Development and validation of a stability-indicating method, structural elucidation of new degradation products from misoprostol by LC-MS time-of-flight, and an ex vivo study of vaginal permeation.

Misoprostol (MSP) is commonly prescribed in obstetrics and gynecology clinical practice for labor induction, cervical ripening, first-trimester pregnancy termination, and the treatment of postpartum hemorrhage. Furthermore, there is a lack of comprehensive discussion evaluating how different commercially available formulations influence the overall efficacy of MSP, even though reports indicate issues with the quality of these formulations, particularly regarding stability and vaginal absorption processes. This study investigates the stability of MSP under acidic conditions and its in vitro permeation using swine vaginal mucosa. A forced degradation study was conducted using 0.2 M HCl, and a high-efficiency LC method was developed. Three degradation products were identified and characterized using electrospray ionization-high-resolution quadrupole-time-of-flight-MS, with respective m/z values of 391.2508, 405.2705, and 387.2259, respectively. These results suggest that the degradation mechanism involves dehydration of the ß-hydroxy ketone moiety, followed by isomerization to its most resonance-stable form and de-esterification. Finally, the in vitro permeation study revealed that the esterified form of MSP was unable to permeate the mucosa and required prior degradation for any component to be detected in the receptor fluid.

Development of the stability-indicating method, structural elucidation of new photodegradation products from terconazole by LC-MS TOF, and in vitro toxicity.

Terconazole (TCZ) was the first triazole antifungal drug launched in the market and has been used in the treatment of vulvovaginal candidiasis. It is also indicated to treat dermatophytosis and fungal ocular infections. However, some of the degradation products from triazole drugs have been reported to be toxic, justifying the need of further investigations about the stability of TCZ. identification of its degradation products and evaluation of their toxicity considering the new possibilities of therapeutic indications. Therefore, in this work a systematic investigation regarding photostability of TCZ was conducted. The active pharmaceutical ingredient (API) and its methanolic solution (100 µg mL-1) were kept into a photostability chamber under a UV light (200 Wh/m2; 1.2 × 106 lux/h) during 5 days and 90 min, respectively. A high-efficiency liquid chromatography method was developed for separation and identification of TCZ and its degradation products. The solid-state API remained stable throughout the test, whereas an extensive degradation was observed when in solution. In this case, four degradation products not yet reported in the literature were identified and characterized by electrospray ionization high-resolution quadrupole time-of-flight mass spectrometry (ESI-QTOF-MS). Two degradation products presented m/z of 498 and the other two of 496 and 464, respectively. The results suggest that the degradation follows a first-order kinetic and involves the loss of chlorine atoms from the 2,4-dichlrophenyl moiety. Finally, TCZ submitted to the same stress condition as the API solution, increased significantly the opacity during the bovine corneal opacity and permeability test method (BCOP) indicating a potential to cause ocular toxicity. Further studies using the pure photolysis degradation products of TCZ characterized in this work are still necessary to confirm this find.

Population Pharmacokinetic Model of Piperacillin in Critically Ill Patients and Describing Interethnic Variation Using External Validation.

Objectives: This study aimed to develop a piperacillin population PK model for critically ill Brazil-ian patients and describe interethnic variation using an external validation. Methods: Plasma samples were obtained from 24 ICU patients during the fifth day of piperacillin treatment and assayed by HPLC-UV. Population pharmacokinetic modelling was conducted using Pmetrics. Empiric dose of 4 g IV 6- and 8-hourly were simulated for 50 and 100% fT > MIC and the probabil-ity of target attainment (PTA) and the fractional target attainment (FTA) determined. Results: A two-compartment model was designed to describe the pharmacokinetics of critically ill Brazillian patients. Clearance and volume of distribution were (mean ± SD) 3.33 ± 1.24 L h−1 and 10.69 ± 4.50 L, respectively. Creatinine clearance was positively correlated with piperacillin clearance and a high creatinine clearance was associated with lower values of PTA and FTA. An external vali-dation was performed using data from two different ethnic ICU populations (n = 30), resulting in acceptable bias and precision. Conclusion: The primary pharmacokinetic parameters obtained from critically ill Brazilian patients were similar to those observed in studies performed in critically ill patients of other ethnicities. Based on our results, the use of dose adjustment based on creati-nine clearance is required in Brazilian patients.

Selective LC-MS/MS determination of citalopram enantiomers and application to a pharmacokinetic evaluation of generic and reference formulations.

