Prediction of Human Disproportionate and Biliary Excreted Metabolites Using Chimeric Mice with Humanized Liver.

The PXB-mouse is potentially a useful in vivo model to predict human hepatic metabolism and clearance. Four model compounds, [14C]desloratadine, [3H]mianserin, cyproheptadine, and [3H]carbazeran, all reported with disproportionate human metabolites, were orally administered to PXB- or control SCID mice to elucidate the biotransformation of each of them. For [14C]desloratadine in PXB-mice, O-glucuronide of 3-hydroxydesloratadine was observed as the predominant metabolite in both the plasma and urine. Both 3-hydroxydesloratadine and its O-glucuronide were detected as major drug-related materials in the bile, whereas only 3-hydroxydesloratadine was detected in the feces, suggesting that a fraction of 3-hydroxydesloratadine in feces was derived from deconjugation of its O-glucuronide by gut microflora. This information can help understand the biliary clearance mechanism of a drug and may fill the gap in a human absorption, distribution, metabolism, and excretion study, in which the bile samples are typically not available. The metabolic profiles in PXB-mice were qualitatively similar to those reported in humans in a clinical study in which 3-hydroxydesloratadine and its O-glucuronide were major and disproportionate metabolites compared with rat, mouse, and monkey. In the control SCID mice, neither of the metabolites was detected in any matrix. Similarly, for the other three compounds, all human specific or disproportionate metabolites were detected at a high level in PXB-mice, but they were either minimally observed or not observed in the control mice. Data from these four compounds indicate that studies in PXB-mice can help predict the potential for the presence of human disproportionate metabolites (relative to preclinical species) prior to conducting clinical studies and understand the biliary clearance mechanism of a drug. SIGNIFICANCE STATEMENT: Studies in PXB-mice have successfully predicted the human major and disproportionate metabolites compared with preclinical safety species for desloratadine, mianserin, cyproheptadine, and carbazeran. In addition, biliary excretion data from PXB-mice can help illustrate the human biliary clearance mechanism of a drug.

Efficacy and Pharmacokinetic Considerations of Loratadine Nanoformulations and its Combinations for Pancreatic Cancer Chemoprevention.

PURPOSE: Pancreatic cancer (PC) is predicted to become the second leading cause of cancer associated deaths by 2020. Earlier, we confirmed the development and efficacy of our novel Loratadine Self-Microemulsifying-Drug-Delivery-System - Sulforaphane (LOR SMEDDS -SFN) nanoformulation in PC chemoprevention. In this report, we extend our studies to evaluate the PC chemoprevention efficacy of LOR SMEDDS - SFN. METHODS: The nanoformulation was subjected to in vitro colony formation assays, in vivo oral pharmacokinetics and stability studies. RESULTS: The colony formation assay using Panc-1 PC cells demonstrated a survival fraction of 0.74 with LOR-SFN (p < 0.001) which further reduced to 0.35 with LOR SMEDDS-SFN treatment (p < 0.0001) confirming the synergistic chemoprevention efficacy of the nanoformulation. Further, the oral pharmacokinetic studies of LOR SMEDDS-SFN showed 4-fold and 9-fold increase in Cmax (503.2 ± 5.8 ng/mL) and oral bioavailability (20,274.8 ± 3711.0 ng·h/mL) for LOR compared to LOR-SFN combination respectively assuring the enhanced performance by the SMEDDS. Additionally, the formulation exhibited statistically non-significant alteration in globule size, zeta potential, drug content and in vitro drug release during stability studies confirming its stability and pharmaceutical acceptability. CONCLUSION: Our studies have demonstrated a potential of LOR SMEDDS-SFN nanoformulation as an effective PC chemoprevention strategy.

Effect of taste masking technology on fast dissolving oral film: dissolution rate and bioavailability.

Fast dissolving oral film is a stamp-style, drug-loaded polymer film with rapid disintegration and dissolution. This new kind of drug delivery system requires effective taste masking technology. Suspension intermediate and liposome intermediate were prepared, respectively, for the formulation of two kinds of fast dissolving oral films with the aim of studying the effect of taste masking technology on the bioavailability of oral films. Loratadine was selected as the model drug. The surface pH of the films was close to neutral, avoiding oral mucosal irritation or side effects. The thickness of a 2 cm × 2 cm suspension oral film containing 10 mg of loratadine was 100 µm. Electron microscope analysis showed that liposomes were spherical before and after re-dissolution, and drugs with obvious bitterness could be masked by the encapsulation of liposomes. Dissolution of the two films was superior to that of the commercial tablets. Rat pharmacokinetic experiments showed that the oral bioavailability of the suspension film was significantly higher than that of the commercial tablets, and the relative bioavailability of the suspension film was 175%. Liposomal film produced a certain amount of improvement in bioavailability, but lower than that of the suspension film.

