Chiral Discrimination of P-glycoprotein in Parturient Women: Effect of Fluoxetine on Maternal-Fetal Fexofenadine Pharmacokinetics.

BACKGROUND AND OBJECTIVE: Fluoxetine, antidepressant widely-used during pregnancy, is a selective inhibitor for P-glycoprotein (P-gp). Fexofenadine, an in vivo P-gp probe, is an antihistamine drug for seasonal allergic rhinitis and chronic urticaria treatment during pregnancy and it is available as a racemic mixture. This study evaluated the chiral discrimination of P-gp investigating the effect of fluoxetine on maternal-fetal pharmacokinetics of fexofenadine. METHODS: Healthy parturient women received either a single oral dose of 60 mg racemic fexofenadine (Control group; n = 8) or a single oral dose of 40 mg racemic fluoxetine 3 h before a single oral dose of 60 mg racemic fexofenadine (Interaction group; n = 8). Maternal blood and urine samples were collected up to 48 h after fexofenadine administration. At delivery, maternal-placental-fetal blood samples were collected. RESULTS: The maternal pharmacokinetics of fexofenadine was enantioselective (AUC0-∞R-(+)/S-(-) ~ 1.5) in both control and interaction groups. Fluoxetine increased AUC0-∞ (267.7 vs 376.1 ng.h/mL) and decreased oral total clearance (105.1 vs 74.4 L/h) only of S-(-)-fexofenadine, whereas the renal clearance were reduced for both enantiomers, suggesting that the intestinal P-gp-mediated transport of S-(-)-fexofenadine is influenced by fluoxetine to a greater extent that the R-(+)-fexofenadine. However, the transplacental transfer of fexofenadine is low (~16%), non-enantioselective and non-influenced by fluoxetine. CONCLUSIONS: A single oral dose of 40 mg fluoxetine inhibited the intestinal P-gp mediated transport of S-(-)-fexofenadine to a greater extent than R-(+)-fexofenadine in parturient women. However, the placental P-gp did not discriminate fexofenadine enantiomers and was not inhibited by fluoxetine.

Comparison of the pharmacokinetics and tolerability of montelukast/levocetirizine administered as a fixed-dose combination and as separate tablets.

OBJECTIVE: A novel fixed-dose combination (FDC) capsule of 10/5 mg of montelukast/levocetirizine may lead to better compliance than two separate tablets taken together. The aim of this study was to evaluate the pharmacokinetics (PK) and tolerability of an FDC of montelukast and levocetirizine compared to separate tablets. MATERIALS AND METHODS: A randomized, open-label, single-dose, two-sequence, two-period, crossover study was conducted with healthy male subjects. In each period, either an FDC or separate tablets were administered orally, and serial blood samples were collected for PK analysis for up to 34 hours after dosing. PK parameters were calculated using noncompartmental methods. The 90% confidence intervals (CIs) of the geometric mean ratios (GMRs) of the maximum plasma concentration (Cmax) and the area under the curve to the last measurable concentration (AUClast) for the two interventions were estimated. Tolerability assessments were performed for all the subjects who received the drug at least once. RESULTS: The PK profiles of the two interventions were comparable. For montelukast, the GMRs and 90% CIs for the Cmax and AUClast were 0.9800 (0.8903 - 1.0787) and 1.0706 (0.9968 - 1.1498), respectively. The corresponding values for levocetirizine were 0.9195 (0.8660 - 0.9763) and 1.0375 (1.0123 - 1.0634), respectively. Both interventions were well tolerated. CONCLUSION: The PK and tolerability profiles of montelukast and levocetirizine after a single oral administration were comparable between the FDC and separate tablets. For patients with allergic rhinitis who require a combination treatment, the FDC of montelukast and levocetirizine will be a convenient therapeutic option.
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HPLC Determination of Fexofenadine in Human Plasma For Therapeutic Drug Monitoring and Pharmacokinetic Studies.

A simple and sensitive method was developed for fexofenadine determination in human plasma by liquid chromatography with ultraviolet detection. Satisfactory separation was achieved on a Hypersil® BDS C18 column (250 × 4.6 mm, 5µm) using a mobile phase comprising 20 mm sodium dihydrogen phosphate-2 hydrate (pH adjusted to 3 with phosphoric acid)-acetonitrile at a ratio of 52:48, v/v. The elution was isocratic at ambient temperature with a flow rate of 1.0 mL/min. The UV detector was set at 215 nm for the drug and 330 nm for the internal standared (tinidazole). The total time for a chromatographic separation was ~6.5 min. Linearity was demonstrated over the concentration range 0.01-4 µg/mL. The observed within- and between-day assay precision ranged from 0.346 to 13.6%; accuracy varied between 100.4 and 111.2%. This method was successfully applied for therapeutic drug monitoring in patients treated with clinical doses of fexofenadine and for pharmacokinetic studies. Copyright © 2015 John Wiley & Sons, Ltd.

