Osteosarcoma with extensive calcified pleural metastases at diagnosis.

We report the case of an 18 year old woman presenting with shortness of breath and pain in the left shoulder. Imaging of the lungs revealed pleural effusion and calcification of the left pleura. An osteosarcoma of the left humerus was the final diagnosis. A review of the literature reveals that calcified pleural metastatic disease in cases of osteosarcoma has been infrequently reported. Other causes of pleural calcification are briefly discussed.

Intravenous versus subcutaneous injections of apomorphine in rabbits: a pharmacokinetic paradox.

The objective of this investigation was an attempt to conclusively prove the accidental observation that the AUC of apomorphine in rabbits was repeatedly lower after intravenous injection compared to subcutaneous injection. Apomorphine was administered to rabbits by intravenous and subcutaneous routes at 2 different doses (0.31 mg/kg, n=10; and 0.25 mg/kg, n=6). Plasma drug concentrations were measured by HPLC-ECD and pharmacokinetic parameters were estimated by compartmental and non-compartmental approaches. The AUC of apomorphine in rabbits were: for subcutaneous injection, 14138 +/- 502 ng/ml/min and 12680 +/- 855 ng/ml/min, n=10 and 6, respectively; for intravenous injection, 11850 +/- 718 ng/ml/min and 9147 +/- 671 ng/ml/min, n=10 and 6, respectively. These AUC values were statistically significantly lower when given as intravenous injection compared to subcutaneous injection (p=0.0011 and 0.0117, n=10 and 6, respectively). The T1/2,elim values were: for subcutaneous injection, 17.1 +/- 1.70 min and 18.7 +/- 1.68 min, n=10 and 6, respectively; for intravenous injection, 15.3 +/- 1.20 min and 15.0 +/- 2.24 min, n=10 and 6, respectively. There were no significant differences between the T1/2,elim from both administration routes (p=0.3984 and 0.2158, n=10 and 6, respectively). Given the reproducibility of the results, it was concluded that the AUC of apomorphine after intravenous injection in rabbits is anomalously lower than that of subcutaneous injection.

In-vitro nasal drug delivery studies: comparison of derivatised, fibrillar and polymerised collagen matrix-based human nasal primary culture systems for nasal drug delivery studies.

The aim of this study was to establish a collagen matrix-based nasal primary culture system for drug delivery studies. Nasal epithelial cells were cultured on derivatised (Cellagen membrane CD-24), polymerised (Vitrogen gel) and fibrillar (Vitrogen film) collagen substrata. Cell morphology was assessed by microscopy. The cells were further characterised by measurement of ciliary beat frequency (CBF), transepithelial resistance (TER), permeation of sodium fluorescein, mitochondrial dehydrogenase (MDH) activity and lactate dehydrogenase (LDH) release upon cell exposure to sodium tauro-24, 25 dihydrofusidate (STDHF). Among the three collagen substrata investigated, the best epithelial differentiated phenotype (monolayer with columnar/cuboidal morphology) occurred in cells grown on Cellagen membrane CD-24 between day 4 and day 11. Cell culture reproducibility was better with Cellagen membrane CD-24 (90%) in comparison with Vitrogen gel (70%) and Vitrogen film (< 10%). TER was higher in cells grown on Vitrogen gel than on Cellagen membrane CD-24 and Vitrogen film. The apparent permeability coefficient (Papp x 10(-7)cm s(-1)) of sodium fluorescein in these conditions was 0.45+/-0.08 (Vitrogen gel) and 1.91+/-0.00 (Cellagen membrane CD-24). Except for LDH release, CBF and cell viability were comparable for all the substrata. Based on MDH activity, LDH release, CBF, TER and permeation studies, Cellagen membrane CD-24- and Vitrogen gel-based cells were concluded to be functionally suitable for in-vitro nasal drug studies. Vitrogen film-based cultures may be limited to metabolism and cilio-toxicity studies.

The lung as a route for systemic delivery of therapeutic proteins and peptides.

The large surface area, good vascularization, immense capacity for solute exchange and ultra-thinness of the alveolar epithelium are unique features of the lung that can facilitate systemic delivery via pulmonary administration of peptides and proteins. Physical and biochemical barriers, lack of optimal dosage forms and delivery devices limit the systemic delivery of biotherapeutic agents by inhalation. Current efforts to overcome these difficulties in order to deliver metabolic hormones (insulin, calcitonin, thyroid-stimulating hormone [TSH], follicle-stimulating hormone [FSH] and growth hormones) systemically, to induce systemic responses (immunoglobulins, cyclosporin A [CsA], recombinant-methionyl human granulocyte colony-stimulating factor [r-huG-CSF], pancreatic islet autoantigen) and to modulate other biological processes via the lung are reviewed. Safety aspects of pulmonary peptide and protein administration are also discussed.

