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PubMed1986

Simultaneous determination of codeine and chlorpheniramine in human plasma by capillary column gas chromatography.

A specific and highly sensitive capillary column gas chromatographic method was developed for the simultaneous determination of codeine and chlorpheniramine in human plasma. The method involves a solvent extraction and analysis by capillary column gas chromatography on a cross-linked 50% phenylmethyl silicone fused-silica capillary column with flame thermionic detection. A 10% solution of n-butanol in toluene was used as extraction medium and pyrilamine was used as internal standard. Reproducibility, linearity of calibration curves and specificity were all satisfactory with both drugs. The plasma concentration of codeine and chlorpheniramine could be measured at levels down to 0.9 ng/ml as codeine phosphate and 0.4 ng/ml as chlorpheniramine maleate, respectively. The method was applied to plasma samples from normal volunteers, and was confirmed to be adequate for biopharmaceutical and pharmacokinetic studies.

Adult↗

PubMed1981

Determination of ibuprofen in serum by high-performance liquid chromatography and application to ibuprofen disposition.

A high-performance liquid chromatographic method for quantitation of ibuprofen from serum and application of this method to ibuprofen disposition in the dog is described. The drug was extracted from acidified plasma with dichloromethane. The internal standard used was a methanolic solution of 4-n-butylphenylacetic acid. A muBondapak C18 column was used for analysis; this mobile phase was methanol-water-glacial acetic acid (pH 3.4) (75 : 24 : 1, v/v). A wavelength of 272 nm was used to monitor ibuprofen and the internal standard. Method sensitivity was 0.5 microgram/ml serum using either 0.5 or 1.0 ml of sample, and no interference was found from endogenous compounds or other commonly used anti-inflammatory agents. The coefficients of variation of the method were 4.2% and 6.0% for sample containing 50.0 and 6.25 microgram/ml of ibuprofen, respectively, and the calibration curve was linear for the range of 0.5 to 100 microgram/ml. This method was demonstrated to be suitable for pharmacokinetic and/or biopharmaceutical studies of ibuprofen in man and the dog.

Animals↗

PubMed1985

Gas chromatographic-mass spectrometric method for trazodone and a deuterated analogue in plasma.

A plasma assay method for trazodone and a 2H4 analogue is described which uses gas chromatography--electron-impact selected-ion monitoring mass spectrometry. Etoperidone is used as an internal standard. The analytes are extracted from basic medium into n-butyl chloride, then back extracted into aqueous 0.1 M hydrochloric acid. The aqueous layer is made basic and re-extracted with n-butyl chloride. The solvent is reduced under nitrogen at 35 degrees C and the residue is redissolved in toluene for gas chromatographic--mass spectrometric analysis. The ions monitored are m/z 231, 235, and 225 for trazodone, [2H4] trazodone and etoperidone, respectively. Quantitation is in the range 40-1000 ng/ml with acceptable precision and accuracy. The method is suitable for biopharmaceutical studies.

Biological Availability↗

PubMed1999

Determination of candesartan cilexetil, candesartan and a metabolite in human plasma and urine by liquid chromatography and fluorometric detection.

Liquid chromatographic methods are described for the determination of a new effective anti-hypertensive drug candesartan (CV-11974), its prodrug candesartan cilexetil (TCV-116) and a metabolite, CV-15959 in human plasma and urine. The assays comprise liquid-liquid extraction and separation on a phenyl column with fluorometric detection. The methods give absolute recoveries of 70, 83 and 78% for candesartan cilexetil, candesartan and CV-15959, respectively, and the limit of quantification is 5, 1 and 3 nM of plasma (RSD < 20%), respectively. The methods were applied to plasma and urine samples from biopharmaceutical and clinical studies in man.

Antihypertensive Agents↗

PubMed2001

Correlation of in vitro and in vivo acetaminophen availability from albumin microaggregates oral modified release formulations.

The aim of this study was to develop albumin microaggregated oral formulations for controlled drug release, and to reveal the possible influence of the release site on drug absorption. Acetaminophen was chosen as the model drug, which is included in the Class 1 group of the Biopharmaceutics Classification System (BCS). Albumin micro aggregates were formulated into tablets to obtain different drug release rates: Immediate Release (IR) tablets, multiparticulate systems with an intermediate release rate, and matrix systems showing slow release rate. The properties of the products were initially tested via dissolution studies, and then via bioavailability studies in healthy volunteers. Controlled release albumin microaggregated acetaminophen formulations for oral administration were obtained. The extent of drug absorption was comparable for all formulations, suggesting that the differences found in saliva concentration and urine cumulative profiles could be attributed merely to differences in drug release kinetics, as confirmed by the in vitro-in vivo correlation study. Therefore, it can be concluded that extended release of acetaminophen does not influence its absorption via intestinal heterogeneity.

