Oral Absorption (oral + absorption)

Distribution by Scientific Domains

Selected Abstracts

CODES/Neural Network Model: a Useful Tool for in Silico Prediction of Oral Absorption and Blood-Brain Barrier Permeability of Structurally Diverse Drugs

Isabel Dorronsoro
Abstract Two different neural network models able to predict both oral absorption (OA) and blood-brain barrier (BBB) permeability of structurally diverse drugs in use clinically are presented here. Using the descriptors generated by CODES, a program which codifies molecules from a topological point of view, we avoid the uncertain choice of molecular conformation and physicochemical parameters. In this work, a method called Reduction of Dimensions, designed for compressing data, is applied for the first time in order to minimize the bias factor added to a QSAR study when the selection of descriptors are performed. [source]

Toxico-kinetics, recovery efficiency and microsomal changes following administration of deltamethrin to black Bengal goats

Sanis Juliet
Abstract A study of the toxico-kinetics, recovery percentage from different substrates, cytotoxicity and role of cytochrome P450 and b5 of liver microsome in the metabolism of deltamethrin were carried out in female black Bengal goat. The ALD50 value of deltamethrin in goat by intravenous route lies between 0.2 and 0.6,mg,kg,1. Intravenous disposition kinetics using a dose of 0.2,mg,kg,1 showed that the maximum blood concentration of deltamethrin was recorded at 0.5,min, followed by rapid decline, and a minimum concentration was detected at 6,min after administration. The following values were obtained,:,Vdarea 0.148 (,0.02) litre,kg,1; t1/2 (,) 0.22 (,0.02),min; t1/2 (,) 2.17 (,0.37),min; Kel 1.05 (,0.24) min,1; AUC 4.30(,0.45),g min,ml,1; ClB 0.05 (,0.006) litre,kg,1 min,1; T,B 1.93 (,0.58); fc 0.40(,0.05). After 10,min, liver retained the maximum residue, and heart, adrenal gland, kidney, spleen, fat and brain also held the insecticide; liver, fat, heart and spleen retained residue after 30,min, and bone, liver and fat retained residue after 60,min of intravenous administration. Oral absorption of deltamethrin was poor and inconsistent, and approximately 65% of administered dose was recovered from faeces and gastrointestinal contents. The excretion of deltamethrin through urine was meagre, and only 0.01 and 0.013% of the administered dose was recovered after 3 and 5 days of oral administration respectively. All the tissues retained the residue after 3 days; while fat, rumen, reticulum, omasum, abomasum, large and small intestine and bone retained the residue after 5 days of oral administration; and the percentage recoveries were 1.73 and 0.027 respectively. Deltamethrin reduced the level of cytochrome P450 content of liver microsomal pellet of goat after 5 days of oral administration. Histopathological examination of liver, kidney, heart, spleen brain and lung sections of treated goats did not reveal any pathological changes. 2001 Society of Chemical Industry [source]

In vitro and in vivo characterization of TC-1827, a novel brain ,4,2 nicotinic receptor agonist with pro-cognitive activity

Georg Andrees Bohme
Abstract Nicotine activates specific receptors that are cation-permeable ionic channels located in the central and autonomous nervous systems, as well as at the neuromuscular junction. Administration of nicotine to animals and humans has been shown to enhance cognitive processes. However, side effects linked to the activation of peripheral nicotinic receptors limit the usefulness of nicotine for the treatment of cognitive disorders such as Alzheimer's disease (AD) or mild cognitive impairments (MCI). The synthesis and properties of TC-1827, a novel metanicotine derivative that activates brain ,4,2 nicotinic receptors is described. TC-1827 has high affinity for nicotine-labeled receptors in the cortex (Ki=34 nM), full-agonist intrinsic activity in ,4,2 -mediated neurotransmitter release studies in synaptosomes, and has no functional activity at nicotinic receptors in ganglionic or muscular cell lines. The compound enhances long-term potentiation in hippocampal slices, a form of synaptic plasticity thought to be involved in information storage at the cellular level. In vivo studies demonstrate that TC-1827 dose-dependently occupies thalamic nicotinic receptors labeled with [3H]-cytisine, increases cortical extracellular acetylcholine levels following oral administration, and enhances cognitive performance in rat and mice behavioral procedures of learning and memory. Pharmacokinetic studies in mice, rats, and monkeys indicated that TC-1827 has good oral absorption with a first pass effect resulting in bioavailabilities of 13,65% across dose/species. Cardiovascular safety studies indicate good cardiovascular tolerability for this compound. The present data demonstrate that TC-1827 is a selective and potent activator of brain ,4,2 nicotinic receptors and is a prototypical member of a new class of compounds with potential utility in the symptomatic treatment of cognitive disorders including AD and MCI. Drug Dev. Res. 62:26,40, 2004. 2004 Wiley-Liss, Inc. [source]