Statistical optimization of controlled release microspheres containing cetirizine hydrochloride as a model for water soluble drugs.

The purpose was to improve the encapsulation efficiency of cetirizine hydrochloride (CTZ) microspheres as a model for water soluble drugs and control its release by applying response surface methodology. A 3(3) Box-Behnken design was used to determine the effect of drug/polymer ratio (X1), surfactant concentration (X2) and stirring speed (X3), on the mean particle size (Y1), percentage encapsulation efficiency (Y2) and cumulative percent drug released for 12 h (Y3). Emulsion solvent evaporation (ESE) technique was applied utilizing Eudragit RS100 as coating polymer and span 80 as surfactant. All formulations were evaluated for micromeritic properties and morphologically characterized by scanning electron microscopy (SEM). The relative bioavailability of the optimized microspheres was compared with CTZ marketed product after oral administration on healthy human volunteers using a double blind, randomized, cross-over design. The results revealed that the mean particle sizes of the microspheres ranged from 62 to 348 µm and the efficiency of entrapment ranged from 36.3% to 70.1%. The optimized CTZ microspheres exhibited a slow and controlled release over 12 h. The pharmacokinetic data of optimized CTZ microspheres showed prolonged tmax, decreased Cmax and AUC0-∞ value of 3309 ± 211 ng h/ml indicating improved relative bioavailability by 169.4% compared with marketed tablets.

Effects of one-time apple juice ingestion on the pharmacokinetics of fexofenadine enantiomers.

PURPOSE: We examined the effect of a single apple juice intake on the pharmacokinetics of fexofenadine enantiomers in healthy Japanese subjects. METHODS: In a randomized two phase, open-label crossover study, 14 subjects received 60 mg of racemic fexofenadine simultaneously with water or apple juice. For the uptake studies, oocytes expressing organic anion-transporting polypeptide 2B1 (OATP2B1) were incubated with 100 µM (R)- and (S)-fexofenadine in the presence or absence of 10 % apple juice. RESULTS: One-time ingestion of apple juice significantly decreased the area under the plasma concentration-time curve (AUC0-24) for (R)- and (S)-fexofenadine by 49 and 59 %, respectively, and prolonged the time to reach the maximum plasma concentration (t max) of both enantiomers (P < 0.001). Although apple juice greatly reduced the amount of (R)- and (S)-fexofenadine excretion into urine (Ae0-24) by 54 and 58 %, respectively, the renal clearances of both enantiomers were unchanged between the control and apple juice phases. For in vitro uptake studies, the uptake of both fexofenadine enantiomers into OATP2B1 complementary RNA (cRNA)-injected oocytes was significantly higher than that into water-injected oocytes, and this effect was greater for (R)-fexofenadine. In addition, apple juice significantly decreased the uptake of both enantiomers into OATP2B1 cRNA-injected oocytes. CONCLUSIONS: These results suggest that OATP2B1 plays an important role in the stereoselective pharmacokinetics of fexofenadine and that one-time apple juice ingestion probably inhibits intestinal OATP2B1-mediated transport of both enantiomers. In addition, this study demonstrates that the OATP2B1 inhibition effect does not require repeated ingestion or a large volume of apple juice.

The inhibition by levocetirizine and fexofenadine of the histamine-induced wheal and flare response in healthy Caucasian and Japanese volunteers.

This randomized, double-blind, placebo-controlled crossover study compared inhibition by one 5 mg dose of levocetirizine with two 60 mg doses of fexofenadine separated by 12 h of histamine-induced wheal and flare responses in 9 Caucasian and 9 Japanese healthy male volunteers. Levocetirizine was more inhibitory than fexofenadine on wheal, flare and pruritus (p < 0.005). Variability, evaluated from the standard deviation of inhibition, ranged from 14% to 23.2% for levocetirizine and 65.4% to 112.4% for fexofenadine. Levocetirizine had a faster onset of action (30-90 min versus 2 h), shorter time to maximum effect (3-4 versus 3-6 h) and longer duration of action (at least 24 h versus ~12 h) than fexofenadine. The plasma levels of levocetirizine rose more quickly, reached higher levels, were more consistent and decreased slower than those of fexofenadine. There were no clinically significant ethnic differences in responsiveness to the drugs.