Acetaminophen↗

PubMed2002

Intestinal absorption characteristics of the low solubility thiocarboxanilide UC-781.

The aim of this study was to determine the intestinal absorption characteristics of the antiviral agent UC-781 and to optimize the experimental conditions of the in vitro system for low solubility compounds. The absorption potential of UC-781 was studied with the Caco-2 system and with the rat intestinal perfusion technique. The low solubility of UC-781 required the use of solubility/dissolution rate enhancing agents (e.g. VitE-TPGS, Gelucire 44/14). The creation of sink conditions in the receiver compartment of the Caco-2 system was a prerequisite to reliably study the transport of this poorly soluble compound. After inclusion of VitE-TPGS in the acceptor solution, UC-781 could be characterized as a class II drug of the Biopharmaceutical Classification System (low solubility, high permeation across membranes). A significant concentration-dependent decrease in transport of UC-781 was observed upon increasing the concentration of VitE-TPGS in the apical compartment. This observation contrasts to the absorption enhancing properties of VitE-TPGS, and can probably be attributed to a decrease in the concentration of free UC-781 when using higher concentrations of the solubility/dissolution rate enhancing agents. The use of Gelucire 44/14 as a solubilizing agent resulted in a batch-dependent degradation of UC-781. The inclusion of the solubility/dissolution rate-enhancing agent VitE-TPGS did not result in absorption enhancement in the intestinal perfusion technique.

Anilides↗

PubMed2002

6-O-alpha-(4-O-alpha-D-glucuronyl)-D-glucosyl-beta-cyclodextrin: solubilizing ability and some cellular effects.

Some physicochemical and biopharmaceutical properties of a new branched cyclodextrin, 6-O-alpha-(4-O-alpha-D-glucuronyl)-D-glucosyl-beta-cyclodextrin (GUG-beta-CyD), were investigated. The interaction of GUG-beta-CyD with drugs was studied by spectroscopic and solubility methods, and compared with those of parent beta-CyD and 6-O-alpha-maltosyl-beta-CyD (G(2)-beta-CyD). The hemolytic activity of GUG-beta-CyD on rabbit erythrocytes was lower than those of beta-CyD and G(2)-beta-CyD. GUG-beta-CyD and G(2)-beta-CyD showed negligible cytotoxicity on Caco-2 cells up to at least 0.1 M. The inclusion ability of GUG-beta-CyD to neutral and acidic drugs was comparable to or slightly smaller than those of beta-CyD and G(2)-beta-CyD, probably because of a steric hindrance of the branched sugar. On the other hand, GUG-beta-CyD showed greater affinity for the basic drugs, compared with beta-CyD and G(2)-beta-CyD, owing to an electrostatic interaction of its carboxylate anion with positive charge of basic drugs. Thus, GUG-beta-CyD may be useful as a safe solubilizing agent particularly for basic drugs.

Animals↗

PubMed2003

In vivo evaluation of matrix granules containing microcrystalline chitosan as a gel-forming excipient.

Interest in drug delivery to the gastrointestinal tract by means of chitosan has been increasing. In the study reported, the biopharmaceutical properties of granules containing microcrystalline chitosan (MCCh; molecular weight 150 kDa, degree of deacetylation 75%) were evaluated via bioavailability tests in human volunteers. Ibuprofen and furosemide were used as model drugs. With ibuprofen, granules containing 40% of MCCh behaved as a slow-release formulation (t(max) 2.9 h). With furosemide, the most marked difference between a conventional dosage form and granules containing 40% MCCh was a marked lag time (0.5 h) before absorption from the latter. This difference was reflected in t(max) values for furosemide. Despite the lag time, AUC values for furosemide were high, indicating that the granules containing MCCh had remained in the stomach and that drug release had taken place in the stomach rather than in the intestine. The results of the bioavailability studies indicate that MCCh matrix granules allow a simple preparation of slow-release and perhaps stomach-specific dosage forms. Use of model drugs differing in relation to sites of absorption in the gastrointestinal tract aided identification of sites of absorption of drugs from the granules. Further studies, including gamma-scintigraphic evaluations, will be performed on how the granules behave in the stomach.