Reduced oral itraconazole bioavailability by antacid suspension

M. Lohitnavy
Summary Aims:, To investigate the effects of antacid suspension on oral absorption of itraconazole. Methods:, A randomized, open-labelled, two-period, crossover study with a 1-week washout period was conducted in 12 healthy Thai male volunteers. The participants were allocated in either treatment A or B in the first period. In treatment A, the volunteers were orally administered with 200 mg of itraconazole alone. In treatment B, the volunteers were administered orally with 200 mg of itraconazole co-administered with antacid suspension. Serial serum samples were collected over the period of 24 h and subsequently analysed by using a validated high-pressure liquid chromatographic method with ultraviolet detection. Pharmacokinetic parameters were determined by non-compartmental analysis. Results:, Time to reach maximal concentration (Tmax), maximal concentration (Cmax) and area under the curve (AUC0--,) were markedly decreased in antacid-treated group. Tmax for treatment A was 30 04 and 51 27 h for treatment B. Cmax and AUC0--, of treatments A and B were 1463 705 vs. 436 169 (ng/mL) and 19285 11146 vs. 6548 4522 (ngh/mL) respectively. 90% Confidence interval (90% CI) of Cmax and AUC0--, were 241,421 and 162,659 respectively. Conclusions:, Rate and extent of itraconazole oral absorption were markedly decreased by concurrent use of antacid suspension. Hence, co-administration of itraconazole and antacid suspension should be avoided. [source]

Enhanced oral absorption of paclitaxel in N -deoxycholic acid- N, O -hydroxyethyl chitosan micellar system,

Hong Li
Abstract The overall goal of this study was to develop a micellar system of paclitaxel (PTX) to enhance its oral absorption. An amphiphilic chitosan derivative, N -deoxycholic acid- N, O -hydroxyethyl chitosan (DHC), was synthesized and characterized by FTIR, 1H NMR, elemental analysis, and X-ray diffraction (XRD) techniques. The degree of substitution (DS) of hydroxyethyl group and deoxycholic acid group ranged from 89.5,114.5% and 1.11,8.17%, respectively. The critical micelle concentration (CMC) values of DHC decreased from 0.26 to 0.16,mg/mL as the DS of deoxycholic acid group increased. PTX was successfully loaded in DHC micelles with a high drug loading (31.68,,0.14%) and entrapment efficiency (77.57,,0.51%). The particle size of PTX-loaded DHC micelles ranged from 203.35,,2.19 to 236.70,,3.40,nm as the DS of deoxycholic acid group increased. After orally administration of PTX-loaded DHC micelles, the bioavailability was threefold compared with that of an orally dosed Taxol. The single-pass intestinal perfusion studies (SPIP) showed that the intestinal absorption of micelles was via endocytosis involving a saturable process and a p-glycoprotein (P-gp)-independent way. All these indicated that the DHC micelles might be a promising tool for oral delivery of poorly water-soluble drugs. 2010 Wiley-Liss, Inc. and the American Pharmacists Association J Pharm Sci 99:4543,4553, 2010 [source]

Effect of the oral absorption of benzenesulfonanilide-type cyclooxygenase-1 inhibitors on analgesic action and gastric ulcer formation

Xiaoxia Zheng
Abstract A benzensulfonanilide-type cyclooxygenase-1 (COX-1)-selective inhibitor, ZXX2-77: 4-amino-4,-chloro- N -methylbenzenesulfonanilide (4a), has been reported as a novel analgesic that does not cause gastric damage. This compound has a weak analgesic effect but has potent in vitro COX-1 inhibitory activity. Since the reason for the weak analgesic effect in vivo was thought to be the low rate of oral absorption, the blood concentration of ZXX2-77 (4a) was measured in rats. It was found that the Cmax value (1.2 M) of ZXX2-77 (4a) at a dose of 30 mg/kg did not reach the COX-1 IC50 value (3.2 M). On the other hand, ZXX2-79 (4b) (SO2NH derivative of ZXX2-77 (4a); 4-amino-4,-chlorobenzenesulfonanilide), which shows less potent COX inhibitory activities (COX-1 IC50,=,12 M, COX-2 IC50,=,150 M) than those of ZXX2-77 (4a) in vitro, was found to be more absorbable (Cmax,=,16 M at a dose of 30 mg/kg in rats) than ZXX2-77 (4a). Furthermore, ZXX2-79 (4b) not only showed a potent analgesic effect in a formalin test but also caused little gastric damage. These findings indicate that demethylated sulfonamide compounds are more easily absorbed than are N -methylated sulfonamide compounds and suggest that COX-1-selective inhibitors will be useful as analgesics that do not cause gastric damage. 2008 Wiley-Liss, Inc. and the American Pharmacists Association J Pharm Sci [source]

