Meperidine pharmacokinetics and effects on physiologic parameters and thermal threshold following intravenous administration of three doses to horses.

BACKGROUND: Meperidine is a synthetic opioid that belongs to the phenylpiperidine class and is a weak mu receptor agonist. In horses there are a limited number of published studies describing the analgesic effects of systemically administered meperidine in horses. The objective of this study was to describe the pharmacokinetics, behavioral and physiologic effects and effect on thermal threshold of three doses of intravenously administered meperidine to horses. Eight University owned horses (four mares and four geldings, aged 3-8 years were studied using a randomized balanced 4-way cross-over design. Horses received a single intravenous dose of saline, 0.25, 0.5 and 1.0 mg/kg meperidine. Blood was collected before administration and at various time points until 96 hours post administration. Plasma and urine samples were analyzed for meperidine and normeperidine by liquid chromatography-mass spectrometry and plasma pharmacokinetics determined. Behavioral and physiologic data (continuous heart rate, step counts, packed cell volume, total plasma protein and gastrointestinal sounds) were collected at baseline through 6 hours post administration. The effect of meperidine administration on thermal nociception was determined and thermal excursion calculated. RESULTS: Meperidine was rapidly converted to the metabolite normeperidine. The volume of distribution at steady state and systemic clearance (mean ± SD) ranged from 0.829 ± 0.138-1.58 ± 0.280 L/kg and 18.0 ± 1.4-22.8 ± 3.60 mL/min/kg, respectively for 0.5-1.0 mg/kg doses. Adverse effects included increased dose-dependent central nervous excitation, heart rate and cutaneous reactions. Significant effects on thermal nociception were short lived (up to 45 minutes at 0.5 mg/kg and 15 minutes at 1.0 mg/kg). CONCLUSIONS: Results of the current study do not support routine clinical use of IV meperidine at a dose of 1 mg/kg to horses. Administration of 0.5 mg/kg may provide short-term analgesia, however, the associated inconsistent and/or short-term adverse effects suggest that its use as a sole agent at this dose, at best, must be cautiously considered.

Determination of pethidine of abuse and relevant metabolite norpethidine in urine by ultra-performance liquid chromatography-tandem mass spectrometry.

Pethidine is an opiate agonist used orally and parenterally. Pethidine-containing drugs abuse is frequently encountered on health workers and patients. The analysis methods used to determine the abuse of pethidine are important for forensic toxicology. Pethidine is metabolized to norpethidine by the liver. Therefore, the determination of pethidine and norpethidine in urine is one of the methods to determine the abuse of pethidine. In this study, we have developed a precise, simple and rapid ultra-performance liquid chromatography-tandem mass spectrometer method for the determination of pethidine and norpethidine simultaneously. The developed method was validated in terms of selectivity and linearity which was in the range of 9-1800 ng/mL for both pethidine and norpethidine. The intra-assay and inter-assay accuracy and precision were found within acceptable limits of the EMA guideline. Lower limits of quantitation were 9 ng/mL for both pethidine and norpethidine. The developed method was successfully applied for the determination of both analytes in the real samples.

Metabolic Patterns of Fentanyl, Meperidine, Methylphenidate, Tapentadol and Tramadol Observed in Urine, Serum or Plasma.

