Determination of Meserine, a new candidate for Alzheimer's disease in mice brain by liquid chromatography-tandem mass spectrometry and its application to a pharmacokinetic and tissue distribution study.

A rapid and sensitive liquid chromatography-tandem mass spectrometry (LC-MS/MS) method for determination of Meserine ((-)-meptazinol phenylcarbamate), a novel potent inhibitor of acetylcholinesterase (AChE), was developed, validated, and applied to a pharmacokinetic study in mice brain. The lower limit of quantification (LLOQ) was 1 ng mL(-1) and the linear range was 1-1,000 ng mL(-1). The analyte was eluted on a Zorbax SB-Aq column (2.1 × 100 mm, 3.5 µm) with the mobile phase composed of methanol and water (70:30, v/v, aqueous phase contained 10 mM ammonium formate and 0.3% formic acid) using isocratic elution, and monitored by positive electrospray ionization in multiple reaction monitoring (MRM) mode. The flow rate was 0.25 mL min(-1). The injection volume was 5 µL and total run time was 4 min. The relative standard deviation (RSD) of intraday and interday variation was 2.49-7.81 and 3.01-7.67%, respectively. All analytes were stable after 4 h at room temperature and 6 h in autosampler. The extraction recoveries of Meserine in brain homogenate were over 90%. The main brain pharmacokinetic parameters obtained after intranasal administration were T max = 0.05 h, C max = 462.0 ± 39.7 ng g(-1), T 1/2 = 0.4 h, and AUC(0-∞) = 283.1 ± 9.1 ng h g(-1). Moreover, Meserine was distributed rapidly and widely into brain, heart, liver, spleen, lung, and kidney tissue. The method is validated and could be applied to the pharmacokinetic and tissue distribution study of Meserine in mice.

Determination of a novel carbamate AChE inhibitor meserine in mouse plasma, brain and rat plasma by LC-MS/MS: application to pharmacokinetic study after intravenous and subcutaneous administration.

In this paper a simple and sensitive method for determination of a novel phenylcarbamate AChE inhibitor, meserine, in mouse plasma, brain and rat plasma was evaluated using high-performance liquid chromatography-tandem mass spectrometry (LC-MS/MS). Separation was achieved on an Alltech Alltima-C18 column (150mm×2.1mm, 3µm, Deerfield, IL, USA) with isocratic elution at a flow rate of 0.35ml/min. Detection was performed under the multiple reaction monitoring (MRM) mode using an electrospray ionization (ESI) in the positive ion mode. The protein precipitation and liquid-liquid extraction methods were used for the pretreatment of plasma and brain homogenates, respectively. The calibration curves of meserine showed good linearity over the concentration range of 0.5-1000ng/ml for mouse and rat plasma and 0.5-500ng/ml for mouse brain. The intra- and inter-day precision were less than 9.34% and the accuracy was from 95.34% to 107.78% for QC samples. The validated method was successfully applied to a preclinical pharmacokinetic study of meserine in mice and rats after intravenous and subcutaneous administration. The results showed that this novel drug could easily cross the blood-brain barrier to reach the site of drug action. Meserine was rapidly absorbed with a high subcutaneous absolute bioavailability (>90%).

Meptazinol and ethanol: a fatal intoxication.

Meptazinol (Meptid(®)) is an analgesic drug that is used to treat mild to moderate pain including postoperative pain, obstetrical pain, and the pain of renal colic. This case reports a death due to the combined effects of meptazinol and alcohol in a man with significant heart disease and alcoholic liver disease. A 57-year-old male was found unresponsive in his bed at home with empty blister packets of meptazinol around him. A general drug screen detected the presence of meptazinol, and caffeine and metabolites, in cardiac blood. Analysis, both quantitative (HPLC-DAD) and qualitative (HPLC-DAD, LC-MS), of meptazinol was carried out. Meptazinol was found at the following concentrations: 15.5 mg/L in unpreserved femoral blood; 18.6 mg/L in preserved (fluoride-oxalate) femoral blood; 52.1 mg/L in unpreserved cardiac blood; 16.8 mg/L in preserved vitreous; 61.7 mg/L in unpreserved urine; and 9.8 g/L in stomach contents. Ethanol, analyzed by headspace GC-FID, was present in preserved (fluoride-oxalate) femoral venous blood, urine, and vitreous at concentrations of 232 mg/100 mL, 297 mg/100 mL, and 192 mg/100 mL, respectively. Death was attributed to meptazinol and ethanol toxicity, with atherosclerotic coronary artery disease as a contributing factor.

