Stealth Amphotericin B nanoparticles for oral drug delivery: In vitro optimization.

PURPOSE: Amphotericin B (AmB) is an effective anti-fungal and anti-leishmanial agent. However, AmB has low oral bioavailability (0.3%) and adverse effects (e.g., nephrotoxicity). The objectives of this study were to improve the oral bioavailability by entrapping AmB in pegylated (PEG) poly lactide co glycolide copolymer (PLGA-PEG) nanoparticles (NPs). The feasibility of different surfactants and stabilizers on the mean particle size (MPS) and entrapment efficiency were also investigated. MATERIALS AND METHODS: NPs of AmB were prepared by a modified emulsification diffusion method employing a vitamin E derivative as a stabilizer. Physicochemical properties and particle size characterization were evaluated using Fourier Transform Infra-Red spectroscopy (FTIR), differential scanning calorimetry, scanning electron microscopy and transmission electron microscopy. Moreover, in vitro dissolution profiles were performed for all formulated AmB NPs. RESULTS: MPS of the prepared spherical particles of AmB ranged from 26.4 ± 2.9 to 1068 ± 489.8 nm. An increased stirring rate favored AmB NPs with a smaller MPS. There was a significant reduction in MPS, drug content and drug release, when AmB NPs were prepared using the diblock polymer PLGA-PEG with 15% PEG. Addition of three emulsifying agents poly vinyl pyrrolidone (PVP), Vitamin E (TPGS) and pluronic F-68 to AmB formulations led to a significant reduction in particle size and increase in drug entrapment efficiency (DEE) compared to addition of PVP alone. FTIR spectroscopy demonstrated a successful loading of AmB to pegylated PLGA-PEG copolymers. PLGA-PEG copolymer entrapment efficiency of AmB was increased up to 56.7%, with 92.7% drug yield. After a slow initial release, between 20% and 54% of AmB was released in vitro within 24 h phosphate buffer containing 2% sodium deoxycholate and were best fit Korsmeyer-Peppas model. In conclusion, PLGA-PEG diblock copolymer with 15% PEG produced a significant reduction (>70%) in MPS with highest drug content. The percentage of PEG in the copolymer and the surfactant/stabilizer used had a direct effect on AmB release in vitro, entrapment efficiency and MPS. These developed formulations are feasible, effective and improved alternatives to other carriers for oral delivery of AmB.

Therapeutic monitoring of amphotericin B in Saudi ICU patients using UPLC MS/MS assay.

Amphotericin B (AmB) is the first-line agent for the treatment of life-threatening invasive fungal infections. The aim of this study was to monitor AmB in critically ill Saudi patients in ICU after i.v. administration of 0.68 ± 0.1 mg/kg/day Fungizone®. A selective, sensitive and precise UPLC MS/MS method was developed to measure AmB concentrations in these patients. Seven ICU patients with creatinine clearance (ClCr) >40 mL/min were included. AmB levels were analyzed using a Waters Aquity UPLC MS/MS system, a BEH Shield RP18 column and detection via electrospray ionization source with positive ionization mode. The precision and accuracy of the developed UPLC method in the concentration range of 200-4000 ng/mL show no significant difference among inter- and-intra-day analysis (p > 0.05). Linearity was observed over the investigated range with correlation coefficient, r > 0.995 (n = 6/day). The pharmacokinetics of AmB in these patients, at steady state, showed a high terminal half-life of 124.6 ± 73.4 h, with a highest concentration of 513.9 ± 281.1 ng/mL, a lowest concentration 316.4 ± 129.0 ng/mL and a mean clearance 91.1 ± 39.2 mL/h/kg. The pharmacokinetics of AmB in critically ill Saudi patients in ICU was studied using a fully validated assay. A weak correlation (r = -0.22) of AmB Cl with ClCr was obtained, which suggests the need for further investigation in a larger population.

Pharmacokinetics of Afatinib after Intravenous and Oral Administrations in Rats Using Validated UPLC MS/MS Assay.

