epigenetic disruption during the brain maturation process. 相似文献17.
Melanie A. Felmlee Qi Wang Dapeng Cui Samuel A. Roiko Marilyn E. Morris 《The AAPS journal》2010,12(3):407-416
γ-Hydroxybutyric acid (GHB), a drug of abuse, exhibits saturable renal clearance and capacity-limited metabolism. The objectives of this study were to construct a mechanistic toxicokinetic (TK) model describing saturable renal reabsorption and capacity-limited metabolism of GHB and to predict the effects of inhibition of renal reabsorption on GHB TK in the plasma and urine. GHB was administered by iv bolus (200–1,000 mg/kg) to male Sprague-Dawley rats and plasma and urine samples were collected for up to 6 h post-dose. GHB concentrations were determined by LC/MS/MS. GHB plasma concentration and urinary excretion were well-described by a TK model incorporating plasma and kidney compartments, along with two tissue and two ultrafiltrate compartments. The estimate of the Michaelis-Menten constant for renal reabsorption (K m,R) was 0.46 mg/ml which is consistent with in vitro estimates of monocarboxylate transporter (MCT)-mediated uptake of GHB (0.48 mg/ml). Simulation studies assessing inhibition of renal reabsorption of GHB demonstrated increased time-averaged renal clearance and GHB plasma AUC, independent of the inhibition mechanism assessed. Co-administration of GHB (600 mg/kg iv) and l-lactate (330 mg/kg iv bolus plus 121 mg/kg/h iv infusion), a known inhibitor of MCTs, resulted in a significant decrease in GHB plasma AUC and an increase in time-averaged renal clearance, consistent with the model simulations. These results suggest that inhibition of renal reabsorption of GHB is a viable therapeutic strategy for the treatment of GHB overdoses. Furthermore, the mechanistic TK model provides a useful in silico tool for the evaluation of potential therapeutic strategies. 相似文献
18.
A chiral mobile phase HPLC method is described for chiral separation and determination of chlorpheniramine (CP) enantiomers
in various commercial preparations. Chromatographic separation was achieved on a conventional ODS column with a mixture of
aqueous sodium phosphate (5 mM) containing 0.5 mM carboxymethyl-β-cyclodextrin, methanol and triethylamine (73:25:2, v/v/v,
pH 4.3) as the mobile phase. The flow rate of isocratic elution was 0.24 mL/min and peaks were detected at 224 nm. The method
was applied to nine commercial CP preparations in six dosage forms and CP enantiomers were well separated without any disturbance
of other ingredients or impurities present. The results showed that only one preparation was d-CP and the others were dl-CP preparations. The contents of all the preparations were found to be in the range of 97%–104% of labeled contents. This
method was economical and convenient, affording sufficient accuracy, precision and reproducibility, as well as sensitivity
and selectivity. 相似文献
19.
Kyeong Ho Kim Hyun Ju Kim Eun Young Jeun Sang Hun Seo Seon-Pyo Hong Jong-Seong Kang Jeong-Rok Youm Sang Cheal Lee 《Archives of pharmacal research》2001,24(4):281-285
Enantiomers of five racemic beta2-agonists were investigated by capillary electrophoresis employing a hydroxypropyl-beta-cyclodextrin (HP-beta-CD). The effects of the concentration of HP-beta-CD added to the background electrolyte and of the pH of the buffer on the effective mobility and resolution of the studied compounds were examined. Very good resolution was achieved for terbutaline and clenbuterol; salbutamol and bambuterol was able to be partially resolved. Enantioselectivity and resolution were influenced by the concentration of the HP-beta-CD, buffer composition and pH. 相似文献
20.
Ville Vartiainen Luis M. Bimbo Jouni Hirvonen Esko I. Kauppinen Janne Raula 《Pharmaceutical research》2017,34(1):25-35