When Hydromorphone Is Not Working, Try Loratadine: An Emergency Department Case of Loratadine as Abortive Therapy for Severe Pegfilgrastim-Induced Bone Pain.

BACKGROUND: Intractable bone pain is a notorious adverse effect of granulocyte-colony stimulating factors (G-CSFs), such as pegfilgrastim and filgrastim, which are given to help prevent neutropenia in patients who are undergoing chemotherapy. G-CSF-induced bone pain is surprisingly common and often refractory to treatment with conventional analgesics. CASE REPORT: This article describes an emergency department case of opiate and nonsteroidal anti-inflammatory drug-resistant pegfilgrastim-induced bone pain that was successfully alleviated with 10 mg of oral loratadine, allowing for discharge home. WHY SHOULD AN EMERGENCY PHYSICIAN BE AWARE OF THIS?: This case suggests that loratadine may be an easy to implement, safe, and effective therapy in the emergency department management of intractable bone pain caused by G-CSF use. Emergency physicians should be aware that loratadine may successfully relieve otherwise intractable G-CSF-induced bone pain and allow for discharge home.

Coamorphous Loratadine-Citric Acid System with Enhanced Physical Stability and Bioavailability.

Coamorphous systems using citric acid as a small molecular excipient were studied for improving physical stability and bioavailability of loratadine, a BCS class II drug with low water solubility and high permeability. Coamorphous loratadine-citric acid systems were prepared by solvent evaporation technique and characterized by differential scanning calorimetry, X-ray powder diffraction, and Fourier transform infrared spectroscopy. Solid-state analysis proofed that coamorphous loratadine-citric acid system (1:1) was amorphous and homogeneous, had a higher T g over amorphous loratadine, and the intermolecular hydrogen bond interactions between loratadine and citric acid exist. The solubility and dissolution of coamorphous loratadine-citric acid system (1:1) were found to be significantly greater than those of crystalline and amorphous form. The pharmacokinetic study in rats proved that coamorphous loratadine-citric acid system (1:1) could significantly improve absorption and bioavailability of loratadine. Coamorphous loratadine-citric acid system (1:1) showed excellently physical stability over a period of 3 months at 25°C under 0% RH and 25°C under 60% RH conditions. The improved stability of coamorphous loratadine-citric acid system (1:1) could be related to an elevated T g over amorphous form and the intermolecular hydrogen bond interactions between loratadine and citric acid. These studies demonstrate that the developed coamorphous loratadine-citric acid system might be a promising oral formulation for improving solubility and bioavailability of loratadine.

Fabrication of lipidic nanocarriers of loratadine for facilitated intestinal permeation using multivariate design approach.

In this investigation, multivariate design approach was employed to develop self-nanoemulsifying drug delivery system (SNEDDS) of loratadine and to exploit its potential for intestinal permeability. Drug solubility was determined in various vehicles and existence of self-nanoemulsifying region was evaluated by phase diagram studies. The influence of formulation variables X1 (Capmul MCM C8) and X2 (Solutol HS15) on SNEDDS was assessed for mean globule sizes in different media (Y1-Y3), emulsification time (Y4) and drug-release parameters (Y5-Y6), to improve quality attributes of SNEDDS. Significant models were generated, statistically analyzed by analysis of variance and validated using the residual and leverage plots. The interaction, contour and response plots explicitly demonstrated the influence of one factor on the other and displayed trend of factor-effect on responses. The pH-independent optimized formulation was obtained with appreciable global desirability (0.9266). The strenuous act of determining emulsification time is innovatively replaced by the use of oil-soluble dye to produce visibly distinct globules that otherwise may be deceiving. TEM images displayed non-aggregated state of spherical globules (size < 25 nm) and also revealed the structural transitions occurring during emulsification. Optimized formulation exhibited non-Newtonian flow justified by the model-fit and also presented the stability to dilution effects and thermodynamic stress testing. The ex vivo permeation study using confocal laser scanning microscopy indicate strong potential of rhodamine 123-loaded loratadine-SNEDDS to inhibit P-gp efflux and facilitate intestinal permeation. To conclude, the effectiveness of design yields a stable optimized SNEDDS with enhanced permeation potential, which is expected to improve oral bioavailability of loratadine.