Afatinib is designated as the first-line management therapy for patients with advanced non-small cell lung cancer, and metastatic head and neck cancer. LC coupled to MS/MS can be utilised in therapeutic drug monitoring to ensure optimal use of Afatinib with the reduction of its possible adverse reactions. The aim of this investigation was to determine the pharmacokinetics of Afatinib in rats after single IV (2 mg/kg) and oral (8 mg/kg) doses. Therefore, a selective, sensitive and precise UPLC MS/MS assay thru electrospray ionisation basis with positive ionisation approach was established to measure Afatinib concentrations in the rat. The precision and accuracy of the developed assay method in the concentration range of 10-1000 ng/ml show no significant difference among inter- and-intra-day analysis (P > 0.05). Linearity was detected over the studied range with correlation coefficient, r > 0.995 (n = 6/day). The pharmacokinetics of Afatinib in the rat after a single IV dose showed a mean terminal half-life of 4.6 ± 0.97 h, and a mean clearance 480 ± 80 ml/h/kg. After PO administration, a short absorption phase with a mean Tmax of 1.3 ± 0.6 h with the highest concentration of 513.9 ± 281.1 ng/ml, and the lowest concentration detected after 24 h was 18.8 ± 10.7 ng/ml.

Association between CYP3A4/CYP3A5 genetic polymorphisms and treatment outcomes of atorvastatin worldwide: is there enough research on the Egyptian population?

INTRODUCTION: Atorvastatin is regarded as the most frequently prescribed statin worldwide for dyslipidemia. However, clinical response and risk of adverse effects to statin therapy are associated with genetic variations. Numerous research linked statins pharmacokinetics (PK) variations to genetic polymorphisms in cytochromes P450 (CYPs) metabolic enzymes. OBJECTIVE: This article reviews the association between CYP3A4/5 genetic variations and response to atorvastatin therapy globally, which includes atorvastatin PK, and the risk for adverse reactions, with a hint to the Egyptians. METHODS: Up to March 30, 2022, electronic medical databases like PubMed, Web of Science, MEDLINE, and Egyptian Knowledge Bank (EKB) were searched. All articles that highlighted the relationship between CYP3A4/5 genetic polymorphisms and atorvastatin efficacy/safety profile were included in this review. RESULTS: Initially, 492 articles were retrieved after an exhaustive search. There were 24 articles included according to the inclusion criteria. Findings of association studies of CYP3A4/5 genetic polymorphisms with response to atorvastatin varied among different ethnicities. CYP3A4*1B was associated with better therapeutic outcomes after atorvastatin therapy in Chileans and vice versa in Americans. Caucasians with myalgia while using atorvastatin were at significant risk of suffering severe muscle damage if they were carriers of CYP3A5*3/*3. As far as we can report for the Egyptian population, the impact of CYP3A4/5 genetic variations on the response to atorvastatin therapy was understudied. CONCLUSION: More pharmacogenetic studies amongst diverse populations worldwide, like the Egyptian population, are necessary to detect further atorvastatin-gene interactions.

Formulation and evaluation of Piroxicam nanosponge for improved internal solubility and analgesic activity.

Cyclodextrin nanosponges are solid nanoparticles, designed by cross-linking of cyclodextrin polymer; it has been used widely as a good delivery system for water insoluble drugs. The aim of this study is to enhance the solubility of Piroxicam (PXM) using ß-Cyclodextrin based nanosponges formulations. PXM nanosponge (PXM-NS) formulations were prepared using ß-cyclodextrin and carbonyldiimidazole as a cross linker, three ratios of ß-cyclodextrin to crosslinker in addition to three drug to nanosponges ratios were tested. Piroxicam nanosponge formulations were characterized for its particle size, zeta potential, physical compatibility and in vitro release. Stability studies at three temperatures (4 °C, 25 °C and 40 °C) were done for optimal formula. Finally, the in vivo analgesic activity and pharmacokinetic parameters of the optimal formula were conducted. The optimized PXM-NS formula (PXM-NS10) showed particle size (362 ± 14.06 nm), polydispersity index (0.0518), zeta potential (17 ± 1.05 mV), and %EE (79.13 ± 4.33). The dissolution study showed a significant increase in the amount of PXM dissolved compared with the unformulated drug. Stability studies confirmed that nanosponge showed accepted stability for 90 days at 4 °C and 25 °C. In vivo analgesic studies verified that there was a significant enhancement in the analgesic response to PXM in mice, and 1.42 fold enhancement in the relative bioavailability of PXM-NS10 as compared to commercial tablets. Nanosponge prepared under optimal conditions is an encouraging formula for increasing the solubility and therefore the bioavailability of Piroxicam.

Determination of free and total warfarin concentrations in plasma using UPLC MS/MS and its application to a patient samples.