Drug testing is a useful tool to identify drug use or monitor adherence to prescription drugs. The interpretation of drug results can be complicated based on the pattern and proportional concentrations of drugs and/or drug metabolite(s). The purpose of this retrospective study was to detect the positivity rates and metabolic patterns of five prescription drugs, including fentanyl, meperidine, methylphenidate, tapentadol and tramadol. Retrospective data were retrieved from the laboratory information system in a national reference laboratory. Drug testing was performed using four mass spectrometry methods that were validated for clinical use. For urine specimens, the positivity rate was the highest for methylphenidate (62.3%, n = 2,489), followed by tramadol (43.7%, n = 3,483), fentanyl (41.9%, n = 4,657), tapentadol (37.9%, n = 736) and meperidine (8.3%, n = 138). Among positive samples, both parent drug and metabolite(s) was detectable in 94.9% of meperidine samples, 94.5% of tramadol samples, 93.8% of fentanyl samples, 89.9% of methylphenidate and 86.6% of tapentadol samples. For serum or plasma specimens, the positivity rate was the highest for tapentadol (75.0%, n = 39), followed by methylphenidate (74.2%, n = 569), fentanyl (53.6%, n = 113), meperidine (41.9%, n = 18) and tramadol (28.9%, n = 213). Similar metabolic patterns were found in serum or plasma. Of positive results, both parent drug and metabolite(s) were found in 94.7% of fentanyl samples, 83.3% of meperidine samples, 79.6% of methylphenidate samples, 53.8% of tapentadol samples and 44.1% of tramadol samples. Our data demonstrates the metabolic patterns of five drugs from a random urine or serum/plasma collection in patients that have been prescribed these medications. The data presented can be used to guide clinicians in determining drug adherence by assessing the positivity rates of the parent drug and corresponding metabolite(s).

Factors impacting variability of the urinary normeperidine-to-meperidine metabolic ratio in patients with chronic pain.

Meperidine (Demerol(®)) is a mu- and kappa-opiate receptor agonist used for moderate to severe pain. Overdose can result in respiratory depression, hypotension and coma, while accumulation of its toxic metabolite, normeperidine, can cause delirium and seizures. Little data exist examining the inter- and intrasubject variability of the normeperidine-to-meperidine metabolic ratio (MR) in urine. This retrospective data analysis examined meperidine and normeperidine urine concentrations collected from chronic pain patients. In 98 subjects with multiple visits, the geometric mean urinary MR = 6.1 (coefficient of variation, %CV = 68%). From single specimens obtained from 799 subjects, the geometric mean urinary MR = 6.2 (%CV = 212%). The urinary MR increased in young subjects compared with elderly (P = 0.004) and middle-aged subjects (P = 0.01). A 27% difference was found between the male and female urinary MR (male geometric mean MR = 5.1, female geometric mean MR = 7.0, P = 0.02). Intersubject variability in meperidine metabolism was 3-fold greater than intrasubject variability. A significant difference in the urinary MR was found between males and females. The substantial variability in meperidine metabolism and the serious side effects of its metabolite normeperidine require greater vigilance in patient medication monitoring.

Pethidinic acid: corroboration of a doctor's denial of pethidine re-use.

Pethidine (meperidine), a synthetic opiate, formally used as an analgesic in surgery and obstetrics, has been an abused drug of choice for some doctors. A case is presented in which a doctor, who previously admitted to using pethidine, was suspected of re-using, following a second positive urine test. A laboratory had reported the presence of pethidine in the doctor's urine; however, the doctor denied re-use. The norpethidine (normeperidine) metabolite, normally found in urine, had not been detected, raising concern over the laboratory's conclusion and necessitating an independent investigation. Because the major metabolite of pethidine is pethidinic acid (meperidinic acid), accounting for approximately 40% of the excreted dose, its presence or absence were deemed to be important criteria in interpreting the laboratory result. Pethidinic acid was synthesized by alkaline hydrolysis of pethidine and used as a control. Urine samples from a patient receiving pethidine for pain, from the previous pethidine use of the doctor, and the urine under question plus the control were analyzed for the presence of pethidinic acid using electrospray mass spectrometry. Pethidinic acid was found in all samples except the one under dispute. The absence of pethidinic acid appeared to corroborate the doctor's denial of re-use.

Determination of pethidine hydrochloride using potentiometric coated graphite and carbon paste electrodes.