Combined use of crystalline salt forms and precipitation inhibitors to improve oral absorption of celecoxib from solid oral formulations

Hctor R. Guzmn
Abstract Biopharmaceutical evaluation of crystalline celecoxib salts in novel solid formulations, which were designed to simultaneously facilitate dissolution and inhibit precipitation in vitro, showed fast and complete absorption in beagle dogs at doses up to 7.5 mg/kg orally. In contrast, 5 mg/kg celecoxib in the form of Celebrex showed approximately 40% absolute bioavailability in a cross-over experiment. An in vitro,in vivo correlation was observed in dog, and a threshold level of in vitro dissolution needed to maximize in vivo performance was highlighted. Oral bioavailability was limited in the absence of excipient combinations that delayed precipitation of celecoxib free acid as the salt neutralized in the GI fluid. Formulations of crystal forms having high energy (a ,spring'), thus transiently increasing solubility in aqueous solution relative to the free acid, combined with excipients functioning as precipitation inhibitors (,parachutes') were shown to provide both enhanced dissolution and high oral bioavailability. 2007 Wiley-Liss, Inc. and the American Pharmacists Association J Pharm Sci 96: 2686,2702, 2007 [source]

Biowaiver monographs for immediate release solid oral dosage forms: Prednisolone,,

M. Vogt
Abstract Literature data relevant to the decision to allow a waiver of in vivo bioequivalence (BE) testing for the approval of immediate release (IR) solid oral dosage forms containing prednisolone are reviewed. Data on its solubility, oral absorption, and permeability are not totally conclusive, but strongly suggest a BCS Class 1 classification. Prednisolone's therapeutic indications and therapeutic index, pharmacokinetics, and the possibility of excipient interactions were also taken into consideration. Available evidence indicates that a biowaiver for IR solid oral dosage forms formulated with the excipients tabulated in this article would be unlikely to expose patients to undue risks. 2006 Wiley-Liss, Inc. and the American Pharmacists Association J Pharm Sci 96:27,37, 2007 [source]

Enhancing the oral bioavailability of the poorly soluble drug dicumarol with a bioadhesive polymer

Chris G. Thanos
Abstract This article investigates the effect of particle size and the incorporation of a bioadhesive polymer, poly(fumaric- co -sebacic) anhydride p(FA:SA), on the relative bioavailability of dicumarol. A novel method was used to reduce particle size of the drug, and encapsulated formulations were fabricated using a phase inversion technique to produce nanospheres and microspheres with varying size. Groups of Yorkshire swine were catheterized and gavaged after fasting for 12 h with each formulation in a 50 mg/mL suspension. Blood was collected at different time points, from 0 to 96 h, and pharmacokinetic analysis revealed that formulations incorporating the smaller drug particles showed the highest bioavailability: micronized drug with 7% p(FA:SA) 17:83 polymer had 190% relative bioavailability, and phase inverted p(FA:SA) 17:83 microspheres with 31% (w/w) loading had 198% relative bioavailability to spray dried formulation. Formulations with larger drug particles achieved 71% relative bioavailability. A nonadhesive formulation, fabricated with poly(lactic acid) (PLA), showed 91% relative bioavailability. Both particle size and polymer composition play a role in oral absorption of dicumarol. 2003 Wiley-Liss, Inc. and the American Pharmacists Association J Pharm Sci 92:1677,1689, 2003 [source]

Formulation and food effects on the oral absorption of a poorly water soluble, highly permeable antiretroviral agent

Bruce J. Aungst
Abstract DPC 961 is a low-solubility, high-permeability, second-generation non-nucleoside reverse transcriptase inhibitor. The purpose of these studies was to evaluate the effects of drug substance and formulation variables on DPC 961 oral absorption, and to compare fed and fasted state oral absorption. To accomplish this, groups of four to six dogs were dosed with various formulations of DPC 961 under fasted or fed conditions, and DPC 961 pharmacokinetics were examined. Absolute oral bioavailability, based on i.v. AUC in the same dogs, was 24% after a suspension dose in fasted dogs and was 51% in fed dogs. Bioavailability with an unoptimized tablet formulation was 30% in fasted dogs and 86% in fed dogs. DPC 961 oral absorption was shown to be dependent on drug substance particle size in fasted dogs, after dosing with a tablet formulation where only the drug substance particle size was varied, but there was no difference in fed dogs. AUC and Cmax increased in proportion with increases in tablet strength from 100 to 400 mg, using tablets manufactured from a common granulation. Tablets made with 50 and 66% drug loadings showed similar relative oral bioavailabilities. Tablets prepared with two different polymorphic forms of DPC 961 were also compared, and these were found to be equivalent. These studies provided a useful component of the formulation development process, to help identify and control the variables affecting oral absorption of this potential new therapeutic agent. 2002 Wiley-Liss, Inc. and the American Pharmaceutical Association J Pharm Sci 91:1390,1395, 2002 [source]