Warfarin is routinely monitored by assessing its pharmacologic effects on the international normalized ratio. However, having a patient with INR not responding to increasing warfarin dose mandates a direct measurement of warfarin concentrations (total and free) for better patient clinical management of warfarin therapy. Therefore, a new fully validated specific, precise and accurate ultra-performance liquid chromatography tandem mass spectrometry was developed for the determination of free and total warfarin in human plasma. Free warfarin was measured in plasma filtrate, prepared by ultrafiltration, and sample pretreatment involved protein precipitation with acetonitrile. Linear response (r(2) ≥0.99) was observed over the studied range of free and total warfarin, with the lower limit of detection of 0.25 ng/mL. The intra- and inter-day precision (relative standard deviation) values were <10% and the accuracy (relative error) was ≤6.6 for free and total warfarin. There was no significant difference (p>0.05) between inter- and intra-day studies for the free and total warfarin, which confirmed the reproducibility of the assay method. The mean extraction efficiency was 88.6-107.2% of free and total warfarin. The assay was sensitive to follow warfarin pharmacokinetics (free and total) in a patient with resistance to warfarin up to 24 h after a daily dose of warfarin.

Monitoring metformin in cardiac patients exposed to contrast media using ultra-high-performance liquid chromatography tandem mass-spectrometry.

BACKGROUND: There is no evidence that the use of contrast media (CM) in diabetic patients with serum creatinine <130 µmole/L leads to metformin accumulation and subsequent lactic acidosis. Therefore, the objective of this investigation was to monitor cardiac patients for the effects of CM on their metformin plasma concentration and serum creatinine clearance (ClCr). METHODS: Metformin plasma concentrations were measured by a new, fully validated specific, precise, and accurate ultra-high-performance liquid chromatography tandem mass-spectrometric assay. The detection was performed using positive electrospray ionization in the multiple reaction monitoring mode. Fifty patients with serum creatinine levels <130 µmole/L were monitored for the effect of CM exposure on metformin concentration and ClCr. Pharmacokinetic parameters were calculated in 8 of these patients, and metformin accumulation was monitored in 10 patients before and after their exposure to CM. RESULTS: Linear response (r ≥ 0.998) was observed over the range of 5-2000 ng/mL of metformin, with the lower limit of quantification of 2.3 ng/mL. The intraday and interday precision (relative standard deviation) values were <13%, and the accuracy (relative error) was <-10% for metformin concentrations. The assay was sensitive to follow the pharmacokinetics of metformin in humans during a dosing interval after an oral dose at steady state. Metformin pharmacokinetic parameters were estimated in 8 patients exposed to CM. The mean C(max) of 1.9 ± 0.6 mg/L was attained at 4.1 ± 1.9 hours. There was no evidence of any drug accumulation or altered elimination due to the exposure to CM in the current population. ClCr showed no significant difference (P > 0.05) before (92.8 ± 11.3 mL/min) and after 48 hours (90.5 ± 10.5 mL/min) of exposure to CM. CONCLUSIONS: Our data suggest that the recommendation to withhold metformin in diabetic patients during CM exposure could be revised to withholding the drug only in patients with moderate to severe renal dysfunction.

The effect of chronic cadmium exposure on the pharmacokinetics of theophylline and ciprofloxacin in rats.

Cadmium has been associated with a number of adverse health effects but the impact of those effects on the pharmacokinetics of different drugs has not been investigated. Therefore, the pharmacokinetics of theophylline and ciprofloxacin were studied in cadmium-exposed and control rats (72 rats) following i.p. (6.5mg/kg) and p.o. (10mg/kg) administration, respectively. The third-generation offsprings of rats exposed to 100 microg/mL of cadmium chloride in drinking water were used in this study. Following 8 weeks of exposure, animals received the drugs as a single dose. Blood samples were withdrawn at different time-points and the plasma concentrations of both drugs were analyzed by HPLC. The pharmacokinetic parameters of theophylline and ciprofloxacin were altered significantly in the cadmium-exposed animals. For theophylline, a statistically significant increase (p<0.0001) in C(max) (69%) and AUC(0-)(infinity) (68%) of theophylline in the cadmium-exposed rats as compared to the control were observed. A corresponding significant (p<0.0001) reduction of 41% in clearance (CL/F) of theophylline was detected in the exposed group. Neither the half-life nor the mean residence time (MRT) showed any significant change due to the exposure to cadmium. For ciprofloxacin, no significant difference was seen in the C(max) of the exposed group as compared to the control animals. However, a delay in T(max) was observed in the exposed group (from 0.16(+/-0.003) to 0.37(+/-0.14)h). A small, but significant increase in t(1/2) (p<0.05) was detected (1.74(+/-0.25) vs. 1.45(+/-0.12)h). A significant reduction (p<0.05) of CL/F from 30.54(+/-1.9) to 24.01(+/-3.81)mL/min/kg was seen in the treated group. The current investigation showed that chronic exposure to cadmium could have a very significant impact on altering the pharmacokinetic parameters of various drugs. Therefore, in cadmium-polluted areas, dose adjustments and drug monitoring, especially for drugs with a narrow therapeutic window, should be carried out.

