Pharmacokinetics of fexofenadine: Evaluation of a microdose and assessment of absolute oral bioavailability

Lappin, Graham; Shishikura, Yoko; Jochemsen, R.; Weaver, Richard J.; Gesson, Charlotte; Houston, B.; Oosterhuis, B.; Bjerrum, Ole J.; Rowland, Malcolm; Garner, Colin

doi:10.1016/j.ejps.2010.03.009

Cited by 98 publications

(70 citation statements)

References 25 publications

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“…dose at the T max of the oral dose determines i.v. pharmacokinetics at therapeutically relevant concentrations of the compound, thereby addressing concerns regarding pharmacokinetic linearity of the microdose, and improves precision of the bioavailability estimate due to the lack of interoccasion variability 8, 9, 10, 11…”

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confidence: 99%

“…The microtracer approach, where doses are typically 1/100th to 1/1,000th of the therapeutic dose (or ≤100 μg), and, in cases in which radioisotopes are administered, radioactivity is <1,000 nCi, provides several advantages over traditional methods 8, 9, 10, 11. If the radioactive dose administered is very low (<1,000 nCi), subjects are exposed to extremely low amounts of radiation; therefore, supporting data from dosimetry studies in animals are not required 8.…”

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confidence: 99%

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Novel Application of the Two‐Period Microtracer Approach to Determine Absolute Oral Bioavailability and Fraction Absorbed of Ertugliflozin

Raje

Callegari

Sahasrabudhe

et al. 2018

Clinical Translational Sci

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Ertugliflozin, a sodium glucose cotransporter‐2 inhibitor, is approved in the United States for treatment of type 2 diabetes mellitus. A novel two‐period study design with 14C microtracer dosing in each period was used to determine absolute oral bioavailability (F) and fraction absorbed (Fa) of ertugliflozin. Eight healthy adult men received 100‐μg i.v. 14C‐ertugliflozin (400 nCi) dose 1 h after a 15‐mg oral unlabeled ertugliflozin dose (period 1), followed by 100 μg 14C‐ertugliflozin orally along with 15 mg oral unlabeled ertugliflozin (period 2). Unlabeled ertugliflozin plasma concentrations were determined using high‐performance liquid‐chromatography tandem mass spectrometry (HPLC‐MS/MS). 14C‐ertugliflozin plasma concentrations were determined using HPLC‐accelerator mass spectrometry (AMS) and 14C urine concentrations were determined using AMS. F ((area under the curve (AUC)p.o./14C‐AUCi.v.)*(14C‐Dosei.v./Dosep.o.)) and Fa ((14C_Total_Urinep.o./14C_Total_Urinei.v.)* (14C‐Dosei.v./14C‐Dosep.o.)) were estimated. Estimates of F and Fa were 105% and 111%, respectively. Oral absorption of ertugliflozin was complete under fasted conditions and F was ∼100%. Ertugliflozin was well tolerated.

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confidence: 99%

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confidence: 99%

Novel Application of the Two‐Period Microtracer Approach to Determine Absolute Oral Bioavailability and Fraction Absorbed of Ertugliflozin

Raje

Callegari

Sahasrabudhe

et al. 2018

Clinical Translational Sci

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“…[7][8][9][10][11][12][13][14] However, the drug concentration of samples in a microdose study cannot be measured at an LLOQ of only ng/mL because of lack of sensitivity. 5,6,[15][16][17][18][19][20] In case of employing SPE or liquid-liquid extraction for sample preparation, it is possible to set the LLOQ at pg/mL, but total sample analysis is required, which demands increased time as the procedure of sample preparation is quite complex. 6,[15][16][17][18] If an online SPE method could be established to reduce the time required for sample preparation, Regular Article * To whom correspondence should be addressed.…”

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confidence: 99%

“…Fexofenadine, a non-radiolabeled compound, is an antihistamine drug that was orally administrated at a dose of 100 µg/ man/d in the first microdose clinical study in Japan in 2005; subsequently, the concentration of fexofenadine in human plasma was measured by LC-MS/MS. 5,6) The lower limit of quantification (LLOQ) was 10 pg/mL when the concentration of fexofenadine in human plasma, prepared by solid-phase extraction (SPE), was determined using LC-MS/MS. Previous studies have frequently used the protein precipitation method using an organic solvent for sample treatment and the LLOQs in the "ng/mL" range to determine the concentration of fexofenadine in biological samples by LC-MS/MS.…”