Improvement of dissolution and oral absorption of ER-34122, a poorly water-soluble dual 5-lipoxygenase/cyclooxygenase inhibitor with anti-inflammatory activity by preparing solid dispersion

Ikuo Kushida
Abstract Several formulation approaches were attempted to improve the dissolution and the oral absorption of ER-34122, which is a novel dual 5-lipoxygenase/cyclooxygenase inhibitor with potent anti-inflammatory activity. The solid dispersion of ER-34122 with hydroxypropylmethylcellulose (TC-5RW), which is an inert solid carrier, resulted in a significant improvement in the dissolution rate of ER-34122. The solid dispersion was prepared by a solvent evaporation method using ethanol and water. The solid-state characteristics of the solid dispersion, the corresponding physical mixture, and ER-34122 alone were investigated by X-ray powder diffraction, Fourier transform infrared spectroscopy (FTIR), and an automated controlled-atmosphere microbalance. The X-ray powder diffraction patterns suggest that the solid dispersion exists in a totally amorphous state and the others exist in a crystalline state. The FTIR spectra results suggest that ER-34122 can interact with TC-5RW through intermolecular hydrogen bonding in the solid dispersion. This interaction may cause a stabilization of ER-34122 in the higher-energy, faster-dissolving amorphous state. The dissolution rate of ER-34122 from the solid dispersion was significantly greater than that from the physical mixture or the pure drug. Furthermore, when orally administrated to beagle dogs, ER-34122 showed about a 100-fold increase in both maximum concentration (Cmax) and area under the curve of concentration versus time (AUC) compared with the pure drug. Consequently, it was determined that the solid dispersion technique with TC-5RW provides a promising way to increase the dissolution rate and the oral absorption of poorly water-soluble drugs such as ER-34122. 2002 Wiley-Liss, Inc. and the American Pharmaceutical Association J Pharm Sci 91:258,266, 2002 [source]

Review: physical chemistry of solid dispersions

Sandrien Janssens
Abstract Objectives With poorly soluble drug candidates emerging in the drug discovery pipeline, the importance of the solid dispersion formulation approach is increasing. This strategy includes complete removal of drug crystallinity, and molecular dispersion of the poorly soluble compound in a hydrophilic polymeric carrier. The potential of this technique to increase oral absorption and hence bioavailability is enormous. Nevertheless, some issues have to be considered regarding thermodynamic instability, as well in supersaturated solutions that are formed upon dissolution as in the solid state. Key findings After a brief discussion on the historical background of solid dispersions and their current role in formulation, an overview will be given on the physical chemistry and stability of glass solutions as they form supersaturated solutions, and during their shelf life. Conclusions Thorough understanding of these aspects will elicit conscious evaluation of carrier properties and eventually facilitate rational excipient selection. Thus, full exploitation of the solid dispersion strategy may provide an appropriate answer to drug attrition due to low aqueous solubility in later stages of development. [source]

Importance of pharmaceutical composition and evidence from clinical trials and pharmacological studies in determining effectiveness of chondroitin sulphate and other glycosaminoglycans: a critique

Professor K.D. Rainsford
Abstract Objectives Chondroitin sulphate (CS) has attracted much interest over the past two decades or so as a biological agent for use in the relief of pain and joint symptoms in osteoarthritis. Earlier clinical investigations produced variable, if encouraging results. This variability was partly due to limitations on the study designs and the lack of availability of standardized CS. Recently, high quality and fully standardized CS (Condrosulf) has become available and its effects have been studied in large-scale osteoarthritis trials, which are discussed here. Key findings There is now evidence for symptom - and structure-modifying (radio-logically-observed) effects. These studies show that CS (a) has slow onset of response and that relief of pain may not be like that of the direct analgesic actions of non-steroidal anti-inflammatory drugs (NSAIDs), (b) there are indications of reduced need for intake of analgesics (e.g. NSAIDs) in patients taking CS, and (c) quality of life and cost-benefits may be associated with use of CS. Safety evaluations show that the incidence of adverse reactions is low. Pharmacokinetic studies indicate that although oral absorption is relatively fast CS has moderate oral bioavailability (15,24%) and that depolymerised and degraded CS that is evident after absorption, together with CS itself, may take some time to accumulate in target joints. The pharmacodynamic actions of CS indicate that it has anti-inflammatory effects that include multiple actions involving reduction of catabolic reactions and enhanced anabolic (proteoglycan) synthetic reactions in cartilage and may block osteoclast activation in bone. Further studies are required to (a) establish the effects of depolymerised and degraded CS on degradation of cartilage and bone in vitro, and (b) MRI and other investigations of the effects in osteoarthritis of long-term CS treatment. Summary The findings from this review show there may be potential value of CS in reducing the dependence on intake of NSAIDs and analgesics in patients with osteoarthritis, while at the same time having favourable safety. [source]