Oral administration of amphotericin B nanoparticles: antifungal activity, bioavailability and toxicity in rats.

Amphotericin B (AMB) is used most commonly in severe systemic life-threatening fungal infections. There is currently an unmet need for an efficacious (AMB) formulation amenable to oral administration with better bioavailability and lower nephrotoxicity. Novel PEGylated polylactic-polyglycolic acid copolymer (PLGA-PEG) nanoparticles (NPs) formulations of AMB were therefore studied for their ability to kill Candida albicans (C. albicans). The antifungal activity of AMB formulations was assessed in C. albicans. Its bioavalability was investigated in nine groups of rats (n = 6). Toxicity was examined by an in vitro blood hemolysis assay, and in vivo nephrotoxicity after single and multiple dosing for a week by blood urea nitrogen (BUN) and plasma creatinine (PCr) measurements. The MIC of AMB loaded to PLGA-PEG NPs against C. albicans was reduced two to threefold compared with free AMB. Novel oral AMB delivery loaded to PLGA-PEG NPs was markedly systemically available compared to Fungizone® in rats. The addition of 2% of GA to the AMB formulation significantly (p < 0.05) improved the bioavailability from 1.5 to 10.5% and the relative bioavailability was > 790% that of Fungizone®. The novel AMB formulations showed minimal toxicity and better efficacy compared to Fungizone®. No nephrotoxicity in rats was detected after a week of multiple dosing of AMB NPs based on BUN and PCr, which remained at normal levels. An oral delivery system of AMB-loaded to PLGA-PEG NPs with better efficacy and minimal toxicity was formulated. The addition of glycyrrhizic acid (GA) to AMB NPs formulation resulted in a significant oral absorption and improved bioavailability in rats.

Stereoselective HPLC assay of donepezil enantiomers with UV detection and its application to pharmacokinetics in rats.

This investigation describes a new precise, sensitive and accurate stereoselective HPLC method for the simultaneous determination of donepezil enantiomers in tablets and plasma with enough sensitivity to follow its pharmacokinetics in rats up to 12h after single oral dosing. Enantiomeric resolution was achieved on a cellulose tris (3,5-dimethylphenyl carbamate) column known as Chiralcel OD, with UV detection at 268 nm, and the mobile phase consisted of n-hexane, isopropanol and triethylamine (87:12.9:0.1). Using the chromatographic conditions described, donepezil enantiomers were well resolved with mean retention times of 12.8 and 16.3 min, respectively. Linear response (r > 0.994) was observed over the range of 0.05-2 microg/ml of donepezil enantiomers, with detection limit of 20 ng/ml. The mean relative standard deviation (R.S.D.%) of the results of within-day precision and accuracy of the drug were < or =10%. There was no significant difference (p > 0.05) between inter- and intra-day studies for each enantiomers which confirmed the reproducibility of the assay method. The mean extraction efficiency was 92.6-93.2% of the enantiomers. The proposed method was found to be suitable and accurate for the quantitative determination of donepezil enantiomers in tablets. The assay method also shows good specificity to donepezil enantiomers, and it could be successfully applied to its pharmacokinetic studies and to therapeutic drug monitoring.

In vitro performance of carbamazepine loaded to various molecular weights of poly (D,L-lactide-co-glycolide).