The biopharmaceutical aspects of nasal mucoadhesive drug delivery.

Nasal drug administration has frequently been proposed as the most feasible alternative to parenteral injections. This is due to the high permeability of the nasal epithelium, allowing a higher molecular mass cut-off at approximately 1000 Da, and the rapid drug absorption rate with plasma drug profiles sometimes almost identical to those from intravenous injections. Despite the potential of nasal drug delivery, it has a number of limitations. In this review, the anatomy and physiology of the nasal cavity, as well as ciliary beating and mucociliary clearance as they relate to nasal drug absorption, are introduced. The rationale for nasal drug delivery and its limitations, some factors that influence nasal drug absorption, and the experimental models used in nasal drug delivery research are also reviewed. Nasal mucoadhesion as a promising method of nasal absorption enhancement is discussed, and factors that influence mucoadhesion, as well as safety of nasal mucoadhesive drug delivery systems are reviewed in detail. Nasal drug administration is presently mostly used for local therapies within the nasal cavity. Anti-allergic drugs and nasal decongestants are the most common examples. However, nasal drug administration for systemic effects has been practised since ancient times. Nasally-administered psychotropic drugs by native Americans, the use of tobacco snuffs, and nasal administration of illicit drugs such as cocaine are all well known (Illum & Davis 1992). Nowadays, the nasal cavity is being actively explored for systemic administration of other therapeutic agents, particularly peptides and proteins (Illum 1992; Edman & Björk 1992), as well as for immunization purposes (Lemoine et al 1998). To better understand the basis for nasal drug absorption and factors that can influence it, a brief review of the anatomy and physiology of the nose is appropriate.

Toxicological investigations of the effects carboxymethylcellulose on ciliary beat frequency of human nasal epithelial cells in primary suspension culture and in vivo on rabbit nasal mucosa.

The objective of this study was to investigate the safety of a mucoadhesive carboxymethylcellulose (CMC) formulation for intranasal administration of apomorphine. The effect of different concentrations of CMC on ciliary beat frequency (CBF) was studied using a human nasal epithelial suspension cell culture system. The CBF was determined by computerized microscope photometry. The in vivo rabbit nasal mucosal tolerance of the mucoadhesive polymer was investigated using light microscopy. Twice daily, six rabbits received CMC powder in one nostril and CMC/apomorphine powder in the alternate nostril for 4 weeks. Two control rabbits received air puffs in one nostril and nothing in the alternate nostril. The rabbits were subsequently sacrificed and the stained nasal sections examined microscopically. CMC showed both concentration- and time-dependent inhibitory effects on the CBF. Only mild-to-moderate cilio-inhibition was recorded with the different concentrations of the polymer. CMC (both with and without apomorphine) caused mild-to-moderate inflammation after 4 weeks. Necrosis, squamous metaplasia or ciliary degeneration was not observed. Based on: (1) the mild-to-moderate cilio-inhibition induced by different concentrations of CMC; and (2) the mild-to-moderate nasal mucosal inflammation caused by CMC with and without apomorphine, we conclude that this polymer can be considered as a safe carrier for short-term intranasal administration. However, further investigations are required for its use in the treatment of chronic diseases such as with apomorphine in Parkinson's disease.

Intranasal bioavailability of apomorphine from carboxymethylcellulose-based drug delivery systems.

Carboxymethyl cellulose (CMC) powder formulation of apomorphine was prepared by lyophilization and characterized with respect to the in vitro and intranasal in vivo release of apomorphine in rabbits. This was compared to apomorphine release from degradable starch microspheres (DSM) and lactose, as well as in vivo absorption after subcutaneous injection. In vitro apomorphine release from CMC was sustained, unlike that of DSM and lactose. Changing the drug loading of CMC from 15 to 30% (w/w) influenced drug release rate, which increased with increased drug loading. In vivo absorption of apomorphine from lactose, DSM and subcutaneous injection were rapid and not sustained. Slower absorption rates of apomorphine occurred from CMC. The fastest absorption rate was obtained with lactose and the slowest with CMC of 15% (w/w) drug loading. The T(max) from the CMC dosage forms were significantly prolonged compared to the immediate release forms. Plasma drug levels were sustained with CMC. The plasma concentration was maintained within 50% of the C(max), longer (15% (w/w), 70 min; 30% (w/w), 40 min) compared to the rest (lactose, 20 min; DSM, 25 min, subcutaneous injection, 35 min). The sustained plasma level of apomorphine by CMC was achieved with relative bioavailabilities equivalent to subcutaneous injection.