Preparation of polylactide-co-glycolide and chitosan hybrid microcapsules of amifostine using coaxial ultrasonic atomizer with solvent evaporation

Sarala Pamujula
The objective of this study was to evaluate the effect of various processing and formulation factors on the characteristics of amifostine hybrid microcapsules. Amifostine-loaded hybrid microcapsules were prepared using PLGA and chitosan. In short, amifostine powder was dissolved in de-aerated water with or without chitosan. The amifostine solution was later emulsified into PLGA solution in dichloromethane containing phosphatidylcholine. The resultant emulsion was fed through the inner capillary of a coaxial ultrasonic atomizer. The liquid fed through the coaxial outer capillary was either water or chitosan solution. The atomized droplets were collected into PVA solution and the droplets formed microcapsules immediately. The hybrid microcapsules prepared with chitosan solution only as an outer layer liquid showed the maximum efficiency of encapsulation (30%). The median sizes of all three formulations were 33,44 ,m. These formulations with chitosan showed positive zeta-potential and sustained drug release with 13,45% amifostine released in 24 h. When chitosan was incorporated into inner as well as outer liquid layers, the drug release increased significantly, 45% (compared with other formulations) released in 24 h and almost 100% released in 11 days. Hybrid microcapsules of amifostine showed moderately high efficiency of encapsulation. The cationic charge (due to the presence of chitosan) of these particles is expected to favour oral absorption and thus overall bioavailability of orally administered amifostine. [source]

In-vitro release and oral bioactivity of insulin in diabetic rats using nanocapsules dispersed in biocompatible microemulsion

Suchat Watnasirichaikul
This study evaluated the potential of poly(iso -butyl cyanoacrylate) (PBCA) nanocapsules dispersed in a biocompatible microemulsion to facilitate the absorption of insulin following intragastric administration to diabetic rats. Insulin-loaded PBCA nanocapsules were prepared in-situ in a biocompatible water-in-oil microemulsion by interfacial polymerisation. The microemulsion consisted of a mixture of medium-chain mono-, di- and tri-glycerides as the oil component, polysorbate 80 and sorbitan mono-oleate as surfactants and an aqueous solution of insulin. Resulting nanocapsules were approximately 200 nm in diameter and demonstrated a high efficiency of insulin entrapment (> 80%). In-vitro release studies showed that PBCA nanocapsules could suppress insulin release in acidic media and that release at near neutral conditions could be manipulated by varying the amount of monomer used for polymerisation. Subcutaneous administration of insulin-loaded nanocapsules to diabetic rats demonstrated that the bioactivity of insulin was largely retained following this method of preparing peptide-loaded nanocapsules and that the pharmacodynamic response was dependent on the amount of monomer used for polymerisation. The intragastric administration of insulin-loaded nanocapsules dispersed in the biocompatible microemulsion resulted in a significantly greater reduction in blood glucose levels of diabetic rats than an aqueous insulin solution or insulin formulated in the same microemulsion. This study demonstrates that the formulation of peptides within PBCA nanocapsules that are administered dispersed in a microemulsion can facilitate the oral absorption of encapsulated peptide. Such a system can be prepared in-situ by the interfacial polymerisation of a water-in-oil biocompatible microemulsion. [source]

Therapeutic implications of the MDR-1 gene

K. L. Mealey
Drug transporters significantly influence drug pharmacokinetics and pharmacodynamics. P-glycoprotein (P-gp), the product of the MDR1 (ABCB1) gene, is among the most well-characterized drug transporters, particularly in veterinary medicine. A number of clinically relevant, structurally and functionally unrelated drugs are substrates for P-gp. P-gp is expressed by a variety of normal tissues including the intestines, renal tubular cells, brain capillary endothelial cells, biliary canalicular cells, and others, where it functions to actively extrude substrate drugs. In this capacity, P-gp limits oral absorption and central nervous system entry of many substrate drugs. A number of MDR1 polymorphisms have been described in human patients, some of which result in altered drug pharmacokinetics and susceptibility to diseases such as Parkinson's disease, inflammatory bowel disease, refractory seizures, and others. An MDR1 polymorphism in herding breed dogs, including collies and Australian shepherds, has been demonstrated to be the cause of ivermectin sensitivity in these breeds. Recent evidence suggests that this polymorphism, a 4-bp deletion mutation, results in increased susceptibility to the toxicity of several drugs in addition to ivermectin. Furthermore, data in rodent models suggest that P-gp may play an important role in regulating the hypothalamic,pituitary,adrenal axis. [source]