Determination of Bis(9)-(-)-Meptazinol, a bis-ligand for Alzheimer's disease, in rat plasma by liquid chromatography-tandem mass spectrometry: application to pharmacokinetics study.

A rapid, simple and sensitive LC-MS/MS method was developed and validated for the determination of Bis(9)-(-)-Meptazinol (B9M) in rat plasma. Protein precipitation method was used for sample preparation, using five volumes of methanol as the precipitation agent. The analytes were separated by a Zorbax Extend-C18 column with the mobile phase of methanol-water (containing 5mM ammonium formate, pH 9.8) (95:5, v/v), and monitored by positive electrospray ionization in multiple reaction monitoring (MRM) mode. Retention time of IS (Bis(5)-(-)-Meptazinol) and B9M were 1.9 min and 3.3 min, respectively. The limit of detection was 0.1 ng/ml and the linear range was 1-500 ng/ml. The relative standard deviation (RSD) of intra-day and inter-day variation was 4.4-6.2% and 6.2-8.9%, respectively. The extraction recoveries of B9M in plasma were over 95%. The method proved to be applicable to the pharmacokinetic study of B9M in rat after intravenous and subcutaneous administration.

Liquid chromatography/positive ion electrospray tandem mass spectrometry method for the quantification of hydrochloride meptazinol in human plasma: application to a pharmacokinetic study.

A robust and validated liquid chromatography-tandem mass spectrometry (LC-MS/MS) method with positive electrospray ionization (ESI) was developed for the determination of hydrochloride meptazinol in human plasma. After liquid-liquid extraction of 200mul of human plasma, HPLC separation was achieved on a Thermo Hypurity Cyano column, using acetonitrile:ammonium formate (50mM, aq) (70:30, v/v) as the mobile phase. The mass spectrometer was operated in multiple reaction monitoring (MRM) mode using the transition m/z 234-->234 for meptazinol and m/z 152-->110 for the IS (acetaminophen), respectively. The calibration curves were linear over the range of 0.2925-292.5ng/ml, with the limit of quantification (LOQ) 0.2925ng/ml. The mean absolute recovery of hydrochloride meptazinol was more than 70.21%. Intra- and inter-day precisions were less than 9.05% and 12.89%, respectively. And the accuracy was within -2.99% to 4.96%. This method was applied to a pharmacokinetic study of hydrochloride meptazinol tablets in healthy Chinese volunteers.

Enhancement of systemic and CNS delivery of meptazinol hydrochloride by intranasal administration to rats.

AIM: To investigate the extent of systemic absorption and uptake of meptazinol (MEP) hydrochloride in cerebrospinal fluid (CSF) after intranasal administration on rats and compare with oral administration. METHODS: CSF samples were collected by a serial sampling method. The concentration of MEP in the biological samples was measured by HPLC with fluorescence detector. RESULTS: Rapid and significant levels of MEP in plasma and CSF can be achieved after nasal administration whereas the oral administration resulted in considerably lower drug concentrations. AUC in plasma and CSF from the nasal route are 7.375 and 15.6 folds compared with those of the oral route, respectively. CONCLUSION: Intranasal MEP is able to show quick absorption and improve the bioavailability, which could be a promising alternative to oral administration.

Design, synthesis, and bioavailability evaluation of coumarin-based prodrug of meptazinol.