Two methods using LC-MS/MS were validated to quantify citalopram (CTP) racemate [(R/S)-CTP] and the enantiomers (R)-CTP and (S)-CTP in human plasma, respectively. Paroxetine hydrochloride was used as the internal standard, and samples were extracted by protein precipitation with acetonitrile. The non-enantioselective method was conducted using a C18 column, and the mobile phase consisted of water for solvent A and acetonitrile for solvent B, both with 0.1% formic acid. For the chiral method, an analytical column Lux Cellulose-1 was used. Mobile phase A was composed of water with 0.025% of formic acid and 0.05% of diethylamine, and mobile phase B consisted of acetonitrile:2-propanol (95:5, v/v). No significant matrix effects were observed at the retention times of analytes and internal standard. The mean recovery was 89%, and the assays were linear in the concentration range of 1-50 and 5-30 ng/mL for the non-enantioselective and enantioselective methods, respectively. The intra- and inter-day precisions of both methods were less than 12.30%, and the accuracies were less than 12.13%. The validated methods were successfully applied to a pharmacokinetic study in which 20-mg CTP tablets were administered to healthy volunteers, and their plasma levels were monitored over time in a bioequivalence study. HIGHLIGHTS: Simple and rapid LC-MS/MS method for the quantification of citalopram and its enantiomers in human plasma. Both methods were demonstrated to be selective, reliable, and sensitive. Both methods have sufficient sensitivity to quantify the steady state through concentrations already reported for citalopram and escitalopram. Validated method presented in this study can be suitably applied to pharmacokinetic studies involving citalopram and escitalopram. Bland-Altman analysis suggested that non-enantioselective and enantioselective methods can be applied in pharmacokinetic studies.

Dehydrobufotenin extracted from the Amazonian toad Rhinella marina (Anura: Bufonidae) as a prototype molecule for the development of antiplasmodial drugs.

BACKGROUND: The resistance against antimalarial drugs represents a global challenge in the fight and control of malaria. The Brazilian biodiversity can be an important tool for research and development of new medicinal products. In this context, toxinology is a multidisciplinary approach on the development of new drugs, including the isolation, purification, and evaluation of the pharmacological activities of natural toxins. The present study aimed to evaluate the cytotoxicity, as well as the antimalarial activity in silico and in vitro of four compounds isolated from Rhinella marina venom as potential oral drug prototypes. METHODS: Four compounds were challenged against 35 target proteins from P. falciparum and screened to evaluate their physicochemical properties using docking assay in Brazilian Malaria Molecular Targets (BraMMT) software and in silico assay in OCTOPUS® software. The in vitro antimalarial activity of the compounds against the 3D7 Plasmodium falciparum clones were assessed using the SYBR Green I based assay (IC50). For the cytotoxic tests, the LD50 was determined in human pulmonary fibroblast cell line using the [3(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide] (MTT) assay. RESULTS: All compounds presented a ligand-receptor interaction with ten Plasmodium falciparum-related protein targets, as well as antimalarial activity against chloroquine resistant strain (IC50 = 3.44 µM to 19.11 µM). Three of them (dehydrobufotenine, marinobufagin, and bufalin) showed adequate conditions for oral drug prototypes, with satisfactory prediction of absorption, permeability, and absence of toxicity. In the cell viability assay, only dehydrobufotenin was selective for the parasite. CONCLUSIONS: Dehydrobufotenin revealed to be a potential oral drug prototype presenting adequate antimalarial activity and absence of cytotoxicity, therefore should be subjected to further studies.

Validation of a HPLC method for quantification of midazolam in rat plasma: Application during a Maytenus ilicifolia-drug interaction study.

Midazolam (MDZ) is routinely employed as a marker compound of cytochrome P450 3A (CYP3A) activity. Despite the many HPLC-UV methods described to quantify MDZ in plasma, all of them use acetonitrile (ACN) or a mixture of methanol-isopropanol as organic solvent of the mobile phase. Since the ACN shortage in 2008, efforts have been made to replace this solvent during HPLC analysis. A simple, sensitive, accurate and repeatable HPLC-UV method (220 nm) was developed and validated to quantify MDZ in rat plasma using methanol instead. The method was applied during a herb-drug interaction study involving Maytenus ilicifolia, a Brazilian folk medicine used to treat gastric disorders. Plasma samples were alkalinized and MDZ plus alprazolam (internal standard) were extracted with diethyl ether. After solvent removal, the residue was reconstituted with methanol-water (1:1). The analyte was eluted throughout a C18 column using sodium acetate buffer (10 mm, pH 7.4)-methanol (40:60, v/v). The precision at the lower limit of quantification never exceeded 19.40%, and 13.86% at the higher levels of quality control standards, whereas the accuracy ranged from -19.81 to 14.33%. The analytical curve was linear from 50 to 2,000 ng/ml. The activity of the hepatic CYP3A enzymes was not affected by the extract.