Cyclosporine exposure and calcineurin phosphatase activity in living-donor liver transplant patients: Twice daily vs. once daily dosing

Masahide Fukudo
We have compared the pharmacokinetics and pharmacodynamics of cyclosporine between once- and twice-daily dosing regimens in de novo patients of living-donor liver transplantation (LDLT). A total of 14 patients were enrolled in this study, who had received cyclosporine microemulsion (Neoral) twice a day (BID, n = 5) or once daily in the morning (QD, n = 9) after transplantation. On postoperative day (POD) 6, the QD regimen significantly increased cyclosporine exposure; the blood concentration at 2 hours postdose (C2) and area under the concentration-time curve (AUC) for 4 hours (AUC0,4), compared with the BID regimen. Moreover, the area under the calcineurin (CaN) activity in peripheral blood mononuclear cells time-curve (AUA) for 12 hours (AUA0,12) and 24 hours (AUA0,24) were decreased by approximately 42 and 25% with the QD regimen relative to the BID regimen, respectively. The C2 level was significantly correlated with the AUC0,4 (r2 = 0.95), which was negatively related to the AUA0,12 with a large interindividual variability (r2 = 0.59). However, a significant correlation was found between the AUA0,12 or AUA0,24 and CaN activity at trough time points. According to a maximum inhibitory effect attributable to the drug (Emax) model, the mean estimates of Emax and the Cb value that gives a half-maximal effect (EC50) for CaN inhibition were not significantly different between the 2 groups, respectively. These findings suggest that a once daily morning administration of cyclosporine may improve oral absorption and help to provide an effective CaN inhibition early after LDLT. Furthermore, CaN activity at trough time points would be a single surrogate predictor for the overall CaN activity throughout dosing intervals following cyclosporine administration. Liver Transpl 12:292,300, 2006. 2006 AASLD. [source]

CODES/Neural Network Model: a Useful Tool for in Silico Prediction of Oral Absorption and Blood-Brain Barrier Permeability of Structurally Diverse Drugs

Isabel Dorronsoro
Abstract Two different neural network models able to predict both oral absorption (OA) and blood-brain barrier (BBB) permeability of structurally diverse drugs in use clinically are presented here. Using the descriptors generated by CODES, a program which codifies molecules from a topological point of view, we avoid the uncertain choice of molecular conformation and physicochemical parameters. In this work, a method called Reduction of Dimensions, designed for compressing data, is applied for the first time in order to minimize the bias factor added to a QSAR study when the selection of descriptors are performed. [source]

Chronic granulomatous disease presenting with disseminated intracranial aspergillosis

Abdul Alsultan MD
Abstract We describe an 8-year-old boy who presented with multiple unresectable aspergillus brain abscesses as the initial presentation of X-linked chronic granulomatous disease (CGD). He failed initial therapy with amphotericin B, but was subsequently salvaged with voriconazole. CGD should be considered in the differential diagnosis for all children presenting with invasive fungal infections, particularly, those involving the central nervous system (CNS). Whereas, optimal pharmacologic therapy is still unknown for CNS aspergillosis, voriconazole may have an advantage due to its ability to cross the blood brain barrier and excellent oral absorption and bioavailability. 2005 Wiley-Liss, Inc. [source]

Development of a cytokine analog with enhanced stability using computational ultrahigh throughput screening

Peizhi Luo
Abstract Granulocyte-colony stimulating factor (G-CSF) is used worldwide to prevent neutropenia caused by high-dose chemotherapy. It has limited stability, strict formulation and storage requirements, and because of poor oral absorption must be administered by injection (typically daily). Thus, there is significant interest in developing analogs with improved pharmacological properties. We used our ultrahigh throughput computational screening method to improve the physicochemical characteristics of G-CSF. Improving these properties can make a molecule more robust, enhance its shelf life, or make it more amenable to alternate delivery systems and formulations. It can also affect clinically important features such as pharmacokinetics. Residues in the buried core were selected for optimization to minimize changes to the surface, thereby maintaining the active site and limiting the designed protein's potential for antigenicity. Using a structure that was homology modeled from bovine G-CSF, core designs of 25,34 residues were completed, corresponding to 1021,1028 sequences screened. The optimal sequence from each design was selected for biophysical characterization and experimental testing; each had 10,14 mutations. The designed proteins showed enhanced thermal stabilities of up to 13C, displayed five-to 10-fold improvements in shelf life, and were biologically active in cell proliferation assays and in a neutropenic mouse model. Pharmacokinetic studies in monkeys showed that subcutaneous injection of the designed analogs results in greater systemic exposure, probably attributable to improved absorption from the subcutaneous compartment. These results show that our computational method can be used to develop improved pharmaceuticals and illustrate its utility as a powerful protein design tool. [source]