Based on the known coumarin-based prodrug system, a new meptazinol (Z)-3-[2-(propionyloxy) phenyl]-2-propenoic ester (3) was designed and synthesized as prodrug to minimize the first-pass effect of meptazinol (1) and improve the oral bioavailability. The prodrug (3) showed a 4-fold increase in oral bioavailability over the parent drug meptazinol in rats.

Pharmacokinetic behavior in plasma, cerebrospinal fluid and cerebral cortex after intranasal administration of hydrochloride meptazinol.

The aim of this paper is to investigate the pharmacokinetic behavior of hydrochloride meptazinol (MEP) in plasma, cerebrospinal fluid (CSF) and cerebral cortex after intranasal administration (8 mg/kg) in male Sprague-Dawley rats. The pharmacokinetic study of intravenous administration (8 mg/kg) was also performed in rats. CSF and cerebral cortex samples were collected by serial CSF sampling and intracerebral microdialysis, respectively. The concentration of MEP in the biological samples was measured by high performance liquid chromatography (HPLC). It was determined that the absorption of MEP from the nasal cavity to systemic circulation was rapid and complete. The concentration-time profile showed a prolonged duration of MEP concentration in CSF and cortex following intranasal administration. The ratios of AUC values of intranasal to intravenous administrations were 0.96, 1.07 and 1.81 in plasma, CSF and cortex dialysate, respectively. In conclusion, intranasal administration of MEP is a promising alternative to traditional administration modes. Olfactory mucosa did not present intranasal MEP another pathway, in addition to systemic absorption, for transport to the brain.

Synthesis and relative bioavailability of meptazinol benzoyl esters as prodrugs.

Three meptazinol benzoyl esters (1-3) were synthesized as prodrugs to minimize the first-pass effect of meptazinol and improve the bioavailability. Among these three esters, compound 3 showed better bioavailability than the parent meptazinol. Further, the relative regional bioavailability of prodrug 3 was evaluated using in situ closed loop study in rats, which showed that prodrug 3 has higher absorption efficacy in rat intestine. Thusly, prodrug 3 may be worth for further development.

Opioid analgesics.

This article discusses recent developments in opioid pharmacology. Selective activity at different opioid receptors promises, but has not yet provided, a strong analgesic without opioid side-effects. The startling pharmacokinetic profile of the new esterase-metabolized intravenous opioid, remifentanil, is reflected in the rapid onset of effect and short, predictable recovery, independent of duration of infusion.

Determination of the stereoselective aspects in in-vitro and in-vivo metabolism of the analgesic meptazinol by high-performance liquid chromatography.

A reversed-phase high-performance liquid chromatographic method to separate meptazinol and its phase I metabolites has been developed using a LiChrosper 100 CN column and a mobile phase of trimethylammoniumacetate buffer (pH 5.5)-acetonitrile-methanol. Quantification of meptazinol and N-desmethylmeptazinol in biological samples was achieved by extraction with organic solvents and chromatographic analysis (detection limit 0.4 and 0.25 micrograms/ml, respectively). Afterwards the enantiomeric ratio of the two compounds was determined on a Chiral AGP column with a mobile phase of phosphate buffer (pH 7.0)-acetonitrile (alpha = 1.29 and 1.49, respectively). In-vitro metabolism data after incubation of the racemic compound and the enantiomers with liver supernatant and microsomes of different species are presented. Finally urinary data of two volunteers after oral application of the racemic drug were determined.

The systemic availability of meptazinol in man after oral and rectal doses.

We have studied the pharmacokinetics of the centrally-acting analgesic meptazinol after oral and rectal administration to 15 healthy men. Each subject took a standard 200 mg tablet orally and Witepsol H12 suppositories containing 75, 100, and 150 mg of the drug in a cross-over design. Meptazinol plasma concentrations were measured by HPLC using fluorescence detection and the pharmacokinetics determined. The tmax values for the 100 mg and 150 mg suppositories (median = 0.5 h) were statistically significantly shorter than for the tablet (median = 1.13 h), suggesting that meptazinol was more rapidly absorbed via the rectal route. Despite substantial intersubject variation in Cmax the plasma concentrations after rectal dosage were higher than after oral administration. There was a statistically significant (p less than 0.001) improvement in systemic availability for each of the suppository doses (mean approximately 15.5% compared with the oral tablet (mean approximately 4.5%).