Adult↗

PubMed2003

Effect of buffer media composition on the solubility and effective permeability coefficient of ibuprofen.

The effect of perfusion medium composition on the two important biopharmaceutical parameters drug solubility and permeability was determined for ibuprofen. Eight commonly used buffers were examined. Equilibrium solubility, buffer capacity profiles and permeability coefficients, using the in situ rat gut perfusion model, were determined for each medium at 37 degrees C. The solubility of ibuprofen differed sixfold over the range of buffer systems studied. The differences in solubility were associated with different pHs of the buffers when saturated with drug and also the presence of micelles and divalent ions. The solubility of ibuprofen in FeSSIF was significantly higher than predicted from the pH due to micellisation, while that in Krebs was significantly lower due to ibuprofen-calcium salt formation. Buffer capacities varied over a 40-fold range. The pK(a) values of the buffer components were determined from the buffer capacity versus pH profiles and were in good agreement with the thermodynamic values when corrected for temperature and ionic strength. Smaller, but statistically significant differences in P(app) values for ibuprofen were also observed between some of the buffers. During perfusion, pHs of the perfusate samples gradually changed over time towards a median value of approximately 6.5. HBSS gave a P(app) approximately 50% greater than that observed in PBS 7.4. Physicochemical factors such as medium pH, buffer capacity and osmolarity should be considered when determining the P(app) values of ionisable compounds. Care needs to be exercised when comparing P(app) values from different laboratories as buffer composition can have a significant effect on both solubility and permeability of a drug, whose ionisation is substantially changed over the pH range of the buffers. Despite the high amount ionised, ibuprofen appears to be well absorbed and it can be classified as a highly permeable drug.

Animals↗

PubMed1999

Prediction of dissolution-absorption relationships from a dissolution/Caco-2 system.

While the analysis of in vitro dissolution-in vivo absorption relationships from oral solid dosage forms provides biopharmaceutical insight and regulatory benefit, no well developed method exists to predict dissolution-absorption relationships a priori to human studies. The objective was to develop an integrated dissolution/Caco-2 system to predict dissolution-absorption relationships, and hence the contributions of dissolution and intestinal permeation to overall drug absorption for fast and slow formulations of piroxicam, metoprolol, and ranitidine. Dissolution studies were conducted on fast and slow dissolving immediate-release formulations of piroxicam, metoprolol tartrate, and ranitidine HCl. Dissolution samples were treated with concentrated buffers to render them suitable (i.e., isotonic and neutral pH) for Caco-2 monolayer permeation studies. The dissolution/Caco-2 system yielded a predicted dissolution-absorption relationship for each formulation which matched the observed relationship from clinical studies. The dissolution/Caco-2 system's prediction of dissolution or permeation rate-limited absorption also agreed with the clinical results. For example, the dissolution/Caco-2 system successfully predicted the slow piroxicam formulation to be dissolution rate-limited, and the fast piroxicam formulation to be permeation rate-limited. Moreover, the system predicted this change from dissolution rate-limited absorption for slow piroxicam to permeation rate-limited absorption for fast piroxicam, in spite of piroxicam's high permeability and low solubility. The dissolution/Caco-2 system may prove to be a valuable tool in formulation development. Broader evaluation of such a system is warranted.

Absorption↗

PubMed2000

Microcalorimetry does not predict the cellular phagocytosis of latex microspheres.

Current literature highlights the potential suitability of microcalorimetry for the investigation of cell-drug interactions. Previous work using bacteria or antigens derived from infectious organisms yielded conclusions that heat production is a quantitative means of measuring phagocytosis. In this study we evaluated the potential of flow-through microcalorimetry as a method of quantifying the phagocytosis of microsphere particulates. The technique avoids the need to incorporate radioactive or fluorescent markers into the particulate formulation, and would be widely applicable in biopharmaceutical research. Using the monocyte cell line Mono Mac 6 a power output of 9.00 microW per million cells was increased significantly on addition of zymosan, lipopolysaccaride (LPS) and phorbol myristate acetate but not following exposure to FITC labelled latex microspheres (LM). TNFalpha production increased on exposure to zymosan, LPS and LPS-phorbol myristate acetate, though not on exposure to LB. An assay was developed which allowed the quantification of internalised particulates in phagocytic cells using fluorescent activated cell sorting (FACS). In contrast to the microcalorimetric and TNFalpha data FACS revealed that 20% of the MM6 population phagocytosed a mean of 1.35 LM. Microcalorimetry and measurements of TNFalpha production are assays of cellular activation a phenomenon not necessarily associated with phagocytosis. FACS, however, serves as a specific and quantitative measure of phagocytosis. Microcalorimetry may not be a suitable technique for the quantitative assessment of the phagocytosis of drug delivery particulates.

