ent-dextilidine and nortilidine

The therapeutic activity of tilidine, an opioid analgesic, is mainly related to its active metabolite nortilidine. Nortilidine formation mainly occurs during the high intestinal first-pass metabolism of tilidine by N-demethylation. Elimination of the active nortilidine to the inactive bisnortilidine is also mediated by N-demethylation and is supposed to take place in the liver, probably at a smaller rate. The aim of this study was the investigation of the pre-systemic elimination of tilidine using grapefruit juice (GFJ) as an intestinal CYP3A4 inhibitor and efavirenz (EFV) as a CYP3A4 activator. A randomized, open, placebo-controlled, cross-over study was conducted in 12 healthy volunteers using 100 mg tilidine solution p.o., regular strength GFJ 250 mL (3 times at 12-hr intervals) and EFV 400 mg (12 hr before tilidine administration). Tilidine, nortilidine and bisnortilidine in plasma and urine were quantified by a validated LC/MS/MS analysis. GFJ did not change any pharmacokinetic parameter of tilidine and its metabolites, which suggests that intestinal CYP3A4 does not contribute to the first-pass metabolism of tilidine. No effect of EFV on the pharmacokinetics of the active nortilidine was observed except a significant reduction of the terminal elimination half-life by 15%. Overall elimination (renal and metabolic clearances) was unaffected by every treatment. CYP3A4 does not seem to play a major role in tilidine first-pass and overall metabolism. Other unknown metabolites and their enzymes responsible for their formation have to be investigated as they account for the majority of renally excreted metabolites.

Topics: Adult; Alkynes; Analgesics, Opioid; Benzoxazines; Beverages; Chromatography, Liquid; Citrus paradisi; Cross-Over Studies; Cyclopropanes; Cytochrome P-450 CYP3A; Female; Half-Life; Humans; Male; Middle Aged; Tandem Mass Spectrometry; Tilidine; Young Adult

The analgesic activity of tilidine is mediated by its active metabolite, nortilidine, which easily penetrates the blood-brain barrier and binds to the µ-opioid receptor as a potent agonist. Tilidine undergoes an extensive first-pass metabolism, which has been suggested to be mediated by CYP3A4 and CYP2C19; furthermore, strong inhibition of CYP3A4 and CYP2C19 by voriconazole increased exposure of nortilidine, probably by inhibition of further metabolism. The novel CYP2C19 gene variant CYP2C19*17 causes ultrarapid drug metabolism, in contrast to the *2 and *3 variants, which result in impaired drug metabolism.. Using a panel study with CYP2C19 ultrarapid and poor metabolizers, a major contribution of polymorphic CYP2C19 on tilidine metabolic elimination can be excluded.  The potent CYP3A4 inhibitor ritonavir alters the sequential metabolism of tilidine, substantially reducing the partial metabolic clearances of tilidine to nortilidine and nortilidine to bisnortilidine, which increases the nortilidine exposure twofold. The lowest clearance in overall tilidine elimination is the N-demethylation of nortilidine to bisnortilidine. Inhibition of this step leads to accumulation of the active nortilidine.. To investigate in vivo the effect of the CYP2C19 genotype on the pharmacokinetics of tilidine and the contribution of CYP3A4 and CYP2C19 to the formation of nortilidine using potent CYP3A4 inhibition by ritonavir.. Fourteen healthy volunteers (seven CYP2C19 poor and seven ultrarapid metabolizers) received ritonavir orally (300 mg twice daily) for 3 days or placebo, together with a single oral dose of tilidine and naloxone (100 mg and 4 mg, respectively). Blood samples and urine were collected for 72 h. Noncompartmental analysis was performed to determine pharmacokinetic parameters of tilidine, nortilidine, bisnortilidine and ritonavir.. Tilidine exposure increased sevenfold and terminal elimination half-life fivefold during ritonavir treatment, but no significant differences were observed between the CYP2C19 genotypes. During ritonavir treatment, nortilidine area under the concentration-time curve was on average doubled, with no differences between CYP2C19 poor metabolizers [2242 h ng ml(-1) (95% confidence interval 1811-2674) vs. 996 h ng ml(-1) (95% confidence interval 872-1119)] and ultrarapid metabolizers [2074 h ng ml(-1) (95% confidence interval 1353-2795) vs. 1059 h ng ml(-1) (95% confidence interval 789-1330)]. The plasma concentration-time curve of the secondary metabolite, bisnortilidine, showed a threefold increase of time to reach maximal observed plasma concentration; however, area under the concentration-time curve was not altered by ritonavir.. The sequential metabolism of tilidine is inhibited by the potent CYP3A4 inhibitor, ritonavir, independent of the CYP2C19 genotype, with a twofold increase in the exposure of the active nortilidine.

Topics: Adult; Analgesics, Opioid; Area Under Curve; Aryl Hydrocarbon Hydroxylases; Cross-Over Studies; Cytochrome P-450 CYP2C19; Cytochrome P-450 CYP3A; Dose-Response Relationship, Drug; Double-Blind Method; Drug Combinations; Female; Genotype; Half-Life; Humans; Male; Middle Aged; Naloxone; Polymorphism, Genetic; Prodrugs; Ritonavir; Tilidine; Time Factors; Young Adult

