Hollow fiber-based liquid-liquid-liquid microextraction combined with electrospray ionization-ion mobility spectrometry for the determination of pentazocine in biological samples.

A new method based on liquid-liquid-liquid microextraction combined with electrospray ionization-ion mobility spectrometry (LLLME-ESI-IMS) was used for the determination of pentazocine in urine and plasma samples. Experimental parameters which control the performance of LLLME, such as selection of composition of donor and acceptor phase, type of organic solvent, ionic strength of the sample, extraction temperature and extraction time were studied. The limit of detection and relative standard deviation of the method were 2 ng/mL and 5.3%, respectively. The linear calibration ranged from 10 to 500 ng/mL with r(2)=0.998. Pentazocine was successfully determined in urine and plasma samples without any significant matrix effect.

Development of matrix controlled transdermal delivery systems of pentazocine: In vitro/in vivo performance.

The present study aimed to develop hydroxypropyl methylcellulose based transdermal delivery of pentazocine. In formulations containing lower proportions of polymer, the drug released followed the Higuchi kinetics while, with an increase in polymer content, it followed the zero-order release kinetics. Release exponent (n) values imply that the release of pentazocine from matrices was non-Fickian. FT-IR, DSC and XRD studies indicated no interaction between drug and polymer.The in vitro dissolution rate constant, dissolution half-life and pharmacokinetic parameters (C(max), t(max), AUC(s), t(1/2), Kel, and MRT) were evaluated statistically by two-way ANOVA. A significant difference was observed between but not within the tested products. Statistically, a good correlation was found between per cent of drug absorbed from patches vs. C(max) and AUC(s). A good correlation was also observed when per cent drug released was correlated with the blood drug concentration obtained at the same time point. The results of this study indicate that the polymeric matrix films of pentazocine hold potential for transdermal drug delivery.

Pentazocine monitoring in rat hair and plasma by HPLC-fluorescence detection with DIB-Cl as a labelling reagent.

Pentazocine (PZ) in rat hair and plasma was determined by HPLC-fluorescence detection with 4-(4,5-diphenyl-1H-imidazol-2-yl)benzoyl chloride (DIB-Cl) as a labelling reagent and cyclazocine (CZ) as an internal standard (IS). PZ and IS extracted from hair or plasma sample were derivatized with DIB-Cl and the resulted solution was cleaned up with solid phase extraction. The isocratic separation of DIB-PZ and -CZ within 20 min could be achieved by a Wakopak Handy-ODS column (250 x 4.6 mm i.d.) using a mobile phase composed of 0.1 mol/L acetate buffer (pH 6.2):acetonitrile (25:75, v/v). The detection limits of PZ at a signal-to-noise ratio of 3 for rat hair and plasma were 0.18 ng/mg and 0.57 ng/mL, respectively. Reproducible and precise results could be obtained by an IS method with RSD values less than 6.6% for within- and between-day measurements. The method was successfully applied for the monitoring of PZ levels in Zucker rat hair and plasma samples after a single administration of 25 mg/kg PZ. Moreover, incorporation rates of PZ into black and white hair of Zucker rat were evaluated.

Application of a generic physiologically based pharmacokinetic model to the estimation of xenobiotic levels in rat plasma.

The routine assessment of xenobiotic in vivo kinetic behavior is currently dependent upon data obtained through animal experimentation, although in vitro surrogates for determining key absorption, distribution, metabolism, and elimination properties are available. Here we present a unique, generic, physiologically based pharmacokinetic (PBPK) model and demonstrate its application to the estimation of rat plasma pharmacokinetics, following intravenous dosing, from in vitro data alone. The model was parameterized through an optimization process, using a training set of in vivo data taken from the literature and validated using a separate test set of in vivo discovery compound data. On average, the vertical divergence of the predicted plasma concentrations from the observed data, on a semilog concentration-time plot, was approximately 0.5 log unit. Around 70% of all the predicted values of a standardized measure of area under the concentration-time curve (AUC) were within 3-fold of the observed values, as were over 90% of the training set t1/2 predictions and 60% of those for the test set; however, there was a tendency to overpredict t1/2 for the test set compounds. The capability of the model to rank compounds according to a given criterion was also assessed: of the 25% of the test set compounds ranked by the model as having the largest values for AUC, 61% were correctly identified. These validation results lead us to conclude that the generic PBPK model is potentially a powerful and cost-effective tool for predicting the mammalian pharmacokinetics of a wide range of organic compounds, from readily available in vitro inputs only.