Further Characterization of the Metabolism of Desloratadine and Its Cytochrome P450 and UDP-glucuronosyltransferase Inhibition Potential: Identification of Desloratadine as a Relatively Selective UGT2B10 Inhibitor.

Desloratadine (Clarinex), the major active metabolite of loratadine (Claritin), is a nonsedating antihistamine used for the treatment of seasonal allergies and hives. Previously we reported that the formation of 3-hydroxydesloratadine, the major human metabolite of desloratadine, involves three sequential reactions, namely N-glucuronidation by UGT2B10 followed by 3-hydroxylation by CYP2C8 followed by deconjugation (rapid, nonenzymatic hydrolysis of the N-glucuronide). In this study we assessed the perpetrator potential of desloratadine based on in vitro studies of its inhibitory effects on cytochrome P450 and UDP-glucuronosyltransferase (UGT) enzymes in human liver microsomes (HLM). Desloratadine (10 µM) caused no inhibition (<15%) of CYP1A2, CYP2C8, CYP2C9, or CYP2C19 and weak inhibition (32-48%) of CYP2B6, CYP2D6, and CYP3A4/5. In cryopreserved human hepatocytes (CHH), which can form the CYP2C8 substrate desloratadine N-glucuronide, desloratadine did not inhibit the CYP2C8-dependent metabolism of paclitaxel or amodiaquine. Assessment of UGT inhibition identified desloratadine as a potent and relatively selective competitive inhibitor of UGT2B10 (Ki value of 1.3 µM). Chemical inhibition of UGT enzymes in HLM demonstrated that nicotine (UGT2B10 inhibitor) but not hecogenin (UGT1A4 inhibitor) completely inhibited the conversion of desloratadine (1 µM) to 3-hydroxydesloratadine in HLM fortified with both NADPH and UDP-glucuronic acid. 3-Hydroxydesloratadine formation correlated well with levomedetomidine glucuronidation (UGT2B10 marker activity) with a panel of individual CHH (r(2) = 0.72). Overall, the results of this study confirm the role of UGT2B10 in 3-hydroxydesloratadine formation and identify desloratadine as a relatively selective in vitro inhibitor of UGT2B10.

A long-standing mystery solved: the formation of 3-hydroxydesloratadine is catalyzed by CYP2C8 but prior glucuronidation of desloratadine by UDP-glucuronosyltransferase 2B10 is an obligatory requirement.

Desloratadine (Clarinex), the major active metabolite of loratadine (Claritin), is a nonsedating long-lasting antihistamine that is widely used for the treatment of allergic rhinitis and chronic idiopathic urticaria. For over 20 years, it has remained a mystery as to which enzymes are responsible for the formation of 3-hydroxydesloratadine, the major active human metabolite, largely due to the inability of any in vitro system tested thus far to generate this metabolite. In this study, we demonstrated that cryopreserved human hepatocytes (CHHs) form 3-hydroxydesloratadine and its corresponding O-glucuronide. CHHs catalyzed the formation of 3-hydroxydesloratadine with a Km of 1.6 µM and a Vmax of 1.3 pmol/min per million cells. Chemical inhibition of cytochrome P450 (P450) enzymes in CHHs demonstrated that gemfibrozil glucuronide (CYP2C8 inhibitor) and 1-aminobenzotriazole (general P450 inhibitor) inhibited 3-hydroxydesloratadine formation by 91% and 98%, respectively. Other inhibitors of CYP2C8 (gemfibrozil, montelukast, clopidogrel glucuronide, repaglinide, and cerivastatin) also caused extensive inhibition of 3-hydroxydesloratadine formation (73%-100%). Assessment of desloratadine, amodiaquine, and paclitaxel metabolism by a panel of individual CHHs demonstrated that CYP2C8 marker activity robustly correlated with 3-hydroxydesloratadine formation (r(2) of 0.70-0.90). Detailed mechanistic studies with sonicated or saponin-treated CHHs, human liver microsomes, and S9 fractions showed that both NADPH and UDP-glucuronic acid are required for 3-hydroxydesloratadine formation, and studies with recombinant UDP-glucuronosyltransferase (UGT) and P450 enzymes implicated the specific involvement of UGT2B10 in addition to CYP2C8. Overall, our results demonstrate for the first time that desloratadine glucuronidation by UGT2B10 followed by CYP2C8 oxidation and a deconjugation event are responsible for the formation of 3-hydroxydesloratadine.