A new approach for lowering the detection limit of a pethidine ion-selective electrode is presented. A coated graphite (CGE) and carbon paste (CPE) electrodes for pethidine ions based on pethidine-phosphotungstate (PD-PT) as ion-pair complex are described. The sensors exhibit a Nernstian slope of 58.1 and 54.2 mVdecade(-1) for pethidine ion over a wide concentration range from 2.6 × 10(-7) to 1.0 × 10(-2) M and 2.1 × 10(-6) to 1.0 × 10(-2) M with a detection limit of 1.8 × 10(-7) M and 7.3 × 10(-7) M for pethidine coated graphite (PD-CGE) and pethidine carbon paste electrode (PD-CPE), respectively. These sensors exhibited a fast response time (about 5-8 s) and good stability. The standard electrode potentials, E(o) , were determined at different temperatures and used to calculate the isothermal temperature coefficient (dE(o) /dT) of the PD-CGE and PD-CPE, which was 0.0062 and 0.0071 V/ °C, respectively. Selectivity coefficients, determined by matched potential method (MPM) and separate solution method (SSM), showed high selectivity for pethidine hydrochloride (PDCl) over a large number of inorganic cations, organic cations, sugars, urine components, and some common drug excipients. The sensors were applied for determination of PDCl in ampoule and in spiked urine samples using potentiometric determination, standard addition and the calibration curve methods. The results obtained were satisfactory with excellent percentage recovery comparable and sometimes better than those obtained by other routine methods for the assay.

Development and validation of a sensitive UPLC-MS/MS method for the analysis of narcotic analgesics in urine and whole blood in forensic context.

Narcotic analgesics are widely (ab) used and sometimes only occur in low concentrations in biological samples. Therefore, a highly sensitive liquid chromatography tandem mass spectrometry method was developed for simultaneous analysis of 9 narcotic analgesics and metabolites (buprenorphine, O-desmethyltramadol, fentanyl, norbuprenorphine, norfentanyl, pethidine, piritramide, tilidine and tramadol) in urine and whole blood. Sample preparation was performed on a mixed-mode cation exchange solid phase extraction cartridge with an additional alkaline wash step to decrease matrix effects and thus increase sensitivity. Ionization with electrospray ionization was found to be more efficient than atmospheric pressure chemical ionization. The use of a mobile phase of high pH resulted in higher electrospray ionization signals than the conventional low pH mobile phases. In the final method, gradient elution with 10mM ammonium bicarbonate (pH 9) and methanol was performed on a small particle column (Acquity C18, 1.7 µm, 2.1 mm × 50 mm). Selectivity, matrix effects, recovery, linearity, sensitivity, precision, accuracy and stability were validated in urine and whole blood. All parameters were successfully evaluated and the method showed very high sensitivity, which was the major aim of this study. The applicability of the method was demonstrated by analysis of several forensic cases involving narcotic analgesics.

Liquid-phase microextraction and desorption electrospray ionization mass spectrometry for identification and quantification of basic drugs in human urine.

Hollow fibre liquid-phase microextraction (LPME) and desorption electrospray ionization mass spectrometry (DESI-MS) were evaluated for the identification and quantification of basic drugs in human urine samples. The selective extraction capabilities of three-phase LPME provided a significant reduction in the matrix effects otherwise observed in direct DESI-MS analysis of urine samples. Aqueous LPME extracts (in 10 mM HCl) were deposited on porous Teflon, dried at room temperature, and the dried spots were then analyzed directly with DESI-MS in full scan mode. Pethidine, diphenhydramine, nortriptyline, and methadone were used as model compounds for identification, and their limits of identification were determined to be 100, 25, 100, and 30 ng/mL, respectively. In a reliability test with 19 spiked urine samples, 100% of the positive samples containing the model drugs in concentrations at or above the limit of identification were identified. Diphenhydramine was used as a model compound for quantitative analysis with diphenhydramine-d(5) as an internal standard. The calibration curve was linear in the range 50-2000 ng/mL (R(2) = 0.992) with a limit of quantification at approximately 140 ng/mL. The intra- and inter-day relative standard deviations were <9.5%. In a reliability test with six spiked urine samples, deviations between the measured and the true values for diphenhydramine were in the range 0.2-22.9%.