Determination of pentazocine in human whole blood and urine by gas chromatography/surface ionization organic mass spectrometry.

Pentazocine has been found to be measurable with much higher sensitivity by gas chromatography (GC)/surface ionization (SI) organic mass spectrometry (OMS) than by the conventional GC/electron ionization (EI) mass spectrometry. The compound was extracted from human whole blood and urine with Sep-Pak C(18) cartridges before analysis by GC/SIOMS; recoveries were > 96.6% for both samples. The calibration curves were linear in the range 6.25-100 ng ml(-1) and the detection limits were 500 pg ml(-1) of a sample by selected ion monitoring (SIM) with GC/SIOMS. The intra- and inter-day relative standard deviations for the determination of pentazocine in whole blood and urine were not greater than 9.6%. The sensitivity for pentazocine obtained by SI-SIM was about 60 times higher than that obtained by EI-SIM. To validate the present GC/SIOMS method for pentazocine, whole blood and urine samples collected from two volunteers 1-6 h after intramuscular injection of 15 mg of pentazocine were analyzed. The concentrations were 13.5-59.3 ng ml(-1) for whole blood and 0.39-4.00 microg ml(-1) for urine.

Design, development, and biopharmaceutical properties of buccoadhesive compacts of pentazocine.

Buccoadhesive compacts (BCs) of pentazocine (PZ) were prepared by the direct compression method using polymers like carbopol 974P (CP 974P) and hydroxypropyl methylcellulose (HPMC K4M) in ratios of 1:0 (batch B1), 1:1 (B2), 1:2 (B3), 1:4 (B4), and 0:1 (B5). The compacts were evaluated for thickness uniformity, weight variation, drug content uniformity, and swelling index. Swelling was increased with an increase in HPMC K4M content in the compacts. An in vitro assembly was developed to measure and compare the bioadhesive strength of compacts. The maximum bioadhesive strength was observed in compacts formulated with a combination of CP 974P and HPMC K4M. The compacts were evaluated in vitro for 24 hr in pH 6.6 phosphate buffer using a standardized dissolution apparatus. The data were evaluated by a simple power equation (Mt/M infinity = Ktn); it was observed that all the compacts followed non-Fickian release kinetics. Some of the buccoadhesive compacts were evaluated in vivo in rabbits. The compacts gave controlled blood level profiles with a twofold to threefold increase in area-under-the-curve (AUC) values in comparison to oral administration of aqueous drug solution.

Resolution and quantitation of pentazocine enantiomers in human serum by reversed-phase high-performance liquid chromatography using sulfated beta-cyclodextrin as chiral mobile phase additive and solid-phase extraction.

A sensitive and stereospecific HPLC method was developed for the analysis of (-)- and (+)-pentazocine in human serum. The assay involves the use of a phenyl solid-phase extraction column for serum sample clean-up prior to HPLC analysis. Chromatographic resolution of the pentazocine enantiomers was performed on a octadecylsilane column with sulfated-beta-cyclodextrin (S-beta-CD) as the chiral mobile phase additive. The composition of the mobile phase was aqueous 10 mM potassium dihydrogenphosphate buffer pH 5.8 (adjusted with phosphoric acid)-absolute ethanol (80:20, v/v) containing 10 mM S-beta-CD at a flow-rate of 0.7 ml/min. Recoveries of (-)- and (+)-pentazocine were in the range of 91-93%. Linear calibration curves were obtained in the 20-400 ng/ml range for each enantiomer in serum. The detection limit based on S/N=3 was 15 ng/ml for each pentazocine enantiomer in serum with UV detection at 220 nm. The limit of quantitation for each enantiomer was 20 ng/ml. Precision calculated as R.S.D. and accuracy calculated as error were in the range 0.9-7.0% and 1.2-6.2%, respectively, for the (-)-enantiomer and 0.8- 7.6% and 1.2-4.6%, respectively, for the (+)-enantiomer (n=3).

Analysis of zopiclone (Imovane) in postmortem specimens by GC-MS and HPLC with diode-array detection.