Dissolution evaluation in vitro and bioavailability in vivo of self-microemulsifying drug delivery systems for pH-sensitive drug loratadine.

The aim of this study was to improve the oral absorption of loratadine, a pH-sensitive drug, by self-microemulsifying drug delivery systems (SMEDDSs). The optimal SMEDDS was analysed and evaluated after emulsification in distilled water with diameter of 26.57 ± 0.71 nm and zeta potential of -30.5 ± 4.5 mV. Dissolution experiments in vitro were carried out in different released media of pH values and the SMEDDS formulations were able to release loratadine completely in different media while market tablets just performed similarly in the media of pH 1.2. Furthermore, the oral bioavailability and the pharmacokinetic behaviour of loratadine formulations in vivo were studied after a single dose of 1 mg/kg loratadine in beagle dogs. The SMEDDS formulations displayed higher Cmax and AUC, approximately 9 and 5 times increase than those of market tablets (p < 0.01) respectively. These results demonstrated that SMEDDS formulations had significantly increased the oral absorption of loratadine in beagle dogs.

[Determination of Desloratadine and Its Metabolite 3-OH Desloratadine in Human Plasma by LC-MS/MS].

OBJECTIVE: To develop a liquid chromatography-tandem mass spectrometry (LC-MS/MS) method for the simultaneous determination of desloratadine and its metabolite 3-OH desloratadine in human plasma. METHODS: 24 healthy male volunteers received a single oral dose of 5 mg desloratadine tablets in a randomized crossover bioequivalence study with two preparations of tablets. Serial plasma samples were taken and analyzed by the LC-MS/MS method. The pharmacokinetic parameters of the two preparations were calculated and compared statistically to evaluate their bioequivalence using Winnonlin 6. 3. RESULTS: The calibration curves of desloratadine and 3-OH desloratadine were both linear over the concentration range of 0. 050-6. 0 ng/mL, with intra-batch and inter-batch relative standard deviations less than 15%. The 90% confidence intervals (CIs) of peak concentration (Cmax) area under the curve (AUC)0t and AUC0-∞ of desloratadine and 3-OH desloratadine all resided within the bioequivalence limit 80%-125%. No significant difference in peak time (Tmax) was demonstrated between the two preparations. CONCLUSION: The LC-MS/MS method can be used for simultaneous determination of desloratadine and 3-OH desloratadine in human plasma, which has been successfully applied-to a bioequivalence study.

Loratidine buccal films for allergic rhinitis: development and evaluation.

The objective of this study was to develop a novel patient compliant buccoadhesive film capable of providing a prolonged protection against allergic symptoms. Polymeric buccoadhesive films of loratidine were prepared using hydroxypropylmethyl cellulose (HPMC)-E5 and K100 blend and Eudragit® NE 30D as retardant. Films were prepared using solvent-casting method. The developed films were evaluated for physical properties, hydration, mucoadhesion time, drug release, etc. All the prepared films exhibited excellent mechanical strength and uniform drug content. Increase in drug content did not influence the physicomechanical properties of the film. The mucoadhesive strength of films was significantly enhanced with increase in HPMC content. Increase in Eudragit® NE 30 D content in the film decreases the hydration, erosion and drug release, but enhances the mucoadhesion time. Furthermore, the release of loratidine from the prepared films followed Hixson-Crowell kinetics. Studies in healthy human volunteers using placebo films indicate that the prepared films possess prolonged mucoadhesion in-vivo, and this could potentially lead to clinically relevant drug delivery system.

Mrp2 is involved in the efflux and disposition of fosinopril.