Sensitive determination of pethidine in body fluids by gas chromatography-tandem mass spectrometry.

We have presented a simple and sensitive method for determining pethidine, a narcotic analgesic drug in body fluids by gas chromatography-tandem mass spectrometry (GC-MS/MS). Pethidine and 4'-piperidinoacetophenone (internal standard) were extracted from body fluids with Bond Elut C(18) columns; the recoveries were above 85% for both compounds. The calibration curves for blood and urine showed good linearities in the range of 1.25-40 ng/ml. Its detection limits (signal-to-noise ratio=3) were estimated to be approximately 0.5 ng/ml of whole blood and urine.

[Selected psychoactive drugs--clinical problems and medical-legal aspects]. / Wybrane srodki odurzajace--problemy kliniczne i medyczno-sadowe.

The multifarious aspects of psychoactive drug use present a significant challenge to the contemporary analyst. During the first stage of the present experiment, the recovery from human serum and urine of some psychoactive drugs with acidic or basic properties was studied. The efficiency of this process was determined using solutions of drug standards added to serum or urine. Classic liquid-liquid extraction, as well as solid phase extraction methods were compared. The efficiency of recovery was checked using high-performance liquid chromatography (HPLC). The results of this study confirm the usefulness of RP-18 sorbent from Merck and the importance in terms of quantitative analysis of the technique selected for isolation of the xenobiotic from the biological material. The second stage of the experiment was aimed at qualitative determination of some narcotics using thin-layer chromatography (TLC). By stepwise comparison and elimination it was possible to develop an optimal system of chromatographic separation using laminar staining. The proposed system and the conditions for separation ofxenobiotics with six selected elution systems and laminar visualization confirm the feasibility of separating 22 psychoactive drugs. The practical use of the system is limited mainly to screening. Conditions for quantitative analysis of diazepam, tramadol, and pethidine in biological material (serum, urine) using high-performance liquid chromatography, as well as morphine in serum using an immunoenzyme assay have been developed. The procedures have been applied to analysis of narcotics and psychoactive drugs administered prior to anesthesia (morphine, diazepam, pethidine) or for suppression of post-operative pain (morphine, tramadol) in 31 patients of an intensive care unit. 10 ml of blood was drawn at fixed times: 30 minutes prior to surgery (S1), at start of surgery (S2), 60 minutes later (S3), 30 minutes after administration of analgesic (S4), and 60 minutes after administration of analgesic (S5). Urine samples were also collected: immediately after surgery (M1) and 90 minutes after administration of analgesic (M2).

Identification of glucuronide conjugates of ketobemidone and its phase I metabolites in human urine utilizing accurate mass and tandem time-of-flight mass spectrometry.

The glucuronide conjugates of ketobemidone, norketobemidone and hydroxymethoxyketobemidone were identified in human urine post-intravenous administration of Ketogan Novum. The human urine was extracted on a mixed-mode solid-phase micro-column before analysis with liquid chromatography/electrospray ionization time-of-flight mass spectrometry (LC/ESI-TOF-MS) and tandem MS (MS/MS). Accurate mass and collision-induced dissociation product ion spectra were used for identification of the glucuronide conjugates. Two different TOF mass spectrometers were used and the accurate mass measurements were performed on three separate days with each instrument. The accuracy of the mass measurements was better than 2.1 ppm for two out of three conjugates and the inter-day relative standard deviation was within +/-0.00049%. The MS/MS fragmentation patterns of the conjugates were in accordance with those of the synthetic aglycones and included peaks originating from the [M + H](+) ion of the respective aglycone.

Identification of phase I and phase II metabolites of ketobemidone in patient urine using liquid chromatography-electrospray tandem mass spectrometry.