Scintigraphic evaluation in rabbits of nasal drug delivery systems based on carbopol 971p((R)) and carboxymethylcellulose.

The residence time of apomorphine mucoadhesive preparations incorporating 99mTc labeled colloidal albumin in rabbit nasal cavity was evaluated by gamma scintigraphy. This technique was used to compare the nasal clearance of preparations based either on Carbopol 971P((R)) or lactose (control), each with and without apomorphine, or carboxymethylcellulose with apomorphine. The planar 1-min images showed an excipient-dependent progressive migration of radioactivity with time from the nasal cavity to the stomach and intestine. Thirty minutes post insufflation, the percentages of the formulations cleared from the nasal cavity were 47% for lactose, 26% for lactose/apomorphine, 10% for Carbopol 971P((R)), and 3% for both Carbopol 971P((R))/apomorphine and carboxymethylcellulose/apomorphine. Three hours post insufflation, the percentages of the formulations cleared from the nasal cavity were 70% for lactose, 58% for lactose/apomorphine, 24% for Carbopol 971P((R)), 12% for Carbopol 971P((R))/apomorphine, and 27% for carboxymethylcellulose/apomorphine. Apomorphine inhibited nasal mucociliary clearance since migration of the radioactivity administered with apomorphine containing preparations was in all cases slower than that of the corresponding powder without apomorphine. The peak plasma concentration of apomorphine was attained while all the formulations were still within the nasal cavity. The use of mucoadhesive polymers such as Carbopol 971P((R)) or carboxymethylcellulose in nasal dosage forms increases their residence time within the nasal cavity and provides the opportunity for sustained nasal drug delivery.

Nasal toxicological investigations of Carbopol 971P formulation of apomorphine: effects on ciliary beat frequency of human nasal primary cell culture and in vivo on rabbit nasal mucosa.

OBJECTIVE: The objective of this study was to investigate the nasal toxicity of a mucoadhesive Carbopol 971P formulation of apomorphine. MATERIALS AND METHODS: The effects of different concentrations of Carbopol 971P and apomorphine on ciliary beat frequency (CBF) were studied in suspension cultures of human nasal epithelial cells. The rabbit nasal mucosal tolerance of the formulation and its components were investigated using light microscopy. Different groups of the rabbits received twice daily, air puffs, glucose, glucose/apomorphine, Carbopol 971P or Carbopol 971P/apomorphine for 1 week (glucose-treated rabbits) or 1, 2 and 4 weeks (other treatments). RESULTS: Both Carbopol 971P and apomorphine showed both concentration- and time-dependent inhibitory effects on the CBF. The effects on CBF were: apomorphine, 1.0% w/v, irreversible ciliostasis; 0.1 and 0.5% w/v, reversible cilio-inhibition; 0.01%w/v, irreversible cilio-stimulation; and Carbopol 971P, 0.1 and 0.25% w/v, partially-reversible cilio-inhibition. Glucose and glucose/apomorphine physical mixture caused mild inflammation. Carbopol 971P (both with and without apomorphine) caused severe inflammation, which increased with duration of treatment. Necrosis, squamous metaplasia or ciliary degeneration was not observed. CONCLUSIONS: Due to the severe inflammation caused by Carbopol 971P with and without apomorphine, we conclude that this polymer is not a suitable carrier for intranasal administration of apomorphine. This is in spite of the reversible effects of Carbopol 971P (0.1 and 0. 25% w/v) and apomorphine (0.1 and 0.5% w/v) on CBF.

Safety assessment of selected cyclodextrins - effect on ciliary activity using a human cell suspension culture model exhibiting in vitro ciliogenesis.