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).

Direct analysis of dried blood spots utilizing desorption electrospray ionization (DESI) mass spectrometry.

A novel approach to the quantitative determination of xenobiotics in whole blood samples without sample preparation or chromatography is described. This method is based on direct analysis of microlitre volumes of blood which are spotted onto specialized paper cards and dried, with the resulting dried blood spots (DBS) analyzed directly via desorption electrospray ionization (DESI) mass spectrometry (MS). Using sitamaquine, terfenadine, and prazosin as model compounds with verapamil as a common internal standard, this methodology demonstrated detection of each compound down to 10 ng mL(-1) from DBS where standard calibration curves show linearity from 10-10,000 ng mL(-1) with r(2) > 0.99. Three (3) different untreated types of filter papers (Whatman 903 and 31ETF as well as Ahlstrom 237) and two (2) treated types of filter paper (Whatman FTA and FTA Elute) were examined and the effect of each surface on the recovery of each analyte was evaluated. The results show that the untreated papers provide the best substrates for DBS analysis by DESI. A more in depth study of the quantitation of sitamaquine on 31ETF paper stock provided bias and error measurements of less than 20%. The promising results shown in this study may have important implications in the areas of therapeutic drug monitoring (TDM), clinical and forensic toxicology, and pharmacology.

Hydroxyzine and cetirizine interfere with the PENTINA carbamazepine assay but not with the ADVIA CENTEUR carbamazepine assay.

Because of a published report indicating significant interference of hydroxyzine with the particle-enhanced turbidimetric inhibition immunoassay (PENTINA) carbamazepine assay, we investigated whether such interference can be avoided by using the ADVIA Centaur carbamazepine assay. Both the Dimension Vista analyzer and ADVIA Centaur analyzer are available from Siemens Diagnostics. Aliquots of a drug-free serum pool were supplemented with various concentrations of hydroxyzine or cetirizine (0.05 microg/mL to 20 microg/mL covering therapeutic and toxic levels in serum) followed by analysis using both assays. We observed significant apparent carbamazepine concentrations using the PENTINA assay but no apparent carbamazepine level using the ADVIA Centaur assay. Because crossreactivity should be studied in the presence of the primary analyte, we also prepared a serum carbamazepine pool from patients receiving carbamazepine and then supplemented aliquots of this pool with various amounts of hydroxyzine or cetirizine followed by reanalyzing carbamazepine concentration using both assays. We observed falsely elevated carbamazepine values using the PENTINA assay but no interference was observed using the ADVIA Centaur assay. However, the falsely elevated carbamazepine values using the PENTINA assay were clinically significant at hydroxyzine or cetirizine concentrations expected in patients with severe overdoses with these drugs. We conclude that the ADVIA Centaur carbamazepine assay is free from interference of both hydroxyzine and cetirizine.

Measurement of fexofenadine concentration in micro-sample human plasma by a rapid and sensitive LC-MS/MS employing protein precipitation: application to a clinical pharmacokinetic study.

A simple, rapid and sensitive liquid chromatography/positive ion electro-spray tandem mass spectrometry method (LC-MS/MS) was developed and validated for the quantification of fexofenadine with 100 microL human plasma employing glipizide as internal standard (IS). Protein precipitation was used in the sample preparation procedure. Chromatographic separation was achieved on a reversed-phase C(18 )column (5 microm, 100 x 2.1 mm) with methanol : buffer (containing 10 mmol/L ammonium acetate and 0.1% formic acid; 70 : 30, v/v) as mobile phase. The total chromatographic runtime was approximately 3.0 min with retention time for fexofenadine and IS at approximately 1.9 and 2.1 min, respectively. Detection of fexofenadine and IS was achieved by LC-MS/MS in positive ion mode using 502.1 --> 466.2 and 446.0 --> 321.1 transitions, respectively. The method was proved to be accurate and precise at linearity range of 1-600 ng/mL with a correlation coefficient (r) of > or =0.9976. The validated method was applied to a pharmacokinetic study in human volunteers following oral administration of 60 or 120 mg fexofenadine formulations, successfully.

Short-term effect of quercetin on the pharmacokinetics of fexofenadine, a substrate of P-glycoprotein, in healthy volunteers.