The disposition of meptazinol after single and multiple intravenous administration to pregnant and non-pregnant women.

We have studied the disposition of the centrally-acting analgesic meptazinol in a group of age-matched non-pregnant and pregnant (36-38 weeks gestation) women. Ten non-pregnant and nine multiparous pregnant volunteers each received a single i.v. dose of meptazinol hydrochloride (equivalent to 25 mg base). A further group of 9 non-pregnant (including four of the original participants) and 10 multiparous pregnant subjects were given repeated i.v. doses of meptazinol hydrochloride (each equivalent to 10 mg base) at 30-min intervals for 2.5 h. Meptazinol plasma concentrations were determined by HPLC using fluorescence detection and the pharmacokinetic variables investigated. After single dosing there were no statistical differences in half-life, clearance, or apparent volume of distribution between the two groups, suggesting that the disposition of meptazinol was not altered by pregnancy. This was confirmed in the repeated dose study, in which no significant differences occurred in either the plasma concentrations achieved or in areas under the curves between the non-pregnant and pregnant subjects. Furthermore, the steady-state concentrations were comparable with those predicted from the single dose results. This indicates that there should be no requirement for dosage alteration of meptazinol during pregnancy.

The clinical pharmacokinetics and metabolism of the analgesic meptazinol.

1. The analgesic drug meptazinol is rapidly and completely absorbed after oral, intramuscular (i.m.) and rectal dosage. However, the absolute bioavailability of the drug following oral dosage is low (4.5-8.7%). Rectal administration leads to a higher bioavailability (15.5%) while after i.m. dosage the drug is totally systemically available. 2. Meptazinol is widely distributed outside the vasculature (Vd*area 5.9 l/kg) partly due to the low degree of binding to plasma proteins (27% bound) and also the relatively high lipophilicity of the unionized species (log P = 2.7). 3. Elimination of the drug from plasma proceeds rapidly (t1/2 2 h) largely as the result of glucuronidation and sulphation of the phenolic function in the molecule. The major route of excretion is via the urine, greater than 70% of the dose appearing in the 0-24 h urine collection almost entirely as conjugated metabolites. 4. After multiple dosing, orally or parenterally, there is no accumulation above that predicted from single dose kinetics. 5. The pharmacokinetics of the drug are generally unaltered by age (neonates to geriatrics) and pregnancy. Renal disease also has no effect in this respect, although cirrhotic liver disease results in up to a 4-fold increase in oral bioavailability. 6. Only limited data are available on the pharmacokinetics of meptazinol when given with other drugs. Alcohol appears to have no effect, while general anaesthesia appears to reduce clearance of the drug.

Disposition and pharmacokinetics of meptazinol in the CSF. Studies after intrathecal administration in the non-human primate Erythrocebus patas.

A preliminary study is reported on the kinetics of meptazinol following intrathecal and i.m. administration in the Patas monkey. Following intrathecal administration (single dose of 0.5 mg) at T12/L1, meptazinol rapidly disappeared from the CSF with a T1/2 of 35 min. At 240 min after intrathecal injection, most of the meptazinol had been distributed within the spinal tissue near the region of the injection, with minimal amounts reaching the brain (less than 5% of the concentrations present in the lumbar and thoracic tissue). Following i.m. administration (16 mg kg-1) peak concentrations were present in the CSF and plasma within 60 min. Appreciable concentrations persisted in the CSF up to 180 min after i.m. administration. The results would suggest that meptazinol should give rapid but short acting pain relief following intrathecal injection with minimal CNS-related side effects.