The multidrug-resistance-associated proteins 1 and 2 (MRP1/MRP2) are transporters responsible for the efflux of drugs and endogenous compounds. Madin Darby canine kidney (MDCK) cells transfected with the human MRP1 or MRP2 genes were used to assess whether several widely used pharmaceuticals are potential substrates by examining their differential toxicity, accumulation and efflux. Loratadine, an antihistamine, was 1.4-fold less toxic to MRP1 cells and its retention was 1.3-fold lower than that from MDCK control cells. Fosinopril, an angiotensin converting enzyme inhibitor, was 2.4-fold less toxic and its retention was 4.5-fold lower in MRP2-transfected cells compared with control cells. To determine whether fosinopril contributed to a drug-drug interaction, fosinopril efflux was examined in vitro in combination with other known or suspected MRP2 substrates over a period of 20 min. When fosinopril was coincubated with desloratadine, loratadine or methotrexate, its retention was increased by 2-, 4.7- and 2-fold, respectively, which likely indicates that a drug-drug interaction is occurring. In vivo studies were conducted, in which FVB wild-type and FVB/Mrp2(-/-) mice were dosed with fosinopril and the known MRP2 substrate methotrexate, and tissues collected after 1 h. In mice lacking Mrp2, drug levels were reduced in the intestine by 1.5-fold, but increased in the liver, serum and kidneys, by 2.1-, 2.9- and 3-fold, respectively. These data suggest that, in the absence of Mrp2, fosinopril alters the retention of a second drug. These findings will help increase our understanding of the role that MRP2 plays in altering the retention and disposition of coadministered pharmaceuticals.

H(1)-antihistamines and urticaria: how can we predict the best drug for our patient?

Urticaria, and especially chronic spontaneous urticaria (CSU), is a difficult condition to treat. Consequently, clinicians need to use the best H(1)-antihistamines currently available and the pharmaceutical industries need to keep developing H(1)-antihistamines that are more effective than the ones we have today. To do this we need to be able to compare the clinical efficacy of both established and new drugs. Obviously, the ideal way to do this is to use head-to-head studies in CSU. However, such studies are extremely expensive and, in the case of novel molecules, have ethical and logistical problems. Consequently, we need to have predictive models. Although determination of Ki, an indicator of the in vitro potency of an H(1)-antihistamine, may help in the initial selection of candidate molecules, the large differences in volume of distribution and tissue accumulation in humans, precludes this from being a good predictor of clinical efficacy in CSU. From the data reviewed in this article, especially the direct comparative data of desloratadine and levocetirizine in weal and flare studies and CSU, weal and flare response would appear to be the best indicator we have of effectiveness of H(1)-antihistamines in clinical practice. However, it must be pointed out that the conclusion is, essentially, based on detailed comparisons of two drugs in studies sponsored by pharmaceutical companies. Consequently, to confirm the conclusions of this review, a multicentre study independent from the influence of pharmaceutical companies should be commissioned to compare the speed of onset and effectiveness of desloratadine, fexofenadine and levocetirizine in chronic spontaneous urticaria and against histamine-induced weal and flare responses in the same patients so that we have a clear understanding of the predictive value of our models.

The impact of P-glycoprotein mediated efflux on absorption of 11 sedating and less-sedating antihistamines using Caco-2 monolayers.

Caco-2 cells were used to compare P-gp mediated efflux and passive permeability using bidirectional transport of 11 antihistamines. An efflux ratio >2 indicated active efflux, with PSC833 and GF120918 used as functional P-gp inhibitors. Antihistamines were measured directly by HPLC or LC/MS. Fexofenadine had an efflux ratio of 37, yet had negligible passive permeability, even in the presence of a pH gradient (0.1 × 10(-6) cm/sec). Its precursor, terfenadine, had an efflux ratio of 2.5, while cetirizine, desloratadine and hydroxyzine were 4, 7 and 14, respectively. After incubation with P-gp inhibitors, these ratios dropped significantly. Loratadine, by contrast, had equivalent transport in both directions and passive permeability was high (24 × 10(-6) cm/sec). Dimenhydrinate was the only other sedating antihistamine to exhibit efflux, with a ratio of 10. Gradient conditions of pH (6/7.4) increased efflux of terfenadine and desloratadine to over 31 and 38 fold respectively, yet this increased efflux was not associated with P-gp. Altering functional P-gp in the gut is likely to influence absorption of some sedating antihistamines such as dimenhydrinate and hydroxyzine and most less-sedating antihistamines except loratadine. In addition, desloratadine exhibits pH dependent efflux which could further induce variable absorption of this antihistamine.

Prevalence of desloratadine poor metabolizer phenotype in healthy Jordanian males.