Permeability and toxicological profile estimation of organochlorine compounds by biopartitioning micellar chromatography

L. Escuder-Gilabert
Abstract This paper points out the usefulness of biopartitioning micellar chromatography (BMC) as a high-throughput primary screening tool providing key information about the oral absorption, skin permeability (Kp), brain,blood distribution coefficient (BB) and ecotoxicological parameters such as median lethal concentration (LC50) and bioconcentration factors of 15 organochloride compounds. The retention data of compounds in BMC conditions were interpolated in previously developed quantitative,retention activity relationships by our research group. Results show that the compounds studied readily cross the intestinal barrier (oral absorption >ercnt;) and the blood,brain barrier (log BB >p;0.4). In addition, the organochlorines DDE, chlorobenzene, 1,3-dichlorobenzene and 1,2-dichlorobenzene are the compounds which can more quickly cross the skin barrier (log Kp >nus;0.74 cm/h). From a ecotoxicological point of view, it can be concluded that the most retained compounds, DDE, DDD, hexachlorobenzene and dicofol, are the most toxic and bioacumulative. Copyright 2008 John Wiley & Sons, Ltd. [source]

Transport characteristics of candesartan in human intestinal Caco-2 cell line

Lingjie Zhou
Abstract The intestinal absorptive characteristics and the efflux mechanisms of candesartan (CDS), a novel angiotensin II type 1 receptor blocker, were investigated. The Caco-2 cells were used as models of the intestinal mucosa to assess uptake and transport of CDS. The determination of CDS was performed by HPLC-Flu. In the Caco-2 cells, the uptake and absorptive transport of CDS were pH-independent (in the pH range 6.0,8.0). Passive membrane diffusion dominates the absorptive transport behavior of CDS across Caco-2 cells, while secretory transport was a concentration-dependent and saturable process. In the presence of cyclosporin A and verapamil, potent inhibitors of P-glycoprotein (P-gp), the Pratio decreased from 3.8 to 2.3 and 1.8, respectively, and permeation of apical to basolateral was enhanced. Overall, the current study suggests that efflux transporters are capable of mediating the absorption and secretion of CDS, and they may play significant roles in limiting the oral absorption of CDS. Copyright 2009 John Wiley & Sons, Ltd. [source]

Minimal effect of ketoconazole on cyclosporine (SangCyATM) oral absorption and first-pass metabolism in rats: evidence of a significant vehicle effect on SangCyA absorption

Susan Wong
Abstract The current work evaluated the effect of the CYP3A inhibitor ketoconazole on the oral absorption and first-pass metabolism of cyclosporine administered as the SangCyA formulation. Groups of 6 male Sprague,Dawley rats were administered SangCyA (5 and 15 mg/kg) by oral gavage alone and with ketoconazole (30 mg/kg). Blood cyclosporine levels were measured over 6 h, encompassing the cyclosporine absorption window. A significant vehicle effect on SangCyA absorption was observed. Comparing a 15 mg/kg dose, cyclosporine Cmax (meanSD 1.120.16 g/ml) and AUC0,6 (5.340.71 g h/ml) were 50% lower when propylene glycol was used as gavage vehicle instead of saline (2.190.94 g/ml and 9.522.52 g h/ml, respectively). Coefficients-of-variation for these parameters were halved in the propylene glycol vehicle however Tmax was unaffected. Ketoconazole increased cyclosporine Cmax and AUC0,6 by 50,60%, regardless of the vehicle or the cyclosporine dose, without altering Tmax (2,3 h). The small effect of ketoconazole suggests that CYP3A-mediated intestinal and first-pass hepatic metabolism are minor determinants of cyclosporine oral bioavailability in rats. Copyright 2002 John Wiley & Sons, Ltd. [source]

Population pharmacokinetics of intravenously and orally administered docetaxel with or without co-administration of ritonavir in patients with advanced cancer