Ketobemidone and five of its phase I metabolites were identified in the urine of four patients post intravenous administration of Ketogan Novum. Furthermore, indications of the presence of the glucuronide conjugates of ketobemidone and norketobemidone is presented. Both hydrolyzed (beta-glucuronidase) and unhydrolyzed human urine was extracted on a mixed-mode slightly polar cation-exchange SPEC cartridge prior to analysis with LC-ESI-MS-MS. The phase I metabolites were identified by comparison of their daughter spectra with those of synthesized standards. The glucuronides were identified by their molecular mass and interpretation of the daughter spectra, as no standards were available for these compounds.

Sensitive determination of pethidine in body fluids by surface ionization organic mass spectrometry.

We have presented a simple and sensitive method for determining pethidine, a narcotic analgesic drug in body fluids by gas chromatography (GC)/surface ionization organic mass spectrometry (SIOMS). Good linearity was obtained in the range of 0.625-25 ng/ml of whole blood and urine by mass chromatography, and in the range of 0.05-2 ng/ml of whole blood by selected ion monitoring (SIM). Pethidine and diphenylpyraline (internal standard) were extracted from body fluids with Bond Elut Certify cartridges; their recoveries were above 95%. The detection limits (signal-to-noise ratio=3) were estimated to be 0.2 ng/ml of whole blood or urine by mass chromatography, 0.02 ng/ml of whole blood by SIM.

Determination of ketobemidone and its metabolites in plasma and urine using solid-phase extraction and liquid chromatography-mass spectrometry.

The authors developed a sensitive, specific, and rapid liquid chromatography--mass spectrometry (LC-MS) method for determining ketobemidone and its major metabolites in plasma and urine. The method involves a solid-phase extraction, high-performance liquid chromatography (HPLC), and electrospray mass spectrometry. The limit of quantification for ketobemidone and norketobemidone was 3 nmol/L. Recovery rates for ketobemidone and norketobemidone were 84.8% and 81.1%, respectively. Coefficients of variation (CV) ranged from 2.8 % to 9.5%. The method was used to determine ketobemidone and its major metabolites in clinical samples from relevant patient groups.

Tris(2,2'-bipyridine)ruthenium(II) electrogenerated chemiluminescence of alkaloid type drugs with solid phase extraction sample preparation.

An electrogenerated chemiluminescence (ECL) method for the determination of pethidine, atropine, homatropine and cocaine is described. The optimum conditions were found to be similar for all of these compounds although the ECL emission intensity for cocaine was an order of magnitude lower than for pethidine due to their different chemical structures. Linear calibrations were obtained for all the compounds at pH 10 in borate buffer (0.05 mol l-1) at 1.3 V. Limits of detection of 6.8 x 10(-8), 2.2 x 10(-7), 3.2 x 10(-7) and 6.5 x 10(-7) mol l-1, respectively, were achieved for pethidine, atropine, homatropine and cocaine in standard solutions. Solid-phase extraction was used to separate the drugs from their matrix and the method was applied to the determination of spiked urine samples. The limits of quantitation for pethidine, atropine, homatropine and cocaine in urine were 1.0 x 10(-6), 2.0 x 10(-6), 2.0 x 10(-6) and 4.0 x 10(-6) mol l-1, respectively, with recoveries of between 90 and 110%.

Quantitative analysis of pethidine using liquid secondary ion and tandem mass spectrometry.

A method for the quantatitive determination of pethidine in human urine by liquid secondary ion and tandem mass spectrometry is presented. Quantification was carried out by using ketamine as internal standard. It was found that the collision-induced dissociation (CID) spectrum of the [M + H]+ ion of pethidine exhibited a prominent daughter ion at m/z 220 and ketamine also yielded the same daughter ion at m/z 220. For ((quadrupole)) quantitative analysis, the first quadrupole mass filter was set to transmit m/z 220 and a narrow-range magnet scan yielded a spectrum of parents, including m/z 238 and 248, correspending to ketamine and pethidine, respectively.