The objective of this study was to assess the cilio-inhibitory effect of a series of cyclodextrins using a human cell suspension culture system exhibiting in vitro ciliogenesis. Enzymatically released human nasal epithelial cells were cultured as sequential monolayer-suspension culture showing in vitro ciliogenesis. Ciliary beat frequency (CBF) was determined by computerized microscope photometry. Among the cyclodextrins investigated (gamma-cyclodextrin, hydroxypropyl-beta-cyclodextrin, anionic-beta-cyclodextrin polymer, dimethyl-beta-cyclodextrin and alpha-cyclodextrin), it was shown that after 30 min of exposure, gamma-cyclodextrin (10% w/v), hydroxypropyl-beta-cyclodextrin (10.0% w/v) and anionic-beta-CD polymer (8.0% w/v) were not significantly cilio-inhibitory (P0.05). Similarly, CBF remained stable upon cell exposure to alpha-cyclodextrin (2.0% w/v) and dimethyl-beta-cyclodextrin (1.0% w/v). However, higher concentrations of alpha-cyclodextrin and dimethyl-beta-cyclodextrin resulted in mild to severe cilio-inhibition after 45 min of exposure. The effect of alpha-cyclodextrin (5.0% w/v; 54+/-4% cilio-inhibition) was partially reversible while dimethyl-beta-cyclodextrin (10% w/v; 36+/-4% cilio-inhibition) was irreversible. The cilio-inhibition observed in this model was lower than reported for chicken trachea model. Given the fact that (1) irreversible cilio-inhibition observed in this study occurred only at concentrations exceeding those used in pharmaceutical formulations and/or at an unusual exposure time (45 min) and that (2) in an in vivo situation, dilution and mucociliary clearance contribute to further decrease in local concentrations of the applied compound, the results of this study confirm the safety of the cyclodextrins investigated as nasal absorption enhancers.

Nasal mucoadhesive delivery systems of the anti-parkinsonian drug, apomorphine: influence of drug-loading on in vitro and in vivo release in rabbits.

Lyophilized polyacrylic acid powder formulations loaded with apomorphine HCl were prepared and the influence of drug loading on in vitro release and in vivo absorption studied after intranasal administration in rabbits. These formulations prepared with Carbopol 971P, Carbopol 974P and polycarbophil sustained apomorphine release both in vitro and in vivo. The in vitro release rate and mechanism were both influenced by the drug loading. There was no large influence of drug loading on the time to achieve the peak (Tmax) for a particular polymer, but Tmax differed between different polymers. For a particular drug loading, the Tmax from Carbopol 971P was the slowest compared with that for Carbopol 974P and polycarbophil; however, only the Tmax from Carbopol 971P loaded with 15% w/w of apomorphine was significantly longer than polycarbophil of similar drug loading (P=0.0386). The trend further observed was that increasing drug loading led to increased peak plasma concentration and area under the curve (AUC). In the second part of this study, a mixture containing an immediate release component and sustained release formulation was administered in an attempt to increase the initial plasma level, as this could be therapeutically beneficial. Only one peak plasma concentration was observed and the initial plasma concentrations were no higher than those obtained with solely sustained release formulation. The Tmax, the peak plasma drug concentration (Cmax) and AUC from the lactose-containing formulation were lower than the formulation without lactose but the differences were only marginally statistically significant for Cmax (P=0.0911) and AUC (P=0.0668), but not Tmax (P=0.2788).

Bioavailability of apomorphine following intranasal administration of mucoadhesive drug delivery systems in rabbits.

PURPOSE: The purpose of this study was to investigate both the in vitro and in vivo release of apomorphine from mucoadhesive powder formulations of Carbopol 971P and polycarbophil. METHODS: The in vitro drug release from the mucoadhesive formulations was studied using a modified USP XXII rotating basket. The pharmacokinetics of apomorphine given as a solution was determined after subcutaneous and intranasal administrations to rabbits. The animals also received intranasally the mucoadhesive dosage forms and immediate release lactose powder mixture. Comparisons were made between the salient pharmacokinetic parameters of the different dosage forms. RESULTS: Sustained in vitro drug release was obtained from the mucoadhesive formulations. Apomorphine was absorbed more rapidly in rabbits when administered intranasally than as a subcutaneous injection. The mucoadhesive formulations both gave sustained plasma drug concentrations and bioavailabilities comparable to subcutaneous injections. The times taken to achieve peak plasma drug concentrations from these mucoadhesive formulations were more than three-fold that of lactose. With these mucoadhesive formulations apomorphine lasted longer in the blood. It could be detected for up to 6-8 h compared to approximately 3 h for the other forms of administration. CONCLUSIONS: The nasal bioavailability of powders is higher than that of solutions. Drug release from the mucoadhesive powders was sustained and there was no significant difference between Carbopol 971P and polycarbophil.