Evaluation of the Effects of Maytenus ilicifolia on the Activities of Cytochrome P450 3A and P-glycoprotein.

BACKGROUND: Maytenus ilicifolia is a Brazilian popular medicine commonly used to treat ulcer and gastritis. Despite the absence of toxicity regarding its consumption, possible interactions when co-administrated with conventional drugs, are unknown. OBJECTIVE: This study aimed to evaluate the effects of M. ilicifolia extracts on Cytochrome P450 3A (CYP3A) and P-glycoprotein (P-gp) activities. METHODS: The extracts were obtained by infusion (MI) or turbo-extraction using hydro-acetonic solvent (MT70). The content of polyphenols in each extract was determined. To assess the modulation of M. ilicifolia on P-gp activity, the uptake of fexofenadine (FEX) by Caco-2 cells was investigated in the absence or presence of MI or MT70. The effect on CYP3A activity was evaluated by the co-administration of midazolam (MDZ) with each extract in male Wistar rats. The pharmacokinetic parameters of the drug were determined and compared with those from the control group. The content of total phenolic compounds, tannins, and flavonoids on MT70 extract was about double of that found in MI. RESULTS: In the presence of the extracts, the uptake of the P-gp marker (FEX) by Caco-2 cells increased from 1.7 ± 0.4 ng.mg-1 protein (control) to 3.5 ± 0.2 ng.mg-1 protein (MI) and 4.4 ± 0.5 ng.mg-1 protein (MT70), respectively. When orally co-administrated with MDZ (substrate of CYP3A), the extracts augmented the AUC(0-∞) (Control: 911.7 ± 215.7 ng.h.mL-1; MI: 1947 ± 554.3 ng.h.mL-1; MT70: 2219.0 ± 506.3 ng.h.mL-1) and the Cmax (Control: 407.7 ± 90.4 ng.mL-1; MI: 1770.5 ± 764.5 ng.mL-1; MT70: 1987.2 ± 544.9 ng.mL-1) of the drug in rats indicating a 50% reduction of the oral Cl. No effect was observed when midazolam was given intravenously. CONCLUSION: The results suggest that M. ilicifolia can inhibit the intestinal metabolism and transport of drugs mediated by CYP3A and P-gp, respectively, however, the involvement of other transporters and the clinical relevance of such interaction still need to be clarified.

Validated spectrophotometric method for quantification of total triterpenes in plant matrices.

BACKGROUND: Triterpenes are ubiquitous secondary metabolites present in plants. They can be found in both forms, as genins or conjugated as glycosides. Although distinct analytical methods to quantify these compounds in vegetal tissues are available in the literature, limitations like high cost, complexity on sample preparation, and selectivity are often challenging issues. This study aimed to develop and to validate a simple and rapid spectrophotometric method to detect and quantify total triterpenes in plant matrices. METHODS: The assay was conducted directly into glass tubes using vanillin, acetic acid, and sulphuric acid as reagents, and ß-sitosterol as reference standard. The samples were analyzed at 548 nm assessing the quality parameters of selectivity, linearity, precision, accuracy, limit of detection (LOD), limit of quantification (LOQ), and robustness. RESULTS: The method was selective, with precision and accuracy varying from 0.56% to 4.98% and 96.63% to 113.87%, respectively. The values of the limit of detection and quantification were 0.042 µg.mL-1 and 0.14 µg.mL-1, correspondingly. The correlation coefficient (r) at the concentration range of 3.08 µg.mL-1to 24.61 µg.mL-1 was 0.9998. The total of triterpenes found in of B. holophylla and M. ilicifolia leaves were 132.36 ± 20.36 mg EßS.g-1 of dry extract and 53.91 ± 2.6 mg EßS.g-1 of dry extract, respectively. CONCLUSION: The method was reliable to quantify total triterpenes extracted from Maytenus ilicifolia and Bauhinia holophylla. Graphical abstract.