Calorimetry↗

PubMed1997

Assay of acyclovir in human skin layers by high-performance liquid chromatography.

This paper describes an assay procedure for acyclovir quantification in human skin after in vitro transdermal transport experiments. The procedure employs warm distilled water for acyclovir (ACV) extraction and high-performance liquid chromatography (HPLC) as analytical method. The procedure has good reproducibility, sensitivity and specificity, resulting in a reliable method for biopharmaceutical studies of ACV distribution in skin tissue. The chromatographic conditions set up, using distilled water as mobile phase, makes the analytical procedure simple and easy to perform.

Acyclovir↗

PubMed1999

Development and validation of a new high-performance liquid chromatographic assay of centpropazine, a new antidepressant compound, in serum.

Centpropazine is a new anti-depressant compound developed by Central Drug Research Institute, Lucknow (India). We report here the development and validation of a new HPLC assay of a parent drug in the serum of humans, monkeys and rats for pharmacokinetic studies. Centpropazine was eluted on a C18 column with a mobile phase consisting acetonitrile phosphate buffer (60:40) pumped at 1.5 ml min(-1) flow rate and quantitated by UV detector at 270 nm. Considering the sample volume available from different species and to enhance the sensitivity of assay, three sample clean up methods requiring 0.05, 0.5 and 4 ml serum for a linear quantitation range of 312.5 ng ml(-1)-5 microg ml(-1), 0.04-2.5 microg ml(-1) and 2.5-80 ng ml(-1) respectively were developed. The lowest limit of quantitation of the method was 2.5 ng ml(-1) requiring 4 ml serum, 40 ng ml(-1) requiring 0.5 ml serum and 312 ng ml(-1) requiring 50 microl serum sample. All these methods were fully validated in human serum and extended to monkey and rat serum. The recovery of centpropazine at 5, 80, 625, 1280 and 2500 ng ml(-1) ranged between 92 and 105%. The within and between run variability in precision and accuracy were less than 10% and the drug in serum was stable up to three freeze-thaw cycles. Overall the method is simple, quick and robust for biopharmaceutical applications. The method was applied to analyse concentrations of centpropazine in rat serum after administering single 20 mg kg(-1) peroral and 5 mg kg(-1) i.v. dose. The chromatograms of treated rat serum exhibited three well resolved peaks of metabolites and one of them was identified as hydroxy-metabolite of centpropazine.

Acetonitriles↗

PubMed2000

Small bugs, big business: the economic power of the microbe.

The versatility of microbial biosynthesis is enormous. The most industrially important primary metabolites are the amino acids, nucleotides, vitamins, solvents, and organic acids. Millions of tons of amino acids are produced each year with a total multibillion dollar market. Many synthetic vitamin production processes are being replaced by microbial fermentations. In addition to the multiple reaction sequences of fermentations, microorganisms are extremely useful in carrying out biotransformation processes. These are becoming essential to the fine chemical industry in the production of single-isomer intermediates. Microbially produced secondary metabolites are extremely important to our health and nutrition. As a group, they have tremendous economic importance. The antibiotic market amounts to almost 30 billion dollars and includes about 160 antibiotics and derivatives such as the beta-lactam peptide antibiotics, the macrolide polyketide erythromycin, tetracyclines, aminoglycosides and others. Other important pharmaceutical products produced by microrganisms are hypocholesterolemic agents, enzyme inhibitors, immunosuppressants and antitumor compounds, some having markets of over 1 billion dollars per year. Agriculturally important secondary metabolites include coccidiostats, animal growth promotants, antihelmintics and biopesticides. The modern biotechnology industry has made a major impact in the business world, biopharmaceuticals (recombinant protein drugs, vaccines and monoclonal antibodies) having a market of 15 billion dollars. Recombinant DNA technology has also produced a revolution in agriculture and has markedly increased markets for microbial enzymes. Molecular manipulations have been added to mutational techniques as means of increasing titers and yields of microbial procresses and in discovery of new drugs. Today, microbiology is a major participant in global industry. The best is yet to come as microbes move into the environmental and energy sectors.

Journal Article↗

PubMed1996

Interleukins: the search for an anticancer therapy.