PURPOSE: To study the prevalence of desloratadine slow metabolizer phenotype among a group of healthy Jordanian male volunteers. METHODS: A total of 62 healthy Jordanian male volunteers were included in this study. A single 5 mg desloratadine oral tablet was given and blood samples were taken to determine the desloratadine and 3-hydroxydesloratadine (3-OH-desloratadine) concentrations using a specific liquid chromatography-mass spectrometric method (LC/MS/MS). The determination of pharmacokinetic parameters of all the individuals was determined by using Kinetica® program version 4.1. Poor metabolizers or slow metabolizers of desloratadine were determined as individuals having a 3-OH-desloratadine to desloratadine exposure ratio lower than 10% or a desloratadine half-life ≥ 50 h. RESULTS: Among the 62 volunteers who participated in the study there were only two volunteers who were labeled as desloratadine slow metabolizers, giving a prevalence of 3.2%. The maximum plasma concentrations (C(max)) were similar in the extensive and slow metabolizers groups but a longer time (t(max)) was needed to achieve this concentration in one of the volunteers who was a desloratadine slow metabolizer. CONCLUSION: The incidence of the poor metabolizer phenotype of desloratadine in the Jordanian population studied is similar to certain ethnic groups (e.g. Asian, Caucasians and Hispanic); however, it is lower than other populations (e.g. American Indians and Black).

[Comparative pharmacokinetics of antigrippin-maximum administered in capsules and powder for preparing solutions].

Comparative pharmacokinetics of anti-influenza drug composition Antigrippin-maximum administered in capsules and a powder for preparing solutions has been studied after single administraton in a group of 18 healthy volunteers. Both preparations [manufactured by the Antiviral Research and Production Corporation (St Petersbutg) contain 6 active components, including paracetamol, rimantadine, loratadine, ascorbic acid, calcium gluconate, and rutoside in equal amounts. The concentrations of unchanged paracetamol, rimantadine, and loratadine in the blood plasma were degtermined by HPLC with mass-spectrometric and UV detection. The pharmacokinetic parameters of allindicated active components exhibited no detectable distinctions, except for the time to attaining maximum concentration ofparacetamol and the value of the maximum concentration of loratadine.

Simultaneous Determination of Loratadine and Its Metabolite Desloratadine in Beagle Plasma by LC-MS/MS and Application for Pharmacokinetics Study of Loratadine Tablets and Omeprazole­Induced Drug-Drug Interaction.

BACKGROUND: Loratadine (LTD) is a Biopharmaceutical Classification System II basic drug with pH-sensitive aqueous solubility and dissolution is a speed-limiting step of its absorption. The drug dissolution and the gastrointestinal tract pH conditions are likely to influence the in vivo pharmacokinetic behavior of LTD tablets. MATERIALS AND METHOD: A rapid, sensitive, and reliable bioanalytical method for simultaneous quantitation of LTD and its active metabolite desloratadine (DL) in beagle plasma was developed and validated based on liquid chromatography tandem mass spectrometry (LC-MS/MS). Sample preparation in low plasma consumption was accomplished by liquid-liquid extraction. The chromatographic separation was achieved on a Phenomenex Kinetex C8 column using acetonitrile and 5 mM ammonium formate as the mobile phase. A comparative pharmacokinetics study of three LTD tablets with different dissolution rates was conducted in male beagles in fasting state and an omeprazole-induced drug-drug interaction (DDI) study was subsequently performed under pretreatment of omeprazole. RESULTS AND CONCLUSION: The method showed a good linear correlation over the concentration ranges of 0.008-24 ng/mL for LTD and 0.8-800 ng/mL for DL, and was successfully applied to analyze the two compounds in beagle plasma. Pharmacokinetic results showed in the fasting state the three LTD tablets were equivalent in beagles in terms of effective components. DL of the three tablets were equivalent, indicating metabolite was less susceptible to pharmaceutic preparation factors for LTD tablets in beagles. Moreover, significant changes in LTD and DL pharmacokinetics parameters were observed under the effect of omeprazole-induced pH increase in gastrointestinal tract, suggesting that DDI effects are of concern for the curative effect of LTD when combined with omeprazole. The findings will contribute to the future pharmaceutical preparations research as well as the clinical application of LTD.

Preparation of loratadine nanocrystal tablets to improve the solubility and dissolution for enhanced oral bioavailability.