Solid-phase microextraction for the determination of pethidine and methadone in human urine using gas chromatography with nitrogen-phosphorus detection.

A simple and rapid analytical method is presented for the determination of pethidine (meperidine) and methadone in human urine using solid-phase microextraction (SPME) and gas chromatography with nitrogen-phosphorus detection (GC-NPD). After the analytes had been partitioned between an extracting phase and the aqueous sample matrix, the needle of the coating fiber assembly was injected directly into the GC injector. The analytes were thermally desorbed in the heated injector (240 degrees C) and subsequently separated and detected by the GC-NPD system. The factors influencing the SPME method, such as the salt (NaCl) effect (15%), pH (pH 11), and equilibration time (30 min), were optimized. The calibration graphs for urine samples showed a good linearity. The detection limit was below 1 ng ml-1 for both drugs.

Validation of urine drug-of-abuse testing methods for ketobemidone using thin-layer chromatography and liquid chromatography-electrospray mass spectrometry.

High-performance thin-layer chromatography (TLC) with visual detection (post-chromatographic derivatization) was used in screening for the drug ketobemidone in human urine samples. High-performance liquid chromatography with electrospray mass spectrometry (LC-ESI-MS) was used for final confirmation of the result. The clean-up was performed by mixed-mode solid-phase extraction, and nalorphine was used as internal standard. A screening cut-off for TLC was established at 0.2 microg/ml. The mean recovery for LC-MS was 91% (n=60) with coefficients of variation (C.V.) in the range of 7 to 16%. Qualifying fragment ions of ketobemidone (m/z 190, 201 and 230) were generated by up front collision-induced dissociation (CID) on a single quadrupole instrument. Relative ion intensities were within +/- 15% deviation compared with standards in the same batch. The limit of detection for LC-MS was 0.025 microg/ml. Positive clinical samples from drug abusers (n=10) had concentrations in the range 0.07 to 3.2 microg/ml, which could be determined by LC-MS without matrix interference. During screening of unknown clinical samples (n=27) the results from TLC was in agreement with LC-MS data. After acid hydrolysis of conjugates in clinical samples the analyte response of ketobemidone and norketobemidone was increased by a factor of approximately two and twelve, respectively. A qualitative GC-MS technique was demonstrated for the detection of the spasmolyticum A29 (N,N-dimethyl-4,4-diphenyl-3-buten-2-amine), which can be found in a preparation combined with ketobemidone (Ketogan).

[Analysis and assessment of meperidine and normeperidine concentrations in urine].

In this study, urine concentrations of meperidine and normeperidine after a single therapeutic dose of meperidine in 5 healthy volunteers have been measured and compared the results to those in meperidine addicts. The results showed that there was a significant difference between two groups in the ratio of metabolite to parent drug. If can be concluded that the ratio should be aid in making a cause of meperidine injection.

Urinary excretion of meperidine and normeperidine in man upon acute and chronic exposure to high altitude.

The urinary excretion of unchanged meperidine (M) varies with change of pH and metabolism. Since exposure of man to high altitude (H) may cause significant physiologic changes, we investigated its effects on the urinary excretion of M. The study was carried out in 3 groups of healthy, male volunteers (ages 18-20 years): at sea level (L), at 4360 m the day after arrival at H (HA), and at 4360 m in subjects residing for > 10 months at H (HC). Urine was collected for the periods of 0-4, 4-8, 8-12 and 12-24 h. Urinary pH was measured and the concentrations of M and normeperidine (N) were determined. The 24 h excretion of M and N was significantly decreased for L vs. HA and L vs. HC. Significance was also seen for the periods 0-4, 4-8 and 8-12 h. The ratio of amount excreted M/N for the 24 h period was highly significant for L vs. HA and L vs. HC. The urinary pH ranged from 5.3-5.9 for L, 5.9-7.0 for HA, and 5.1-5.7 for HC. The Fel (fraction of M eliminated in the unchanged form in urine) significantly decreased from L to HA and HC.