Facile Hydrolysis of Mebeverine In Vitro and In Vivo: Negligible Circulating Concentrations of the Drug after Oral Administration

Dickinson, R. G.; Baker, Peter V.; Franklin, Michael E.; Hooper, W. D.

doi:10.1002/jps.2600801010

Cited by 34 publications

(14 citation statements)

References 16 publications

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“…By contrast, the metabolite veratric acid achieved considerable concentrations (mean peak plasma concentration of 13.5 μg/mL at (40-80 min) [11]. Veratic acid (MEB metabolite) is also highly fluorescent compound and the second metabolite is mebeverine alcohol which is non-fluorescent at the studied pH 4 [12].…”

Section: Resultsmentioning

confidence: 99%

Simultaneous determination of sulpiride and mebeverine by HPLC method using fluorescence detection: application to real human plasma

Walash

El-Din

El‐Enany

et al. 2012

Chemistry Central Journal

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A new simple, rapid and sensitive reversed-phase liquid chromatographic method was developed and validated for the simultaneous determination of sulpiride (SUL) and mebeverine Hydrochloride (MEB) in the presence of their impurities and degradation products. The separation of these compounds was achieved within 6 min on a 250 mm, 4.6 mm i.d., 5 m particle size Waters®-C18 column using isocractic mobile phase containing a mixture of acetonitrile and 0.01 M dihydrogenphosphate buffer (45:55) at pH = 4.0. The analysis was performed at a flow rate of 1.0 mL/min with fluorescence-detection at excitation 300 nm and emission at 365 nm. The concentration-response relationship was linear over a concentration range of 10- 100 ng/mL for both MEB and SUL with a limit of detection 0.73 ng/mL and 0.85 ng/mL for MEB and SUL respectively. The proposed method was successfully applied for the analysis of both MEB and SUL in bulk with average recoveries of 100.22 ± 0.757% and 99.96 ± 0.625% respectively, and in commercial tablets with average recoveries of 100.04 ± 0.93% and 100.03 ± 0.376% for MEB and SUL respectively. The proposed method was successfully applied to the determination of MEB metabolite (veratic acid) in real plasma simultaneously with SUL. The mean% recoveries (n = 3) for both MEB metabolite (veratic acid) and SUL were 100.36 ± 2.92 and 99.06 ± 2.11 for spiked human plasma respectively. For real human plasma, the mean% recoveries (n = 3) were and respectively.

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Section: Resultsmentioning

confidence: 99%

Simultaneous determination of sulpiride and mebeverine by HPLC method using fluorescence detection: application to real human plasma

Walash

El-Din

El‐Enany

et al. 2012

Chemistry Central Journal

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“…Because of the relatively short biological half-life of the drug (Dickinson et al 2006), previous trials were performed to formulate the drug as sustained release microspheres (Bayomi et al 1994). As a consequence, targeting drugs to the colon has major advantages in the direct treatment of colonic disorders, since the residence time is more than 24 h (Sinha and Kumria 2001).…”

Section: Introductionmentioning

confidence: 99%

Colon-specific drug delivery for mebeverine hydrochloride

Omar

Aldosari

Refai

et al. 2007

Journal of Drug Targeting

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Mebeverine Hydrochloride (MB-HCl), an effective spasmolytic drug, was formulated as CODES. A colon-specific drug delivery technology CODES was designed to avoid the inherent problems associated with pH- or time-dependent systems. To achieve more protection and control of drug release, MB-HCl was prepared as microspheres and compressed as core tablets of CODES (modified CODES). The core tablets contained the drug either in free form [Formula 1 (F(1))], or as microspheres with 2 different polymer:drug:lactulose ratios (1:1:0.5 [Formula 2 (F(2))] and 2:1:0.5 [Formula 3 (F(3))]. The release profiles of the coated CODES systems were compared with uncoated compressed tablets. The uncoated tablet showed a drug release of 94% after 1 h in simulated gastric condition (pH = 1.2). The release characteristics of the coated systems revealed that the enteric coating (Eudragit L(100)) prevented any drug release in simulated gastric or duodenal conditions in the first 3 h (pH 1.2-6.1), after which drug was slightly liberated in simulated intestinal fluid (pH 7.4) {Phase 1 (P1)}. After 4 h the pH was adjusted to 7 and beta-glucose-oxidase was added, which is an enzyme produced by enterobacteria present in the colon. The acid-soluble coat (Eudragit)E(100)) dissolved and the drug release suddenly increased to reach 95, 72 and 60.4% for F(1)-F(3), respectively. IR spectrum study showed a covalent bond between the drug and the polymer in the formulae F(2) and F(3) resulting in the sustained drug release from the microspheres with a significant difference (p>0.05) to F(1). The findings were confirmed by in vivo investigation using X-ray images for Guinea pigs ingested tablets containing barium sulphate (F(4)), where the tablet began to disintegrate after 10 h of tablet intake. The results of the study indicated that MB-HCl CODES colon-specific drug delivery can act as a successful trigger for drug targeting in the colon. Furthermore, a sustained release of the drug can be achieved from modified CODES containing the drug in the form of microspheres.