OBJECTIVES: Loratadine is a selective H1 receptor inhibitor that has been widely used in the clinical treatment of allergic diseases. Here we aimed to develop a novel solid loratadine nanocrystal to increase the low and pH-dependent water solubility for bioavailability enhancement. METHODS: Loratadine solid nanocrystal was developed through high-speed shear-high pressure homogenization followed by freeze-drying, which was further prepared into tablets through direct compression. The formulation and process parameter were screened. Furthermore, the characterization and oral bioavailability of loratadine nanocrystal were studied. KEY FINDINGS: The loratadine nanocrystal had the satisfactory particle size of 425.9 nm and great redispersibility, which was mainly attributed to the addition of Pluronic F127 and polyvinylpyrrolidone K17 as the stabilizer. The saturation solubility of the loratadine nanocrystal was increased to 3.81, 3.22 and 2.57-fold that of the crude drug in water, pH 6.8 and pH 4.5 buffer respectively. Furthermore, the pharmacokinetic studies in rats revealed that the AUC (0-∞) of the nanocrystal tablets was 2.38-fold that of raw tablets and 1.94-fold that of commercial tablets, respectively. CONCLUSIONS: The nanocrystal tablets could significantly improve the oral bioavailability of loratadine, which would also be a promising approach to enhance the solubility of insoluble drugs.

Effects of silybinin, CYP3A4 and P-glycoprotein inhibitor in vitro, on the bioavailability of loratadine in rats.

The effect of silybinin on the pharmacokinetics of orally and intravenously administered loratadine in rats was investigated. Pharmacokinetic parameters of loratadine were determined in rats following oral (4 mg x kg(-1)) and intravenous (1 mg x kg(-1)) administration to rats in the presence and absence of silybinin (0.3, 1.5 and 6 mg x kg(-1)). Compared to those animals in an oral control group (given loratadine alone), the area under the plasma concentration-time curve (AUC) and the peak plasma concentration (C(max)) of loratadine were increased significantly (P < 0.05 for 1.5 mg x kg(-1), P < 0.01 for 6 mg x kg(-1)) by 50.0-76.7% and 65.4-90.1%, respectively, by silybinin. Consequently, the absolute bioavailability of loratadine in the presence of silybinin (1.5 and 6 mg x kg(-1)) was 8.6-10.2%, which was significantly (1.5 mg x kg(-1), P < 0.05; 6 mg x kg(-1), P < 0.01) enhanced compared to that in oral control group (5.8%). Moreover, the relative bioavailability of loratadine was 1.50- to 1.77-fold greater than that in the control group. In contrast, silybinin had no effect on any pharmacokinetic parameters of loratadine given intravenously, implying that coadministration of silybinin could inhibit the cytochrome P450 (CYP) 3A4-mediated metabolism of loratadine, resulting in reducing gastrointestinal and hepatic first-pass metabolism, and the P-glycoprotein (P-gp) efflux pump in the small intestine. Silybinin significantly enhanced the oral bioavailability of loratadine, suggesting that concurrent use of silybinin and loratadine should be monitored closely for potential drug interactions.

A simple and low-energy method to prepare loratadine nanosuspensions for oral bioavailability improvement: preparation, characterization, and in vivo evaluation.

The effervescent method, as a simple and effective technology to prepare nanosuspensions, has gained great attention. In this present research, loratadine (LTD) nanosuspensions were successfully prepared by the effervescent method using Soluplus as stabilizer to improve the bioavailability of LTD in vivo. The mean particle size was about 100 nm. And the LTD nanosuspensions were lyophilized for further study. The freeze-dried powders could be dissolved quickly, and the mean particle size remained almost unchanged after powders were re-dissolved. By transmission electron microscope (TEM), differential scanning calorimetry (DSC), scanning electron microscopy (SEM), Fourier transform infrared (FT-IR) spectroscopy, and X-ray diffraction (X-RD), the characterizations of LTD nanosuspensions and freeze-dried powders were studied. Commercial tablets were used as the reference to investigate the dissolution behaviors in different release media and of bioavailability in vivo of LTD freeze-dried powders. The cumulative dissolution of the LTD freeze-dried powders was superior in different release media compared with commercial tables. In addition, for the evaluation of the bioavailability of LTD nanosuspensions, the LTD concentration in rat plasma was determined using LC-MS/MS method. The results showed that the AUC0-24 and Cmax of LTD freeze-dried powders were about 2.14- and 2.01-fold higher than those of commercial tablets. In short, the effervescent method has been successfully applied to the preparation of LTD nanosuspensions to improve the bioavailability of LTD in vivo with the advantage of low energy consumption. This simple technology also provides an idea for the preparation of the other nanosuspensions.