Catechol is the major product of salicylate hydroxylation in 1-methyl-4-phenylpyridinium ion treated rats.

Salicylate hydroxylation using hydroxyl free radicals results into formation of 2,3-dihydroxybenzoic acid, 2,5-dihydroxybenzoic acid and catechol. Inspite of the fact that in vitro experiments have shown that catechol is a minor product, we have shown by these in vivo studies that it is a substantial product. Since catechol as well as 2,3-dihydroxybenzoic acid have not been found to be produced enzymatically from salicylates, they appear useful as in vivo indicators for monitoring hydroxyl free radicals. Administration of 1-methyl-4-phenylpyridinium ion (MPP+) to rat striatum using microdialysis results into the formation of hydroxyl radicals. Salicylate perfusion enables the estimation of the three derivatives cited above. They increased significantly after MPP+ administration in comparison to the baseline values, with catechol being the most significant. The maximum amounts were achieved 60 min after MPP+ administration, and the mean percentage increase at this time point were 83.1% for 2,3-DBA (n = 6, P = 0.005), 81.25% for 2,5-DBA (n = 6, P = 0.011) and 1228.8% for catechol (n = 4, p = 0.00008). MPP+ caused substantial decrease of dopamine metabolites. Dihydroxyphenylacetic acid decreased to 13% and homovanillic acid to 11.4%. We conclude that catechol is an important indicator of hydroxyl free radical formation in this animal model which is well suited to study the role of free radicals in Parkinsonism.

Distribution of apomorphine enantiomers in plasma, brain tissue and striatal extracellular fluid.

Steady-state concentrations of apomorphine enantiomers were measured in the extracellular fluid collected from rat brain striatum by microdialysis. The free and total concentrations of both enantiomers were also measured in plasma as well as the total concentrations in different brain regions (striatum, cortex and cerebellum). We noticed no regional difference in the total concentrations of the two enantiomers. The extracellular concentrations were much lower, amounting to 8% for R(-)-apomorphine and 4% for S(+)-apomorphine, of the total brain tissue concentrations. The microdialysis samples contained 12 times more (R(-)-apomorphine and 5 times more S(+)-apomorphine than the free apomorphine measured in plasma. The extracellular concentrations of R(-)-apomorphine (129 +/- 20 pmol/ml) were significantly higher (P = 0.001, n = 6), than those of S(+)-apomorphine (70 +/- 10 pmol/ml). These results indicate that both enantiomers of apomorphine concentrate equally in brain cells, and that a stereoselective uptake system could operate for R(-)-apomorphine at the blood-brain barrier level.

Apomorphine pharmacokinetics in parkinsonism after intranasal and subcutaneous application.

Apomorphine was administered subcutaneously and intranasally to 7 patients suffering from Parkinsonism with 'on-off' problems. This comparative pharmacokinetic study showed that the two routes of administration are comparable with respect to absorption kinetics. Apomorphine is rapidly absorbed when administered intranasally or subcutaneously with an absorption half life of 8.6 min and 5.8 min, respectively. The high rate of absorption is also reflected by the time for the plasma concentration to peak (tmax) and the lag times. The tmax was 23 min for intranasal route and 18 min for the subcutaneous route while the lag times were 2.8 min and 3.9 min, respectively. The bioavailability of intranasal apomorphine compared to the subcutaneous route amounted to 45%. After intranasal and subcutaneous administrations, the elimination half life of apomorphine amounted to 31 min and 27 min, respectively.

Free radical scavenging properties of apomorphine enantiomers and dopamine: possible implication in their mechanism of action in parkinsonism.

The influence of R(-) apomorphine, S(+) apomorphine and dopamine on the oxidation kinetics of two polyunsaturated fatty acids (PUFA) (cholesteryl linoleate (CL) and Trilinolein (TL)) was investigated. The oxidation was initiated by free radicals generated through thermal decomposition of 2.2'-Azobis(2-methyl-propionitrile) (AMPN) in phosphate buffer (pH 7.4) thermostated at 50 degrees C. The hydroperoxides formed were determined by iodine titration using a diode array spectrophotometer at 290nm. Both enantiomers of apomorphine as well as dopamine exerted an inhibitory effect. Tocopherol (alpha-tocopherol) and ascorbic acid were used as controls. The former inhibited while ascorbic acid facilitated the oxidation reaction. These results are discussed in relation with the possible role of oxidative injury in parkinsonism and the usefulness of apomorphine in elevating "on-off" episodes. On this basis, the non-dopaminergic enantiomer of apomorphine (S(+)-isomer) is put foward to test the importance of its radical scavenging properties in parkinsonism which could eventually lead to a therapeutic alternative with less side effects.