Improvement of antimalarial activity of a 3-alkylpiridine alkaloid analog by replacing the pyridine ring to a thiazole-containing heterocycle: Mode of action, mutagenicity profile, and Caco-2 cell-based permeability.

The development of new antimalarial drugs is urgent to overcome the spread of resistance to the current treatment. Herein we synthesized the compound 3, a hit-to­lead optimization of a thiazole based on the most promising 3-alkylpyridine marine alkaloid analog. Compound 3 was tested against Plasmodium falciparum and has shown to be more potent than its precursor (IC50 values of 1.55 and 14.7 µM, respectively), with higher selectivity index (74.7) for noncancerous human cell line. This compound was not mutagenic and showed genotoxicity only at concentrations four-fold higher than its IC50. Compound 3 was tested in vivo against Plasmodium berghei NK65 strain and inhibited the development of parasite at 50 mg/kg. In silico and UV-vis approaches determined that compound 3 acts impairing hemozoin crystallization and confocal microscopy experiments corroborate these findings as the compound was capable of diminishing food vacuole acidity. The assay of uptake using human intestinal Caco-2 cell line showed that compound 3 is absorbed similarly to chloroquine, a standard antimalarial agent. Therefore, we present here compound 3 as a potent new lead antimalarial compound.

Systematic evaluation of the impact of solid-state polymorphism on the bioavailability of thalidomide.

Thalidomide (TLD) is used to treat erythema nodosum leprosum (ENL), multiple myeloma, aphthous ulceration and wasting syndrome in HIV patients. The API can be found in two crystalline habits known as α-TLD and ß-TLD. The saturation solubility (Cs) and the dissolution profiles under non-sink and sink conditions of both polymorphs were assessed. In addition, mini-capsules containing α-TLD or ß-TLD without excipients were orally given (10 mg/kg) to Wistar rats. An intravenous (i.v.) dose was also administrated (5 mg/kg). The Cs values for α-TLD and ß-TLD were not significantly different (α = 56.2 ±â€¯0.5 µg·mL-1; ß = 55.2 ±â€¯0.2 µg·mL-1). However, the dissolution profile of α-TLD presented the fastest rate and the largest extension of drug dissolution than that from ß-TLD (80% in 4 h versus 55% in 4 h). The α-TLD provided a more favorable pharmacokinetic than the ß-TLD (maximum plasma concentration - Cmax: 5.4 ±â€¯0.90 µg·mL-1versus 2.6 ±â€¯0.2 µg·mL-1; area under the curve of the concentration-time profile from time zero to infinity - AUC0-∞: 44.3 ±â€¯8.8 µg·h·mL-1versus 33.9 ±â€¯4.7 µg·h·mL-1; absolute bioavailability - F: 92.2 ±â€¯18.5% versus 70.5 ±â€¯9.9%, respectively). Drug suppliers and pharmaceutical companies should strictly control the technological processes involved in the TLD API synthesis as well as in the production of the pharmaceutical dosage form in order to guarantee the inter-batch homogeneity and therefore, product compliance.

Hollow mesoporous structured molecularly imprinted polymer as adsorbent in pipette-tip solid-phase extraction for the determination of antiretrovirals from plasma of HIV-infected patients.

In this work a hollow mesoporous structured molecularly imprinted polymer was synthetized and used as adsorbent in pipette-tip solid-phase extraction for the determination of lamivudine (3TC), zidovudine (AZT) and efavirenz (EFZ) from plasma of human immunodeficiency virus (HIV) infected patients by high-performance liquid chromatography (HPLC). All parameters that influence the recovery of the pipette tip based on hollow mesoporous molecularly imprinted polymer solid-phase extraction (PT-HM-MIP-SPE) method were systematically studied and discussed in detail. The adsorbent material was prepared using methacrylic acid and 4-vinylpyridine as functional monomers, ethylene glycol dimethacrylate as crosslinker, acetonitrile as solvent, 4,4'-azobis(4-cyanovaleric acid) as radical initiator, benzalkonium chloride as surfactant, 3TC, and AZT as templates. The simultaneous separation of 3TC, AZT and EFZ by HPLC-UV was performed using a Gemini C18 Phenomenex® column (250 mm × 4.6 mm, 5 µm) and mobile phase consisting of acetonitrile: water pH 3.2 (68:32, v/v), flow rate of 1.0 mL/min and λ = 260 nm. The method was linear over the concentration range from 0.25 to 10 µg/mL for 3TC and EFZ, and 0.05 to 2.0 µg mL-1 for AZT, with correlation coefficients larger than 0.99 for all analytes. Recovery ± relative standard deviations (RSDs %) were 41.99 ± 2.38%, 82.29 ± 1.63%, and 83.72 ± 7.52% for 3TC, AZT, and EFZ, respectively. The RSDs and relative errors (REs) were lower than 15% for intra and interday assays. The method has been successfully applied for monitoring HIV-infected patients outside the therapeutic dosage.