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“…There are no published data on its pharmacokinetics in humans, and it is possible that MEB is not bioavailable because of rapid and extensive presystemic hydrolysis in the gut and/or the liver . When administered intravenously, MEB decreases heart rate by 5–33% of the resting rate, but this has never been described for oral administration.…”

Section: Introductionmentioning

confidence: 99%

“…Furthermore, the hydrolysis products of MEB (veratric acid and MEB alcohol) are not known to be pharmacologically active. The esterase inhibitor physostigmine sulfate selectively blocks ex vivo hydrolysis of MEB to veratric acid in fresh human plasma …”

Section: Introductionmentioning

confidence: 99%

“…The esterase inhibitor physostigmine sulfate selectively blocks ex vivo hydrolysis of MEB to veratric acid in fresh human plasma. 4 Although MEB has a chiral center with two (+) and (À) enantiomers, it is clinically administered as a racemic mixture. MEB itself shows clear antispasmodic activity, but its main metabolites, MEB alcohol and veratric acid, do not seem to possess any action on smooth muscles.…”

Section: Introductionmentioning

confidence: 99%

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Fiber‐Based Liquid‐Phase Micro‐Extraction of Mebeverine Enantiomers Followed by Chiral High‐Performance Liquid Chromatography Analysis and Its Application to Pharmacokinetics Study in Rat Plasma

2012

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The applicability of two-phase liquid-phase micro-extraction (LPME) in porous hollow polypropylene fiber for the sample preparation and the stereoselective pharmacokinetics of mebeverine (MEB) enantiomers (an antispasmodic drug) in rat after intramuscular administration were studied. Plasma was assayed for MEB enantiomer concentrations using stereospecific high-performance liquid chromatography with ultraviolet detection after a simple, inexpensive, and efficient preconcentration and clean-up hollow fiber-based LPME. Under optimized micro-extraction conditions, MEB enantiomers were extracted with 25 µl of 1-octanol within a lumen of a hollow fiber from 0.5 ml of plasma previously diluted with 4.5 ml alkalized water (pH 10). The chromatographic analysis was carried out through chiral liquid chromatography using a DELTA S column and hexane-isopropyl alcohol (85:15 v/v) containing 0.2% triethylamine as mobile phase. The mean recoveries of (+)-MEB and (-)-MEB were 75.5% and 71.0%, respectively. The limit of detection (LOD) was 3.0 ng/ml with linear response over the concentration range of 10-2500 ng/ml with correlation coefficient higher than 0.993 for both enantiomers. The pharmacokinetic studies showed that the mean plasma levels of (+)-MEB were higher than those of (-)-MEB at almost all time points. Also, (+)-MEB exhibited greater t(max) (peak time in concentration-time profile), C(max) (peak concentration in concentration-time profile), t(1/2) (elimination half-life), and AUC(0-240 min) (area under the curve for concentration versus time) and smaller CL (clearance) and V(d) (apparent distribution volume) than its antipode. The obtained results implied that the absorption, distribution, and elimination of (-)-MEB were more rapid than those of (+)-MEB and there were stereoselective differences in pharmacokinetics.

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Facile Hydrolysis of Mebeverine In Vitro and In Vivo: Negligible Circulating Concentrations of the Drug after Oral Administration

Cited by 34 publications

References 16 publications

Simultaneous determination of sulpiride and mebeverine by HPLC method using fluorescence detection: application to real human plasma

Simultaneous determination of sulpiride and mebeverine by HPLC method using fluorescence detection: application to real human plasma

Colon-specific drug delivery for mebeverine hydrochloride

Fiber‐Based Liquid‐Phase Micro‐Extraction of Mebeverine Enantiomers Followed by Chiral High‐Performance Liquid Chromatography Analysis and Its Application to Pharmacokinetics Study in Rat Plasma

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