OBJECTIVE: The aim of the present study was to assess whether quercetin exhibited any inhibitory effect on P-glycoprotein (P-gp)-mediated drug disposition in humans using fexofenadine as a P-gp substrate. METHODS: Twelve healthy subjects were enrolled in the study and treated daily for 7 days with 500 mg quercetin or placebo 3 times a day. On day 7, a single dose of 60 mg fexofenadine was administered orally. Plasma and urinary fexofenadine concentrations were measured, and pharmacokinetic differences between placebo and quercetin phases were assessed. RESULTS: The mean plasma concentrations of fexofenadine were significantly increased after quercetin treatment compared to those of the placebo phase. The area under the time versus concentration curve (AUC) of plasma fexofenadine was increased by 55% by quercetin (2,005.3 versus 3,098.6 ng.h/mL, P < 0.001) and similarly the maximum plasma concentration (C(max)) during the quercetin phase was elevated by 68% compared to that of the placebo phase (295.3 versus 480.3 ng/mL, P = 0.006). Although the oral clearance of fexofenadine was decreased significantly by 37% after quercetin treatment (61.4 versus 38.7 L/h, P < 0.001), no differences in the renal clearance and half-life were observed between placebo and quercetin phases. CONCLUSION: The results of the present study showed that short-term use of quercetin elevated the plasma concentrations of fexofenadine, probably by the inhibition of P-gp-mediated efflux in humans.

Simultaneous determination of rupatadine and its metabolite desloratadine in human plasma by a sensitive LC-MS/MS method: application to the pharmacokinetic study in healthy Chinese volunteers.

A sensitive liquid chromatography/tandem mass spectrometry (LC-MS/MS) method was developed for simultaneous determination of rupatadine and its metabolite desloratadine in human plasma. After the addition of diphenhydramine, the internal standard (IS), plasma samples were extracted with a mixture of methyl tert-butyl ether and n-hexane (1:1, v/v). The analysis was performed on a Ultimate AQ-C18 (4.6mm x 100mm, 5microm) column using a mobile phase consisting of a 80/20 mixture of methanol/water containing 0.0005% formic acid pumped at 0.3mlmin(-1). The analytes and the IS were detected in positive ionization mode and monitoring their precursor-->product ion combinations of m/z 416-->309, 311-->259, and 256-->167, respectively, in multiple reaction monitoring mode. The linear ranges of the assay were 0.1-50 and 0.1-20ngml(-1) for rupatadine and desloratadine, respectively. The lower limits of reliable quantification for both rupatadine and desloratadine were 0.1ngml(-1), which offered high sensitivity and selectivity. The within- and between-run precision was less than 7.2%. The accuracy ranged from -9.2% to +6.4% and -7.2% to +7.2% for rupatadine and desloratadine in quality control samples at three levels, respectively. The method has been successfully applied to a pharmacokinetic study of rupatadine and its major metabolite after oral administration of 10, 20 and 40mg rupatadine tablets to healthy Chinese volunteers.

Comparative bioavailability of two cetirizine tablet formulations in Indonesian healthy volunteers.

AIM: To compare the bioavailability of two cetirizine tablet (10 mg) formulations (ZyrtecA from UCB Pharma, Spain as a reference formulation and RyvelA from Novell Pharmaceutical Laboratories, Indonesia as a test formulation). MATERIAL AND METHODS: The study was conducted according to an open, randomized, two-period crossover design with a 1-week washout period. Eighteen volunteers participated and all completed the study successfully. Blood samples were obtained prior to dosing and at 0.25, 0.5, 1, 2, 3, 5, 8, 12, 24 and 30 hours after drug administration. Plasma concentrations of cetirizine were monitored using high-performance liquid chromatography over a period of 30 hours after administration. The pharmacokinetics parameter AUC(0-30h), AUC(0-infinity) and C(max) were tested for bioequivalence after log-transformation of data and ratios of t(max) were evaluated non-parametrically. RESULT: The point estimates and 90% confidence intervals for AUC(0-30h), AUC(0-infinity) and C(max) were 108.23% (101.90 â 114.95%), 108.11% (101.91 â 114.68%) and 99.71% (90.18 â 110.25%), respectively, satisfying the bioequivalence criteria of the European Committee for Proprietary Medicinal Products an the US Food and Drug Administration guidelines. CONCLUSION: These results indicate that two medications of cetirizine are bioequivalent and, thus, may be prescribed interchangeably.

Development and validation of high-throughput liquid chromatography-tandem mass spectrometric method for simultaneous quantification of loratadine and desloratadine in human plasma.