Stijn L. W. Koolen
WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT , Docetaxel is an approved drug for the treatment of cancer of various primary origins. , An oral docetaxel regimen is warranted because of patient convenience and the opportunity to investigate more schedule intensive treatment regimens. , Co-administration of ritonavir significantly enhanced the apparent oral bioavailability of docetaxel. WHAT THIS STUDY ADDS , This study demonstrates that ritonavir increased the absorption of docetaxel after oral administration. , Furthermore, we showed that the clearance of docetaxel was inhibited in a concentration dependent manner. , The developed model will be used for further development of an oral docetaxel regimen. AIM Docetaxel has a low oral bioavailability due to affinity for P-glycoprotein and cytochrome P450 (CYP) 3A4 enzymes. Inhibition of the CYP3A4 enzymes by ritonavir resulted in increased oral bioavailability. The aim of this study was to develop a population pharmacokinetic (PK) model and to evaluate and quantify the influence of ritonavir on the PK of docetaxel. METHODS Data from two clinical trials were included in the data analysis, in which docetaxel (75 mg m,2 or 100 mg) had been administered intravenously or orally (10 mg or 100 mg) with or without co-administration of oral ritonavir (100 mg). Population modelling was performed using non-linear mixed effects modelling. A three-compartment model was used to describe the i.v. data. PK data after oral administration, with or without co-administration of ritonavir, were incorporated into the model. RESULTS Gut bioavailability of docetaxel increased approximately two-fold from 19 to 39% (CV 13%) with ritonavir co-administration. The hepatic extraction ratio and the elimination rate of docetaxel were best described by estimating the intrinsic clearance. Ritonavir was found to inhibit in a concentration dependent manner the intrinsic clearance of docetaxel, which was described by an inhibition constant of 0.028 g ml,1 (CV 36%). A maximum inhibition of docetaxel clearance of more then 90% was reached. CONCLUSIONS A PK model describing both the PK of orally and intravenously administered docetaxel in combination with ritonavir, was successfully developed. Co-administration of ritonavir lead to increased oral absorption and reduced elimination rate of docetaxel. [source]

Computational Oral Absorption Simulation for Low-Solubility Compounds

Kiyohiko Sugano
Abstract Bile micelles play an important role in oral absorption of low-solubility compounds. Bile micelles can affect solubility, dissolution rate, and permeability. For the pH,solubility profile in bile micelles, the Henderson,Hasselbalch equation should be modified to take bile-micelle partition into account. For the dissolution rate, in the Nernst,Brunner equation, the effective diffusion coefficient in bile-micelle media should be used instead of the monomer diffusion coefficient. The diffusion coefficient of bile micelles is 8- to 18-fold smaller than that of monomer molecules. For permeability, the effective diffusion coefficient in the unstirred water layer adjacent to the epithelial membrane, and the free fraction at the epithelial membrane surface should be taken into account. The importance of these aspects is demonstrated here using several in vivo and clinical oral-absorption data of low-solubility model compounds. Using the theoretical equations, the food effect on oral absorption is further discussed. [source]

ADME Investigations of Unnatural Peptides: Distribution of a 14C-Labeled ,,3 -Octaarginine in Rats

Markus Weiss
Abstract The highly positively charged, cell-penetrating ,,3 -octaarginine has been prepared with a radioactive label by acetylation at the N-terminus with a doubly 14C-labeled acetyl group (14CH314CO). With the radioactive compound, an ADME study (Absorption, Distribution, Metabolism, Excretion) was performed in male rats following an intravenous or oral dose of 1,mg/kg. Sampling was carried out after periods ranging from 5,min to 4,d or 7,d for blood/excretia and quantitative whole-body autoradioluminography (QWBA), respectively. After p.o. dosing, no systemic exposure to peptide-related radioactivity was observed, and the dose was completely excreted in the feces within 24,h suggesting the absence of relevant absorption; less than 3% of the i.v. dose was excreted from the animals within 4,d. Blood levels, after i.v. dosing, dropped within 4,d to less than 2% of Cmax and decreased afterwards only very slowly. No metabolites were observed in the systemic circulation. QWBA Data indicated that the distribution of the acetyl- , -octaarginine-related radioactivity in the organs and tissues shifted over time. Notably, after 7,d, the highest concentration was measured in the lymph nodes, and the largest amount was found in the liver. A comparison with the results of two previous ADME investigations of , -peptides (cf. Table,1) reveals that the distribution of the compounds within the animals is structure-dependent, and that there is a full range from oral availability with rather rapid excretion (of a tetrapeptide) to essentially complete lack of both oral absorption and excretion after i.v. administration (of a highly charged octapeptide). A discussion is presented about the in vivo stability and ,drug-ability' of peptides. In general, , -peptides bearing proteinogenic side chains are compared with peptides consisting entirely of D - , -amino acid residues (the enantiomers of the ,natural' building blocks), and suggestions are made regarding a possible focus of future biomedical investigations with , -peptides. [source]