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confidence: 99%

Development of a Highly Sensitive Methodology for Quantitative Determination of Fexofenadine in a Microdose Study by Multiple Injection Method Using Ultra-High Performance Liquid Chromatography with Tandem Mass Spectrometry

Tanaka

Yoshikawa

Yasui

2012

Biological & Pharmaceutical Bulletin

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An ultra high-sensitivity method for quantifying fexofenadine concentration in rat plasma samples by multiple injection method (MIM) was developed for a microdose study. In this study, MIM involved continuous injections of multiple samples containing the single compound into a column of the ultra-HPLC (UHPLC) system, and then, temporary trapping of the analyte at the column head. This was followed by elution of the compound from the column and detection by mass spectrometer. Fexofenadine, used as a model compound in this study, was extracted from the plasma samples by a protein precipitation method. Chromatographic separation was achieved on a reversed-phase C18 column by using a gradient method with 0.1% formic acid and 0.1% formic acid in acetonitrile as the mobile phase. The analyte was quantified in the positive-ion electrospray ionization mode using selected reaction monitoring. In this study, the analytical time per fexofenadine sample was approximately 2 min according to the UHPLC system. The method exhibited the linear dynamic ranges of 5-5000 pg/mL for fexofenadine in rat plasma. The intra-day precisions were from 3.2 to 8.7% and the accuracy range was 95.2-99.3%. The inter-day precisions and accuracies ranged from 3.5 to 8.4% and from 98.6 to 102.6%, respectively. The validated MIM was successfully applied to a microdose study in the rats that received oral administration of 100 µg/kg fexofenadine. We suggest that this method might be beneficial for the quantification of fexofenadine concentrations in a microdose clinical study.

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“…There are several barriers to the oral delivery of such drugs, including luminal enzymatic hydrolysis, low solubility, and low membrane permeability. 31,32 Fexofenadine has good stability against enzymatic hydrolysis and at different pH values. 33 For fexofenadine, low membrane permeability is the main barrier to its oral absorption.…”

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confidence: 99%

Improvement of effect of water-in-oil microemulsion as an oral delivery system for fexofenadine: in vitro and in vivo studies

Gündoğdu¹,

Álvarez²,

Karasulu³

2011

IJN

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Fexofenadine (FEX) has high solubility and low permeability (BCS, Class III). In this work, novel FEX loaded water in oil microemulsion (w/o) was designed to improve bioavailability and compared with Fexofen ® syrup in in vitro and in vivo studies. In addition, pharmacokinetic parameters in permeability studies were estimated by using WinNonLin software program. w/o microemulsion system was optimized using a pseudoternary phase diagram, composed of span 80/lutrol F 68 (9.5:0.5 w/w), oleic acide, isopropyl alcohol and water as surfactant mixture; oil and cosurfactant was developed for oral drug delivery. w/o microemulsion systems were characterized by phase behavior, particle size, viscosity and solubilization capacity. In vitro studies were studied using Caco-2 cell monolayer. Pharmacokinetic parameters of w/o microemulsion were investigated in rabbits and compared to Fexofen ® syrup. Fexofen ® syrup and microemulsion were administered by oral gavage at 6 mg/kg of the same concentration. The experimental results indicated that microemulsion (HLB = 5.53) formed nanometer sized droplets (33.29 ± 1.76) and had good physical stability. This microemulsion increased the oral bioavailability of FEX which was highly water-soluble but fairly impermeable. The relative bioavailability of FEX microemulsion was about 376.76% compared with commercial syrup in rabbits. In vitro experiments were further employed for the enhanced effect of the microemulsion for FEX. These results suggest that novel w/o microemulsion plays an important role in enhancing oral bioavailability of low permeability drugs.

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Pharmacokinetics of fexofenadine: Evaluation of a microdose and assessment of absolute oral bioavailability

Cited by 98 publications

References 25 publications

Novel Application of the Two‐Period Microtracer Approach to Determine Absolute Oral Bioavailability and Fraction Absorbed of Ertugliflozin

Novel Application of the Two‐Period Microtracer Approach to Determine Absolute Oral Bioavailability and Fraction Absorbed of Ertugliflozin

Development of a Highly Sensitive Methodology for Quantitative Determination of Fexofenadine in a Microdose Study by Multiple Injection Method Using Ultra-High Performance Liquid Chromatography with Tandem Mass Spectrometry

Improvement of effect of water-in-oil microemulsion as an oral delivery system for fexofenadine: in vitro and in vivo studies

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