As a continuation of effort to improve our high flow on-line bioanalytical approach for high-throughput quantification of drugs and metabolites in plasma by high-throughput liquid chromatography tandem mass spectrometry (HTLC-MS/MS), we have developed a simple, sensitive and reliable method for simultaneous quantification of loratadine and desloratadine in human plasma. We have performed on-line coupling of extraction with Cyclone P 50 mm x 0.5 mm 50 microm HTLC column and chromatographic separation is performed with Zorbax XDB C18 50 mm x 2.1 mm 5 microm, followed by quantification with mass detector. The method is validated and showed good performances in terms of linearity, sensitivity, precision, accuracy and stability. A marked improvement in sample throughput efficiency is realized with this method and the proposed method will be useful for pharmacokinetic and/or bioequivalence studies.

Determination of loratadine and its active metabolite in human plasma by high-performance liquid chromatography with mass spectrometry detection.

A new sensitive and selective liquid chromatography coupled with mass spectrometry (LC/MS/MS) method for quantification of loratadine (LOR) and its active metabolite descarboethoxyloratadine (DSL) in human plasma was validated. After addition of the internal standard, metoclopramide, the human plasma samples (0.3 ml) were precipitated using acetonitrile (0.75 ml) and the centrifuged supernatants were partially evaporated under nitrogen at 37 degrees C at approximately 0.3 ml volume. The LOR, DSL and internal standard were separated on a reversed phase column (Zorbax SB-C18, 100 mmx3.0 mm i.d., 3.5 microm) under isocratic conditions using a mobile phase of an 8:92(v/v) mixture of acetonitrile and 0.4% (v/v) formic acid in water. The flow rate was 1 ml/min and the column temperature 45 degrees C. The detection of LOR, DSL and internal standard was in MRM mode using an ion trap mass spectrometer with electrospray positive ionisation. The ion transitions were monitored as follows: 383-->337 for LOR, 311-->(259+294+282) for DSL and 300-->226.8 for internal standard. Calibration curves were generated over the range of 0.52-52.3 ng/ml for both LOR and DSL with values for coefficient of determination greater than 0.994 by using a weighted (1/y) quadratic regression. The lower limits of quantification were established at 0.52 ng/ml LOR and DSL, respectively, with an accuracy and precision less than 20%. Both analytes demonstrated good short-term, long-term, post-preparative and freeze-thaw stability. Besides its simplicity, the sample treatment allows obtaining a very good recovery of both analytes, around 100%. The validated LC/MS/MS method has been applied to a pharmacokinetic study of loratadine tablets on healthy volunteers.

Determination of fexofenadine enantiomers in human plasma with high-performance liquid chromatography.

A simple and sensitive high-performance liquid chromatography (HPLC) method was developed as an assay for fexofenadine enantiomers in human plasma. Fexofenadine enantiomers were separated using a mobile phase of 0.5% KH(2)PO(4)-acetonitrile (65:35, v/v) on a Chiral CD-Ph column at a flow rate of 0.5 ml/min and measurement at 220 nm. Analysis required 400 microl of plasma and involved solid-phase extraction with an Oasis HLB cartridge, which gave recoveries for both enantiomers from 67.4 to 71.8%. The lower limit of quantification was 25 ng/ml for (R)- and (S)-fexofenadine. The linear range of this assay was between 25 and 625 ng/ml (regression line r(2)>0.993). Inter- and intra-day coefficients of variation were less than 13.6% and accuracies were within 8.8% over the linear range for both analytes. This method can be applied effectively to measure fexofenadine enantiomer concentrations in clinical samples.

Some pharmacokinetic aspects of the lipophilic terfenadine and zwitterionic fexofenadine in humans.

Fexofenadine, an active metabolite of the second-generation histamine H1 receptor antagonist (antihistamine) terfenadine, does not have the disadvantage of QT prolongation. In addition, unlike first-generation antihistamines, it is associated with few CNS adverse effects. Chemically, fexofenadine has a zwitterionic structure that makes it an interesting molecule for use as an oral drug. Fexo-fenadine has negligible hepatic metabolism in humans, and is recovered mainly in the faeces in an unchanged form after oral administration. The absolute oral bioavailability of fexofenadine in humans is not known because of a lack of studies of intravenous administration of this agent. Its apparent elimination half-life (t1/2) ranges from 3 to 17 hours and is highly dependent on study design, i.e. the length of blood sampling. This large discrepancy might be associated with a 'flip-flop' phenomenon caused by slow absorption of the zwitterionic molecule. This review summarises the available literature related to the absorption, elimination and excretion of fexofenadine and terfenadine. Based on these data, the volume of distribution, t1/2 and oral bioavailability of fexofenadine in humans are estimated. Understanding these pharmacokinetic aspects of this drug might be very useful for medicinal chemists utilising fexofenadine/terfenadine as an example for designing zwitterionic compounds to combat cardiotoxicity and other issues related to basic and lipophilic molecules.