Development of spectrophotometric method for iron determination in fortified wheat and maize flours.

The determination of iron in fortified foods is mandatory by many global regulatory agencies. However, the spectroscopic techniques require elevated investments limiting their applicability especially in developing countries. Therefore, simple, viable and analytical methods with sufficient sensitivity can become an alternative. In this work, a sensitive, simple and viable spectrophotometry method to determine iron in wheat and maize flours was developed following a cloud point extraction (CPE) procedure. The analyte was first complexed with 2-(5-Bromine-2-pyridylazo)-5-diethylaminophenol (Br-PADAP) in the presence of the surfactant octylphenoxypolyethoxyethanol (Triton X-114). For the CPE optimization the variables: pH of the medium, stoichiometry of the complex, surfactant, and salt concentrations were evaluated. Linearity in the analytical blank was obtained by using the square root of absorbance (Abs) in order to adjust the residues of the curve. The precision was lower than 5% and the accuracy ranged from 97 to 101%. The limits of detection and quantification were 0.004µgmL-1 and 0.01µgmL-1, respectively. The method was applied to investigate the content of iron in 14 brands of fortified flours. The concentrations of iron varied from 0.435 to 3.62mg/100g and 0.570 to 3.15mg/100g in wheat and maize flour, respectively. The content of iron in all brands investigated in this study was approximately 10-fold lower than the value required by (ANVISA). The amount of iron in fortified foods was satisfactorily determined by using a simple, sensitive, and low cost spectrophotometric method.

Determining the optimal vancomycin daily dose for pediatrics: a meta-analysis.

OBJECTIVE: The objective of this study was to check which initial dose of vancomycin is needed to achieve the therapeutic target that is currently used in pediatrics. METHODS: The search was conducted in the following data sources: Pubmed (1980-2017), the Cochrane Library, and Embase (1986-2017) and the references of the published studies; searches were performed using the key terms: child, children, pediatrics, infants and adolescents, vancomycin, pharmacokinetics, and pharmacodynamics. The data extracted from the studies were analyzed and grouped using RevMan V 5.2 software. The confidence interval (CI) 95% and the odds ratio (OR) were calculated considering the Mantel-Haenszel random effect. RESULTS: From the 704 studies identified, 40 revealed eligibility for this review and only 20 presented enough data to be included in the statistical analysis. The articles found in this review were published between 1980 and 2017. The vancomycin doses varied between 40 mg/kg/day to 120 mg/kg/day. The statistical tests demonstrated significant clinical heterogeneity of I2 (84%). CONCLUSIONS: The meta-analysis study revealed in the majority of studies that doses lower than 60 mg/kg/day were not enough to achieve desirable vancomycin plasma concentrations "area under the curve in 24 h/minimum inhibitory concentration >400 (AUC0-24/MIC>400) or trough 10-20 mg/L" to control bacterial infections in pediatrics.

Simultaneous Semimechanistic Population Analyses of Levofloxacin in Plasma, Lung, and Prostate To Describe the Influence of Efflux Transporters on Drug Distribution following Intravenous and Intratracheal Administration.