A 26-year-old black female was found dead at home. Her mouth was covered with a fluid containing chalky particles. Empty strips of Imovane (zopiclone) and an empty bottle of Fortal (pentazocine) were also found. No urine was available at autopsy. Screening of postmortem blood and stomach contents with enzyme-multiplied immunoassay technique (EMIT) detected only caffeine. Further screening using routine high-performance liquid chromatography (HPLC) with diode-array detection and gas chromatography (GC) with mass spectrometric detection revealed the presence of large amounts of pentazocine in the blood and stomach contents. In the HPLC chromatogram, a second peak that was only partially resolved from the solvent front was observed. Thin-layer chromatography demonstrated the presence of zopiclone, but optimized HPLC and GC conditions had to be used for proper identification and quantitation. This case illustrates the fact that zopiclone can be easily overlooked during routine forensic screening.

HPLC separation of pentazocine enantiomers in serum using an ovomucoid chiral stationary phase.

A stereospecific HPLC method was developed for the analysis of (-) and (+) pentazocine in human serum. Each enantiomer and the internal standard nalophine were isolated from serum using a liquid-liquid extraction procedure. Recoveries of 99.05 +/- 5.37 and 97.42 +/- 2.78% were obtained for (-) and (+) pentazocine, respectively. Resolution of the enantiomers was obtained by using an ovomucoid chiral stationary phase with a mobile phase of methanol:acetonitrile: 10 mM phosphate buffer, pH 5.8 (20:5.3:74.7 v/v/v). A resolution (Rs) value of 1.80 was obtained for the pentazocine enantiomers. Linear calibration curves were obtained in the 10-100 ng/mL range for each enantiomer in serum. The detection limit based on a signal-to-noise ratio of 3 was 5 ng/mL for each enantiomer in serum using fluorescence detection with excitation at 275 nm and emission set at 335 nm. The lowest quantifiable level was found to be 10 ng for each enantiomer. Precision and accuracy of the method were in the 3.8-4.8% and 1.3-4.2% ranges, respectively.

Pharmacokinetics and pharmacodynamics of pentazocine in children.

Pharmacokinetics and ventilatory effects of a single intravenous dose of 0.5 mg/kg of pentazocine were studied in ten children aged 4 to 8 years after ophthalmic surgery. Elimination half-life (mean +/- S.D.) was 3.0 +/- 1.5 hr and clearance 21.8 +/- 5.9 ml/min./kg. The values for Vc, Vss and V beta were 0.73 +/- 0.21, 4.0 +/- 1.2 and 5.3 +/- 2.1 l/kg, respectively. The pharmacokinetic parameters were similar to those of adults. After administration of pentazocine decrease in ventilatory rate and oxygen saturation and increase in end-tidal carbon dioxide were relatively fast and steep. Oxygen saturation of four patients decreased below 90% and in one patient the decrease did not recover instantly and additional oxygen was given for 2 min. No patient needed assisted ventilation. Only clinically insignificant changes in heart rate and mean arterial pressure were observed. The duration of analgesia was 164 +/- 59 min. No serious side-effects appeared.

[Pharmacokinetics of ketamine and pentazocine during total intravenous anesthesia with droperidol, pentazocine and ketamine].

Pharmacokinetics was studied in ten surgical patients who underwent various operative procedures of about 4 hours under total intravenous anesthesia with droperidol, pentazocine and ketamine (DPK). Plasma levels of ketamine, its metabolites and pentazocine were determined thirteen times during and after DPK. During anesthesia, ketamine (KO) and norketamine (KMI) levels ranged from 0.7 to 1.0 micrograms.ml-1 and from 0.09 to 0.74 micrograms.ml-1, respectively. A small amount of dehydronorketamine (KM II) was detected only 90 min after the start of DPK anesthesia. Plasma half-lives of ketamine were calculated to be 33 min for distribution phase (alpha phase) and 60 min for elimination phase (beta phase), respectively. Pentazocine levels decreased 300 min after the induction of DPK to 10% of the control level measured 5 min after its injection. Plasma half-lives of pentazocine were 60 min for alpha phase and 140 min for beta phase, respectively. The data obtained in this clinical study show that pharmacokinetics of ketamine during DPK is almost similar to that of DFK.

Euthanasia: a challenge for the forensic toxicologist.