Cetirizine Quantification by High-Performance Liquid Chromatography Tandem Mass Spectrometry (LC-MS/MS).

A multiple reaction monitoring (MRM), positive ion electrospray ionization, LC/MS/MS method is described for the quantification of cetirizine. The compound was isolated from human plasma by protein precipitation using acetonitrile. Cetirizine d4 was used as an internal standard. Chromatographic conditions were achieved using a C18 column and a combination of ammonium acetate, water, and methanol as the mobile phase. MRMs were: cetirizine, 389.26 → 165.16, 201.09; cetirizine d4, 393.09 → 165.15, 201.10. Calibration curves were constructed by plotting the peak area ratios of the calibrators' target MRM transition area to labeled internal standard target MRM transition area versus concentration.

LC-ESI-MS/MS estimation of loratadine-loaded self-nanoemulsifying drug delivery systems in rat plasma: Pharmacokinetic evaluation and computer simulations by GastroPlus™.

A rapid, sensitive, and accurate bioanalytical method was established for the quantitation and pharmacokinetic investigation of loratadine (LTD) in rat plasma by liquid chromatography-electrospray ionization mass spectrometry (LC-ESI-MS/MS) using loratadine-d5 as internal standard (ISTD). The analyte and ISTD were extracted by solid-phase extraction and chromatographic separation was achieved on Gemini NX- Reverse Phase C18 (50 × 4.6mm; 5 µ) using mobile phase mixture of 5mM ammonium formate buffer in water (pH 3.5 ± 0.1 with formic acid), and acetonitrile (20:80 v/v), at a flow rate of 0.400 mL/min with injection volume of 10 µL. LTD and ISTD were detected at m/z 383.3 → 337.4 and 388.4 → 337.3 with retention time of 2.62 and 2.59 min, respectively. High sensitivity (1.0 ng/mL) was achieved using small volume of rat plasma (20 µL) and the method was validated over a linearity range of 1.05-405.41 ng/mL with high correlation coefficient (r = 0.9998). The extraction method displayed a mean process efficiency of 63.25 and 65.47% for LTD and ISTD, respectively. The validated method when successfully applied for quantification of LTD in rat plasma revealed enhanced bioavailability of orally administered LTD-loaded self-nanoemulsifying drug delivery system (SNEDDS) (Cmax, 466.65 ± 18.94 ng/mL and AUC0-t 633.00 ± 12.44 ng-h/mL) over LTD-suspension (Cmax, 104.75 ± 2.87 ng/mL and AUC0-t 287.00 ± 9.11 ng-h/mL). The in vivo-in silico prediction by the GastroPlus™ software showed good prediction accuracy for LTD-SNEDDS (fold error < 2). The Loo-Reigelman method (2-compartment) presented best model-fitting indicating adequate in vitro-in vivo correlations. Conclusively, the developed sensitive analytical method displayed enhanced systemic availability of LTD-SNEDDS, and the in vivo in silico approach revealed sufficiently good GI simulation.

[Study on determination of desloratadine in human serum and its pharmacokinetics by HPLC/MS].

OBJECTIVE: To study the determination of desloratadine in human serum and its pharmacokinetics in healthy volunteers. METHODS: A single oral dose of 10 mg desloratadine was given to 18 healthy volunteers. The serum concentrations of desloratadine were determined by HPLC-MS assay. The pharmacokinetics parameters of desloratadine tablets were calculated with program 3P97. RESULT: The main pharmacokinetics parameters of desloratadine tablets were as followsút(max)(1.611 +/-0.366)h, C(max) (4.455+/-1.990)microg x L(-1), AUC(0-t) (58.50+/-21.34)microg x L(-1) x h(-1), AUC(0-infinity) (60.59+/-22.32)microg x L(-1) x h(-1), t(1/2(ke)) (20.303+/-5.833)h, Ke (0.0372+/-0.0116)h(-1) and CL(0.1838+/-0.0563)L x h(-1). CONCLUSION: Desloratadine tablet is absorbed quicker in the 18 healthy volunteers than the reports and its peak blood concentration reached at 1.5 h after oral administration with t(1/2) 20 h.