Levofloxacin (LEV) is a broad-spectrum fluoroquinolone used to treat pneumonia, urinary tract infections, chronic bacterial bronchitis, and prostatitis. Efflux transporters, primarily P-glycoprotein (P-gp), are involved in LEV's tissue penetration. In the present work, LEV free lung and prostate interstitial space fluid (ISF) concentrations were evaluated by microdialysis in Wistar rats after intravenous (i.v.) and intratracheal (i.t.) administration (7 mg/kg of body weight) with and without coadministration of the P-gp inhibitor tariquidar (TAR; 15 mg/kg administered i.v.). Plasma and tissue concentration/time profiles were evaluated by noncompartmental analysis (NCA) and population pharmacokinetics (popPK) analysis. The NCA showed significant differences in bioavailability (F) for the control group (0.4) and the TAR group (0.86) after i.t. administration. A four-compartment model simultaneously characterized total plasma and free lung (compartment 2) and prostate (compartment 3) ISF concentrations. Statistically significant differences in lung and prostate average ISF concentrations and levels of kidney active secretion in the TAR group from those measured for the control group (LEV alone) were observed. The estimated population means were as follows: volume of the central compartment (V1), 0.321 liters; total plasma clearance (CL), 0.220 liters/h; TAR plasma clearance (CLTAR), 0.180 liters/h. The intercompartmental distribution rate constants (K values) were as follows: K12, 8.826 h(-1); K21, 7.271 h(-1); K13, 0.047 h(-1); K31, 7.738 h(-1); K14, 0.908 h(-1); K41, 0.409 h(-1); K21 lung TAR (K21LTAR), 8.883 h(-1); K31 prostate TAR (K31PTAR), 4.377 h(-1). The presence of P-gp considerably impacted the active renal secretion of LEV but had only a minor impact on the efflux from the lung following intratracheal dosing. Our results strongly support the idea of a role of efflux transporters other than P-gp contributing to LEV's tissue penetration into the prostrate.

Determination of fexofenadine in Hank's balanced salt solution by high-performance liquid chromatography with ultraviolet detection: application to Caco-2 cell permeability studies.

The drug-transporting proteins can affect the pharmacokinetics and pharmacodymanics of many drugs, resulting in an erratic and unpredictable pharmacological response. The Caco-2 monolayer is routinely applied to investigate the carrier-mediated transport of drugs. Therefore, the selection of a marker compound able to characterize the activity of such transporters is crucial. Fexofenadine (FEX), a P-gp/OATP substrate, can be considered a suitable probe. However, in order to use be used as a marker compound, it is mandatory to develop an analytical method able to quantify this drug during the in vitro permeability assay. An HPLC method with ultraviolet detection was developed; the mobile phase consisted of phosphate buffer (pH 3.2) containing 10 m m of sodium octanosulphonate and acetonitrile (60:40) and the flow rate was set at 1.2 mL/min. Fexofenadine was eluted at 40°C, the retention time was about 4.6 min. The LOD and LOQ values were 1.9 and 6.2 ng/mL, respectively. Verapamil and ketoconazole, the most common P-gp inhibitors, were eluted as distinct peaks of that corresponding to fexofenadine The method was successfully applied to quantify the amount of FEX transported across the Caco-2 monolayer and could be an additional tool for those investigating the role of membrane transporters on drug absorption.

Evaluation of the pharmacokinetics and ocular tolerance of a microemulsion containing tacrolimus.

PURPOSE: Tacrolimus is a potent immunosuppressive agent with limited corneal penetration. Microemulsions can increase the drug solubility and enhance drug absorption in the eye. This work aimed to develop a tacrolimus microemulsion as well as to characterize and to evaluate its ocular tolerance and pharmacokinetics after topical application in rabbits. METHODS: The microemulsion was prepared by the titration with the cosurfactant technique and its physical-chemical parameters and stability were determined. The cytotoxicity was evaluated using the corneal epithelium and conjunctiva cell lines. The ocular pharmacokinetic parameters in rabbits were determined and compared with that obtained after instillation of tacrolimus suspension. RESULTS: The microemulsion containing tacrolimus was successfully developed. It was nonirritating to rabbits' eyes and it was also not toxic to the corneal and conjunctival cells. When compared to the suspension, the microemulsion containing tacrolimus presented higher values of AUC (2,912.5±245.4 min.ng/mL vs. 1,669.8±93 min.ng/mL) and Cmax (26.8±2.3 ng/mL vs. 20.7±2.8 ng/mL). On the other hand, the Cl/F value was smaller when compared to the suspension that may decrease the number of applications of eye drops. CONCLUSION: The developed microemulsion could be an alternative to reduce the systemic adverse effects of tacrolimus and, consequently, increase the patient compliance to the treatment.

Peritoneal dialysis and inflammation.