The purpose of this study was to develop and assess the in vitro characteristics of carbamazepine-loaded microspheres. A solvent evaporation method was used to incorporate carbamazepine (CBZ) into poly (D,L-lactide-co-glycolide) (PLGA) with different molecular weights. The optimum conditions for CBZ-PLGA microspheres preparation were considered and the in vitro release of CBZ of PLGA microspheres were followed up to 24 hr in USP dissolution medium. The effect of using different ratios of PLGA microspheres, prepared with different molecular weights, for optimizing CBZ release also was investigated. CBZ encapsulation efficiency was 68 to 82% for all prepared formulations. Thermograms of CBZ-PLGA microspheres suggest that CBZ was totally entrapped with the PLGA polymer. The presence of Pluronic F-68 has improved the encapsulation of CBZ, resulted in better and smoother microspheres surfaces and enhanced its release pattern. CBZ release profiles were biphasic patterns; after an initial burst, a constant CBZ release rate was observed up to 24 hr. The release from these PLGA-based spherical matrices was consistent with the diffusion mechanism. CBZ dissolution T(50%) was significantly affected (> 3-fold) by increasing the lactide percent from 33.3 to 66.6% from different microspheres mixtures. The present study provides evidence that the encapsulation of CBZ to PLGA microspheres, either as a single polymer or mixture of two, was a successful attempt to control the release of CBZ.

Pharmacokinetics and analgesic effect of ketorolac floating delivery system.

OBJECTIVES: The efficacy of ketorolac tromethamine (KT) floating alginate beads as a drug delivery system for better control of KT release was investigated. The formulation with the highest drug loading, entrapment efficiency, swelling, buoyancy, and in vitro release would be selected for further in vivo analgesic effect in the mice and pharmacokinetics study in rats compared to the tablet dosage form. METHODS: KT floating alginate beads were prepared by extrusion congealing technique. KT in plasma samples was analyzed using a UPLC MS/MS assay. RESULTS: The percentage yield, drug loading and encapsulation efficiency were increased proportionally with the hydroxypropylmethyl cellulose (HPMC) polymer amount in the KT floating beads. A reverse relationship was observed between HPMC amount in the beads and the KT in vitro release rate. F3-floating beads were selected, due to its better in vitro results (continued floating for >8 h) than others. A longer analgesic effect was observed for F3 in fed mice as compared to the tablets. After F3 administration to rats, the Cmax (2.2 ± 0.3 µg/ml) was achieved at ∼2 h and the decline in KT concentration was slower. F3 showed a significant increase in the AUC (1.89 fold) in rats as compared to the tablets. CONCLUSION: KT was successfully formulated as floating beads with prolonged in vitro release extended to a better in vivo characteristic with higher bioavailability in rats. KT in floating beads shows a superior analgesic effect over tablets, especially in fed mice.

Clinical efficacy and pharmacokinetics of antimony in cutaneous leishmaniasis patients treated with sodium stibogluconate.

The efficacy and pharmacokinetics of antimony were explored in 12 young male patients with cutaneous leishmaniasis following intramuscular administration of sodium stibogluconate equivalent to 600 mg of antimony (Sb). Patients' cure rate was evaluated up to 6 weeks after treatment. Blood samples were collected at different time periods on the first and last days of a 3-week treatment. Twenty-four-hour urine samples were also collected on both occasions for the estimation of renal clearance (CL(r)). The blood concentrations of the Sb time profile were best described by a 2-compartment model with a first-order absorption rate. The mean absorption half-life was 0.21 ± 0.023 and 0.36 ± 0.18 hours for the first and last doses, respectively. A rapid distribution phase was followed by a slower elimination phase of a half-life of 9.4 ± 1.9 and 9.69 ± 2.3 hours for both days, respectively. An accumulation index of 2.33 was calculated. The fraction of dose excreted in urine was 0.386 ± 0.11 and 0.326 ± 0.05 on both occasions, respectively. The mean CL(r) was 4.88 ± 1.13 and 4.58 ± 1.05 L/h. In the current study, all of the patients were completely healed by week 6 after the end of treatment, as judged by the treating physician. In conclusion, the blood profile of antimony seems to be multicompartmental in nature.

A validated chiral HPLC method for the determination of mebeverine HCl enantiomers in pharmaceutical dosage forms and spiked rat plasma.

A new, precise, simple and accurate HPLC method was developed for the first time to separate and determine mebeverine enantiomers. Enantiomeric resolution was achieved on a cellulose Tris (3,5-dimethylphenyl carbamate) column known as Chiralcel OD, with UV detection at 263 nm. The mobile phase consisted of n-hexane, isopropyl alcohol and triethylamine (90:9.9:0.1 v/v/v). Sample run time was 18 min. On using the chromatographic conditions described, mebeverine enantiomers were well resolved with mean retention times of about 11 and 14 min. A linear response (r>0.999) was observed over the concentration range 0.5-20 microg/mL racemic mebeverine. Precision, accuracy and stability were studied according to ICH guidelines. The limit of detection was found to be 0.05 microg/mL for each enantiomer of mebeverine. The proposed method was applied for analysis of mebeverine in commercially available tablets dosage formulations. Examples of application to biological samples are also given. Reanalysis of samples several weeks after the initial analysis showed no degradation of mebeverine.