People die daily in the hospital. Mostly, they die because their illnesses were no longer treatable (natural death). Unfortunately, some people die an unnatural death, in particular, as the result of euthanasia. In contrast to the situation in most countries, in the Netherlands euthanasia is accepted by the courts under strict conditions. It can be very difficult for the legal authorities to establish whether a person has died from natural causes or from suicide, euthanasia, or murder. In addition to the pathologist and the lawyer, the toxicologist also has a number of problems in showing whether euthanasia has been carried out. These can consist of the following analytical problems: (a) interactions--the patients involved have frequently been receiving a large number of toxic and nontoxic drugs simultaneously; (b) identification--not all drugs administered are included in general screening procedures; (c) metabolites--a large number of metabolites may have accumulated toward the end of a long therapeutic regimen; and (d) determination--determination of quaternary muscle relaxants and their various metabolites, as well as other drugs, can be problematic. There are also toxicokinetic problems; because of poor kidney and liver function, low serum albumen, general malaise, and interactions between these factors and other drugs, the kinetics of a given drug can differ from normal. This makes it all the more difficult to determine whether the patient died from an accumulation of medication or from a so-called "euthanetic" drug mixture.(ABSTRACT TRUNCATED AT 250 WORDS)

[Identification of pentazocine, piritramide and methadone in blood using thin layer chromatography]. / Identyfikacja pentazocyny, pirytramidu i metadonu we krwi metoda chromatografii cienkowarstwowej.

Pentazocine, piritramide and methadone, when extracted from blood or plasma with ether at pH ca. 12, were separated by TLC method on alumina or silica gel by ascending technique on 5 x 20 cm and 2.5 x 7.5 cm plates and also by horizontal development, using suitable mobile phases. The substances were identified by reaction with potassium iodoplatinate or 20% Na2CO3 solution (up to the amount 2 micrograms pentazocine, 0.5 microgram piritramide and 1.5 micrograms methadone.

Parenteral pentazocine: effects on psychomotor skills and respiration, and interactions with amitriptyline.

The combined effects on performance and respiration of pentazocine (PZ) and amitriptyline (AMI) were evaluated in a double-blind cross-over study in 11 healthy students. After pretreatment for 1 week with AMI or placebo, on Day 8 the subjects received placebo or 50 mg p.o. AMI and 30 mg PZ or saline i.m. so that the final treatments were 1) placebo, 2) acute AMI 50 mg, 3) acute PZ, 4) subchronic AMI + acute PZ and 5) subchronic AMI. The subacute treatments were started at two-week intervals. Objective and subjective performance tests and respiratory function (minute volume, ETCO2) were measured. Parenteral PZ impaired sensory processing (digit symbol substitution, choice reactions) and extraocular muscle balance (Maddox wing) but left motor skills (tracking, tapping speed) unaffected. A single oral dose of AMI 50 mg affected both sensory and motor performance. The psychomotor effects of PZ were clearest at 1.5 h, and those of AMI at 3.5 h. Both drugs rendered the subjects drowsy, clumsy, and muzzy on visual analogue scales, but PZ also induced positive feelings, like contentedness and friendliness. PZ depressed respiration in terms of lowered minute volume and elevated ETCO2, and subchronic AMI increased this depression. The chemically assayed plasma concentrations of AMI and PZ were as expected; radioreceptor assay revealed low or negligible mu-opiate activity in plasma after PZ. The results suggest that AMI does not enhance the moderate psychomotor decrement produced by PZ. However, respiratory depression may be increased by their concomitant use.

The pharmacokinetics of pentazocine and tripelennamine.

The pharmacokinetics of single and combined doses of pentazocine HCl (40 and 80 mg) and tripelennamine HCl (50 and 100 mg) were studied in six healthy drug abusers. After intramuscular administration of 40 or 80 mg pentazocine alone, mean peak plasma concentrations at 15 minutes were 102 and 227 ng/ml, respectively, and mean plasma t1/2 values were 4.6 and 5.3 hours, respectively. After intramuscular administration of 50 or 100 mg tripelennamine, mean plasma concentrations at 30 minutes were 105 and 194 ng/ml, respectively, and mean plasma t1/2 values were 2.9 and 4.4 hours, respectively. After concurrent administration of pentazocine with tripelennamine, plasma pentazocine and tripelennamine concentrations at all time points were not significantly different from those when pentazocine or tripelennamine was administered alone. Coadministration of pentazocine and tripelennamine had no effect on the distribution, elimination, and clearance of either pentazocine or tripelennamine. In conclusion, there did not appear to be a clinically significant metabolic interaction between pentazocine and tripelennamine.