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.

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.

A novel method to calculate the extent and amount of drug transported into CSF after intranasal administration.

The aim of this paper is to establish a novel method to calculate the extent and amount of drug transported to brain after administration. The cerebrospinal fluid (CSF) was chosen as the target region. The intranasal administration of meptazinol hydrochloride (MEP) was chosen as the model administration and intravenous administration was selected as reference. According to formula transform, the extent was measured by the equation of X(A)CSF, infinity/X0 = Cl(CSF) AUC(0-->infinity)CSF/X0 and the drug amount was calculated by multiplying the dose with the extent. The drug clearance in CSF (Cl(CSF)) was calculated by a method, in which a certain volume of MEP solution was injected directly into rat cistern magna and then clearance was assessed as the reciprocal of the zeroth moment of a CSF level-time curve normalized for dose. In order to testify the accurateness of the method, 14C-sucrose was chosen as reference because of its impermeable characteristic across blood-brain barrier (BBB). It was found out that the MEP concentrations in plasma and CSF after intranasal administration did not show significant difference with those after intravenous administration. However, the extent and amount of MEP transported to CSF was significantly lower compared with those to plasma after these two administrations. In conclusion, the method can be applied to measure the extent and amount of drug transported to CSF, which would be useful to evaluate brain-targeting drug delivery.

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.

Meptazinol for postoperative pain relief in man. Comparison of extradural and i.m. administration.

The analgesic and cardiorespiratory effects of meptazinol 90 mg, given by the extradural or the i.m. route, were studied in 32 postoperative patients. Plasma meptazinol concentrations were measured in five patients in each treatment group. Evaluation using a linear analogue scale indicated that there were significant differences between the groups in the onset, quality and duration of pain relief, with the extradural route being superior to the i.m. route in each instance. The difference in quality of pain relief was not related to the resultant plasma meptazinol concentrations, which were similar in the two groups. Ventilatory rate was decreased equally in both groups in parallel with pain relief, but no incidence of overt respiratory depression was noted. Meptazinol produced no meaningful changes in measured cardiovascular variables, and side effects were minimal in both groups.

Pharmacokinetics of meptazinol after parenteral administration in the elderly.

We have determined the pharmacokinetics of meptazinol after its intravenous and intramuscular administration in a crossover study in 7 elderly hospital in-patients (greater than 70 years), and have compared with the results from 14 healthy, young volunteers (ages 20-40 years). The systemic availability after i.m. administration was comparable to that after i.v. administration, a result consistent with the physicochemical properties of the drug. There was a slight, but statistically significant (p less than 0.01) prolongation in t1/2Z in the elderly (mean 2.93 h) compared with the young (mean 2.06 h). This was associated with a 25% lower clearance in the elderly rather than with any alteration in volume of distribution. However, these changes would not appear to be substantial enough to require a revised dosage recommendation for meptazinol for this age group.

Pharmacokinetics of intravenously administered meptazinol during general anaesthesia in man.

The pharmacokinetics of meptazinol (3 mg kg-1 i.v.), a centrally acting opioid agonist-antagonist, were studied in six male and six female patients during anaesthesia with 1-3 vol.% enflurane and an infusion of 10-30 micrograms kg-1 min-1 etomidate. Arterial blood samples were taken up to 300 min postinjection. The plasma meptazinol concentrations, determined by HPLC, best fitted to a three-compartment open mamillary model with central elimination using a non-linear extended least-squares regression analysis. Derived pharmacokinetic parameters indicated a rapid distribution (T1/2 pi = 1.24 +/- 0.83 min, T1/2 alpha = 7.55 +/- 3.97 min), a short elimination half-life (T1/2 beta = 86.9 +/- 15.6 min), a volume of the central compartment twice as large in females (Vc = 0.557 +/- 0.237 l kg-1) as in males (Vc = 0.274 +/- 0.144 l kg-1), a small distribution volume at steady state (Vss = 2.52 +/- 0.66 l kg-1) and a high total plasma clearance (ClP = 1547 +/- 385 ml min-1). The elimination rate microconstant in females (k10 = 0.0577 +/- 0.0337 min-1) was significantly lower than in males (k10 = 0.1093 +/- 0.0437 min-1 with a lower drug fraction in the central compartment in the post-distributive phase (Fc = males: 0.08 +/- 0.02, females 0.19 +/- 0.11). As Vss and ClP were similar in both groups, sex-related differences were only observed in the dynamics of distribution of the drug. From a pharmacokinetic point of view we suspect that meptazinol shows very little cumulation on repeated i.v. administration as necessary during anaesthesia.

Pharmacokinetics of meptazinol after single and multiple oral administration to elderly patients.

Oral administration of meptazinol (200 mg Meptid) to male and female geriatric patients (greater than 70 years) resulted in rapid absorption, with peak drug concentrations at 0.5 to 3 h after dosage. Subsequent elimination also proceeded rapidly with a half-life of 3.39 h (+/- 0.26 SEM) after a single dose and 4.97 h (+/- 0.80 SEM) after 13 consecutive 6-h doses. These values were not statistically different. There was no accumulation of meptazinol above that expected from the single-dose kinetics. Plasma protein binding of meptazinol was 33.8% (+/- 0.74 SEM). No sex difference was apparent in any of the pharmacokinetic parameters determined. Comparison of these results with those obtained in an earlier study in young volunteers showed that although the half-life of meptazinol was somewhat longer than the value of 2 h seen in the young, peak plasma concentrations after single and multiple dosing were similar for both age groups, implying that clearance remained largely unaltered. It was concluded that there was no pharmacokinetic basis for recommending a reduction in dosage when treating elderly patients with oral meptazinol.

Pharmacokinetics of meptazinol in man following repeated intramuscular administration.

A study was performed in 6 healthy volunteers to determine whether 50 mg intramuscular doses of meptazinol repeated four hourly for 24 h would lead to accumulation of the drug. The first dose of meptazinol was rapidly absorbed with a subsequent mean (+/- SD) elimination half-life of 1.6 +/- 0.33 h. This value was unaffected by the administration of intermediate doses. There was no significant accumulation of the drug; 95% of the steady-state plasma concentration was achieved after a mean (+/- SD) of 1.9 +/- 0.39 and 99% after a mean (+/- SD) of 2.9 +/- 0.63 doses. These findings are consistent with the theoretical prediction for a rapidly absorbed drug with a plasma elimination half-life of 1.6 h. No clinically relevant changes were seen in pulse blood pressure, haematological or biochemical screens. Reported side effects were of a subjective and minor nature.