In vitro release and stereoselective disposition of flurbiprofen loaded to poly(D,L-lactide- co-glycolide) nanoparticles in rats.

Flurbiprofen (FL) is a chiral 2-arylpropionate used clinically as the racemate (rac-FL). This study was undertaken to investigate the influence of sustained release formulation on the pharmacokinetics of flurbiprofen enantiomers (-) -R-FL and (+)-S-FL. Therefore, a stereoselective high-performance liquid chromatographic (HPLC) method was developed and validated for the rapid, quantitative determination of (-)-R-FL and (+)-S-FL in rat plasma. Flurbiprofen-loaded poly(D,L-lactide-co-glycolide) nanoparticles (rac-FL-PLGA) were prepared by in emulsion-solvent evaporation technique. Optimum conditions for rac-FL-PLGA nanoparticle preparation were considered, and the in vitro release of rac-FL, R-FL, and S-FL were followed up to 48 h in phosphate buffer (pH 7.4). The three tested formulations revealed approximately zero-order release of either (-)-R-FL or S-FL up to 24 h with r >/= 0.97.Surprisingly, there was no significant difference between t(50%) of the three formulations (21.6 +/- 1.1 h). The stereoselective disposition of the sustained release rac-FL deliverv system was investigated in rats. There was a rapid release of R-FL, S-FL, or rac-FL followed by a slower one and C(max) values were observed after 2.5 +/- 2.5, 8.3 +/- 3.4 and 8.86 +/- 3.6 h of (-)-R-FL, (+)-S-FL, and rac-FL, respectively, after nanoparticle administration. PLGA nanoparticles increased the mean retention time (MRT) of S-FL by 2.7-fold, from 6.8 to 16.3 h, compared to rac-FL. Although the dose of rac-FL-PLGA nanoparticles was only 2.5 times higher than that of the drug in the suspension, the mean (+)-S-FL concentration after 12 h was 3.4 times higher in the case of nanoparticles than after the free form, 10.35 +/- 1.6 and 3.04 +/- 1.1 mg/l, respectively. The area under the concentration-time curve (AUC) values of (+)-S-FL and rac-FL were about 2.5-fold higher after the nanoparticles compared to suspension, while the AUC of the (-)-R-FL was about 3.5 times higher. This difference may indicate that the two enantiomers have different absorption kinetics. The present study provides evidence that the sorption of racemic flurbiprofen to PLGA nanoparticles was successful in maintaining (at least up to 12 h) elevated plasma drug concentrations of (+)-S-FL in rats. Chirality 16:119-125, 2004.

Synthesis, in vitro and in vivo evaluation of a delivery system for targeting anticancer drugs to the brain.

A 1, 4-dihydropyridine <--> pyridinium salt type redox system is described as a general and flexible method for site-specific and sustained delivery of drugs to the brain. This concept was used in the present investigation as a model to deliver an alkylating antitumor agent into the brain. A bis-(chloroethyl)amine drug was hooked to 1, 4-dihydropyridine chemical delivery system (CDS) through an amide linkage. Five new-target compounds (23-27) of the 1, 4-dihydropyridine CDS type were synthesized through the reduction of five new pyridinium quaternary intermediates (18-22). The synthesized 1, 4-dihydropyridines were subjected to various chemical and biological investigations to evaluate their ability to cross the blood-brain barrier (BBB), and to be oxidized biologically into their corresponding quaternary compounds. The in vitro oxidation studies showed that 1-benzyl-3-[N-[2-bis(2-chloroethyl)aminoethyl]-carbamoyl]-1, 4-dihydropyridine (23) and 1-(4-nitrobenzyl)-3-[N-[2-bis(2-chloroethyl)aminoethyl ]carbamoyl]-1, 4-dihydropyridine (27) could be oxidized into their corresponding quaternary compounds 18 and 22 respectively, at an adequate rate, which ensure the release of the carried anticancer drug. The in vivo studies showed that compound 23 was able to cross the BBB at detectable concentrations. On the other hand, the in vitro alkylation activity studies revealed that 1-(4-nitrobenzyl)-3-[N-[2-bis(2-chloroethyl)aminoethyl]carbamoyl]pyridinium bromide (22) is an alkylating agent with activity comparable to the known drug chlorambucil.