Stability of apomorphine in plasma and its determination by high-performance liquid chromatography with electrochemical detection.

Dilute solutions (50 ng/ml) of apomorphine in plasma are unstable at 37 degrees C and pH 7.4. The chemical half-life is only 39 min. Mercaptoethanol (0.01%) is effective in stabilizing these samples while sodium metabisulphite (1%), which is generally used, is not effective. Biological samples are extracted with diethyl ether (recovery 96.5%) and analysed using HPLC with coulometric detection (oxidation potential 0.25 V). The stationary phase employed was C18 material (4 microns) and the mobile phase was phosphate buffer (pH 3)-acetonitrile (70:30, v/v). The flow-rate was 1.8 ml/min. This bioanalytical method presents a reliable tool for pharmacokinetic studies in man.

Quantitation in chiral capillary electrophoresis: theoretical and practical considerations.

Capillary electrophoresis (CE) represents a decisive step forward in stereoselective analysis. The present paper deals with the theoretical aspects of the quantitation of peak separation in chiral CE. Because peak shape is very different in CE with respect to high performance liquid chromatography (HPLC), the resolution factor Rs, commonly used to describe the extent of separation between enantiomers as well as unrelated compounds, is demonstrated to be of limited value for the assessment of chiral separations in CE. Instead, the conjunct use of a relative chiral separation factor (RCS) and the percent chiral separation (% CS) is advocated. An array of examples is given to illustrate this. The practical aspects of method development using maltodextrins--which have been proposed previously as a major innovation in chiral selectors applicable in CE--are documented with the stereoselective analysis of coumarinic anticoagulant drugs. The possibilities of quantitation using CE were explored under two extreme conditions. Using ibuprofen, it has been demonstrated that enantiomeric excess determinations are possible down to a 1% level of optical contamination and stereoselective determinations are still possible with a good precision near the detection limit, increasing sample load by very long injection times. The theoretical aspects of this possibility are addressed in the discussion.

Comparative metabolism of SC-42867 and SC-51089, two PGE2 antagonists, in rat and human hepatocyte cultures.

1. The metabolism of SC-42867 and SC-51089, two PGE2 antagonists, was studied in cultured rat and human hepatocytes. Both compounds possess an 8-chlorodibenzoxazepine moiety, but differ from each other by the nature of the side chain connected to the nitrogen atom. SC-42867 and SC-51089 and their in vitro metabolites were separated by reversed-phase hplc. The major metabolites of both compounds were identified by mass spectrometry (ms) analysis. 2. SC-42867 was metabolized on the tricyclic moiety only. Oxidative N-dealkylation with opening of the oxazepine ring was the major metabolic pathway obtained in rat hepatocytes. The metabolic profile obtained in cultured human hepatocytes was comparable with that of cultured rat hepatocytes. However, the compound was metabolized to a much lower extent by the human cells. 3. SC-51089 was extensively metabolized by both cultured rat and human hepatocytes. Human cells metabolized this compound quite differently than cultured rat hepatocytes. Aromatic hydroxylation with consequent glucuronidation and sulphation were the main metabolic pathways observed in cultured human hepatocytes. Oxidative N-dealkylation with opening of the oxazepine ring and consequent glucuronidation was the major metabolic pathway observed in rat hepatocytes. Further metabolism occurred, in contrast with the human hepatocytes, mainly on the side chain. 4. The present in vitro results are compared with data of previous in vivo studies performed in rat.

Separation of the enantiomers of coumarinic anticoagulant drugs by capillary electrophoresis using maltodextrins as chiral modifiers.

The separation and quantitation of coumarinic anticoagulant drug enantiomers were achieved by direct chiral capillary electrophoresis using complex maltooligosaccharide mixtures as stereoselective electrolyte modifiers. Chiral separations were characterized by a high selectivity and efficiency, enabling enantiomeric excess determinations. In addition, preliminary results indicate the applicability of the method for the determination of individual enantiomers in biological samples. So the method can be used to perform stereoselective pharmacokinetic studies.