OBJECTIVES: To review each of the interleukins, identify their common toxic effects, and highlight the potential role of interleukins in cancer therapy. DATA SOURCES: Research articles, abstracts, review articles, and book chapters related to interleukins. CONCLUSIONS: Interleukins play a key role in coordinating complex immune defense mechanisms against microbe invasion and cancer. The process of genetic engineering has made an increasing number of these interleukins available as biopharmaceuticals for evaluation of their potential roles as a cancer therapeutic agent. IMPLICATIONS FOR NURSING PRACTICE: Nurses are challenged to understand and manage better both common and unusual side effects of interleukin therapies and provide appropriate patient and family education.

Bone Marrow Transplantation↗

PubMed1997

Gene therapy and blood cell transplantation.

OBJECTIVES: To describe the basics of gene transfer and specific applications in marrow ablative therapy. DATA SOURCES: Review articles, research studies, and book chapters pertaining to gene therapy. CONCLUSIONS: Gene therapy will be a major factor in healthcare options for the 21st century. Genetically engineered biopharmaceuticals will probably have a place in the blood cell transplant regimens of the future. IMPLICATIONS FOR NURSING PRACTICE: Nurses are in a position to guide the successful implementation of gene therapy through their roles as patient educator, counselor, direct-care coordinator, consultant, and through development of resource materials.

Biotechnology↗

PubMed2002

The effect of amiloride on the in vivo effective permeability of amoxicillin in human jejunum: experience from a regional perfusion technique.

The purpose of this human intestinal perfusion study (in vivo) was twofold. Firstly, we aimed to determine the effective in vivo jejunal permeability (P(eff)) of amoxicillin and to classify it according to the Biopharmaceutics Classification System (BCS). Secondly, we investigated the acute effect of amiloride on the jejunal P(eff) of amoxicillin. Amoxicillin, a beta-lactam antibiotic, has been reported to be absorbed across the intestinal mucosa by both passive diffusion and active transport. A regional single-pass perfusion of the jejunum was performed using a Loc-I-Gut perfusion tube in 14 healthy volunteers. Each perfusion lasted for 200 min and was divided into two periods of 100 min each. The concentration of amoxicillin entering the jejunal segment was 300 mg/l in both periods, and amiloride, an inhibitor of the Na+/H+ exchanger, was added at 25 mg/l in period 2. The concentrations of amoxicillin and amiloride in the outlet jejunal perfusate were measured with two different HPLC-methods. Antipyrine and [14C]PEG 4000 were added as internal standards to the perfusion solution. Amiloride had no significant effect on the jejunal P(eff) of amoxicillin. The human in vivo jejunal P(eff) for amoxicillin was 0.34+/-0.11 x 10(-4) and 0.46+/-0.12 x 10(-4) cm/s in periods 1 and 2, respectively. The high jejunal P(eff) for amiloride was 1.63+/-0.51 x 10(-4) cm/s which predicts an intestinal absorption of more than 90%. Following the BCS amoxicillin was classified as a low P(eff) drug, and amiloride had no acute effect on the in vivo jejunal P(eff) of amoxicillin.

Adult↗

PubMed2002

Pharmaceutical education in the wake of genomic technologies for drug development and personalized medicine.

The development of safe and effective new therapeutics is a long, difficult, and expensive process. Over the last 20-30 years, recombinant DNA (rDNA) technology has provided a multiple of new methods, molecular targets and DNA-based diagnostics to pharmaceutical research that can be utilized in assays for screening and developing potential biopharmaceutical drugs. In parallel, new innovative approaches to drug delivery systems were discovered and reached the market. Pharmaceutical biotechnology, pharmacogenomics, combinatorial chemistry, in close relation to high-throughput screening technologies, and bioinformatics are major advances that give a new direction to pharmaceutical sciences. To meet with the needs of this new dynamic era of pharmaceutical research and health care environment, pharmaceutical education has to set new priorities to keep pace with the challenges related to genomic technologies. The development of new initiative education programs, for both undergraduate and graduate curricula, in pharmacy has to be focused on preparing pharmacists oriented for both pharmacy practice and drug research and development. This can be achieved by providing future pharmacists with knowledge, skills and attitudes to be more competitive in the health care system, pharmacy practice-related fields, pharmaceutical industry and drug research and development areas, or finally in academia. Educators and pharmacy school members have the responsibility of deciding how, to what extent, by which methods, and/or in which way these changes and new directions in the education programs should be developed.

Animals↗