Peritoneal dialysis (PD) is a kidney replacement therapy for end stage renal disease (ESRD) patients. Despite being a lifesaving treatment, the rate of mortality in patients under PD is elevated, mainly due to the chronic peritoneal dysfunction which is characterized by inflammation, peritoneal fibrosis and neoangiogenesis. The inflammatory process is trigged and modulated by the type of the peritoneal dialysis solutions (PDSs) used during PD. Currently, different PDSs are commercially available: (i) the conventional solutions; (ii) solutions of neutral pH containing low concentration of glucose degradation products (GDPs); (iii) solutions with icodextrin; and (iv) solutions containing taurine. Therefore, the aim of this review is to describe the different types of peritoneal dialysis solutions used during PD and their relationship with systemic and intraperitoneal inflammation. Some studies suggested that solutions of neutral pH containing low concentration of GDPs, icodextrin and taurine have better biocompatibility and lower influence on the inflammatory process compared to the conventional one. On the other hand, the studies, in general, were performed with a small population and for a short period of time. Therefore, further well-designed and -controlled clinical trials with larger number of individuals are required in order to better understand the role of different peritoneal dialysis solution types in the development of inflammation in patients with chronic peritoneal dialysis. Accordingly, studies that are more well-designed, well-controlled and with a larger number of patients are needed to explain and define the role of different types of PDS in the inflammation development in patients with chronic peritoneal dialysis.

Effect of experimentally induced hypovolemia on ertapenem tissue distribution using microdialysis in rats.

Hypovolemia is a common event in critical care patients that may affect drug distribution and elimination. In order to better understand this issue the effect of hypovolemia on the plasma protein binding and tissue distribution of ertapenem was investigated in rats using microdialysis. Microdialysis probes were inserted into the jugular vein and hind leg muscle. Ertapenem recoveries in muscle and blood were determined in each rat by retrodialysis by drug before drug administration. Hypovolemia was induced in 6 rats by removing 40% of the initial blood volume over 30 min. Ertapenem was infused intravenously at a dose of 40 mg kg(-1) over 30 min, and microdialysis samples were collected for 310 min. The unbound concentration profiles in muscle and blood were virtually superimposed in both groups except at early time points. The ratios of the area under the concentration-time curve (AUC) for tissue to the AUC for blood were 0.7±0.2 and 0.8±0.2 for control and hypovolemic rats, respectively. Hypovolemia induced a 40% decrease in the clearance of ertapenem, with no statistically significant alteration of its volume of distribution. This study showed that ertapenem elimination was altered in hypovolemic rats, probably due to decreased renal blood flow, but its distribution characteristics were not. Unbound concentrations of ertapenem in blood and muscle were always virtually identical.

Relative contributions of active mediated transport and passive diffusion of fluoroquinolones with various lipophilicities in a Calu-3 lung epithelial cell model.

The transport characteristics of six fluoroquinolones (FQs) with various lipophilicities were compared in a Calu-3 cell model. For each FQ, an active polarized transport was observed in the direction of the apical side. However, the apparent permeability of FQs resulted from active transport and passive diffusion that were highly variable between compounds and mainly governed by lipophilicity. Therefore, active transport was predominant for compounds with relatively low lipophilicity but minor for FQs with higher lipophilicity.

P-glycoprotein-mediated transport of moxifloxacin in a Calu-3 lung epithelial cell model.

Moxifloxacin (MXF) is a fluoroquinolone antibiotic that is effective against respiratory infections. However, the mechanisms of MXF lung diffusion are unknown. Active transport in other tissues has been suggested for several members of the fluoroquinolone family. In this study, transport of MXF was systematically investigated across a Calu-3 lung epithelial cell model. MXF showed polarized transport, with the secretory permeability being twice as high as the absorptive permeability. The secretory permeability was concentration dependent (apparent P(max) = 13.6 x 10(-6) cm x s(-1); apparent K(m) = 147 microM), suggesting saturated transport at concentrations higher than 350 microg/ml. The P-glycoprotein inhibitor PSC-833 inhibited MXF transport in both directions, whereas probenecid, a multidrug resistance-related protein inhibitor, appeared to have no effect in the Calu-3 model. Moreover, rifampin, a known inducer of efflux transport proteins, upregulated the expression of P-glycoprotein in Calu-3 cells and enhanced MXF active transport. In conclusion, this study clearly indicates that MXF is subject to P-glycoprotein-mediated active transport in the Calu-3 model. This P-glycoprotein-dependent secretion may lead to higher MXF epithelial lining fluid concentrations than those in plasma. Furthermore, drug-drug interactions may be expected when MXF is combined with other P-glycoprotein substrates or modulators.