To investigate in vivo the influence of the potent CYP2C19 and CYP3A4 inhibitor voriconazole on the pharmacokinetics and analgesic effects of tilidine.. Sixteen healthy volunteers received voriconazole (400 mg) or placebo together with a single oral dose of tilidine (100 mg). Blood samples and urine were collected for 24 h and experimental pain was determined by using the cold pressor test. Noncompartimental analysis was performed to determine pharmacokinetic parameters of tilidine, nortilidine and voriconazole, whereas pharmacodynamic parameters were analysed by nonparametric repeated measures ANOVA (Friedman).. Voriconazole caused a 20-fold increase in exposition of tilidine in serum [AUC 1250.8 h*ng ml(-1), 95% confidence interval (CI) 1076.8, 1424.9 vs. 61 h*ng ml(-1), 95% CI 42.6, 80.9; P < 0.0001], whereas the AUC of nortilidine also increased 2.5-fold. After voriconazole much lower serum concentrations of bisnortilidine were observed. The onset of analgesic activity occurred later with voriconazole, which is in agreement with the prolonged t(max) of nortilidine (0.78 h, 95% CI 0.63, 0.93 vs. 2.5 h, 95% CI 1.85, 3.18; P < 0.0001) due to the additional inhibition of nortilidine metabolism to bisnortilidine. After voriconazole the AUC under the pain withdrawal-time curve was reduced compared with placebo (149 s h(-1), 95% CI 112, 185 vs. 175 s h(-1), 95% CI 138, 213; P < 0.016), mainly due to the shorter withdrawal time 0.75 h after tilidine administration.. Voriconazole significantly inhibited the sequential metabolism of tilidine with increased exposure of the active nortilidine. Furthermore, the incidence of adverse events was almost doubled after voriconazole and tilidine.

Topics: Adult; Analgesics, Opioid; Analysis of Variance; Antifungal Agents; Aryl Hydrocarbon Hydroxylases; Cytochrome P-450 CYP2C19; Cytochrome P-450 CYP3A; Double-Blind Method; Drug Interactions; Female; Humans; Male; Middle Aged; Pyrimidines; Tilidine; Triazoles; Voriconazole; Young Adult

The disposition of nortildine, the active metabolite of the synthetic opioid drug tilidine, was investigated in healthy volunteers in a randomized, single-dose, three-way crossover design. Three different treatments were administered: tilidine 50 mg intravenously, tilidine 50 mg orally, and nortilidine 10 mg intravenously. The plasma concentrations of tilidine, nortilidine, and bisnortilidine were determined and subjected to pharmacokinetic analysis using noncompartmental methods. The systemic bioavailability of tilidine was low (7.6% +/- 5.3%) due to a pronounced first-pass metabolism. The areas under the plasma concentration versus time curves (A UC) of nortilidine were similar following either oral or intravenous administration of tilidine 50 mg (375 +/- 184 vs. 364 +/- 124 ng.h.ml(-1)). AUC of nortilidine was 229 +/- 42 ng.h.ml(-1) after IV infusion of nortilidine 10 mg and thus much greater than after IV tilidine corrected for differences in dose. Nortilidine had a much lower volume of distribution (275 +/- 79 vs. 1326 +/- 477 L) and a somewhat lower clearance (749 +/- 119 vs. 1198 +/- 228 ml/min) than tilidine. About two-thirds of the dose of tilidine was metabolized to nortilidine, although only half of the latter fraction was available in the peripheral circulation. Nortilidine was subsequently metabolized to bisnortilidine. The mean ratio of the AUC of bisnortilidine to nortilidine was 0.65 +/- 0.14 following IV administration of nortilidine but 1.69 +/- 0.38 and 1.40 +/- 0.27 following oral and intravenous administration of tilidine, respectively. The shapes of the plasma concentration-time curves of the metabolites and parent drug declined in parallel, indicating that the disposition of the metabolites is formation rate limited. Thus, although two-thirds of the dose of tilidine is metabolized to nortilidine, only one-third of the dose is available systemically as nortilidine for interaction with the opiate receptors after both intravenous and oral dosing of tilidine. The remaining part of nortilidine is retained in the liver and is subsequently metabolized to bisnortilidine and yet unknown compounds.

Topics: Administration, Oral; Adult; Analgesics, Opioid; Area Under Curve; Biological Availability; Cross-Over Studies; Humans; Injections, Intravenous; Male; Models, Biological; Prodrugs; Tilidine; Time Factors

The aim of the present study was to investigate the pharmacokinetics of tilidine and its metabolites during the dialysis procedure and in the dialysis-free interval. Tilidine is a prodrug that is metabolized presystemically into the active metabolite nortilidine. Nortilidine is degraded thereafter to bisnortilidine and several polar metabolites. Nine patients with a creatinine clearance < 5 ml/min were treated in a crossover design with single oral doses of 1.5 mg/kg on the day of dialysis (dialysis performed from 3 to 6 hours after drug administration) and on a day in the dialysis-free interval. Blood samples were taken frequently and analyzed for tilidine, nortilidine, and bisnortilidine. Drug and metabolite concentrations were also measured in aliquots of dialysate collected during dialysis. Only negligible amounts of tilidine, nortilidine, and bisnortilidine (about 0.9% of the dose) were recovered from the dialysate. The pharmacokinetics of nortilidine and its inactive metabolite bisnortilidine was not affected by dialysis. The presystemic apparent clearance of the prodrug tilidine was decreased significantly during the dialysis-free interval. A significant decrease of the rate of elimination and an increase of the AUC of bisnortilidine were observed if these parameters were compared with data obtained from healthy volunteers. The plasma concentrations of nortilidine were comparable in patients and normal volunteers. Thus, a reduction of the dose of tilidine in patients with severely impaired kidney function seems not to be required. Tilidine and its metabolites cannot be removed from the body by dialysis.

Topics: Adult; Aged; Analgesics, Opioid; Cross-Over Studies; Female; Humans; Kidney Failure, Chronic; Male; Middle Aged; Prodrugs; Renal Dialysis; Tilidine

Valoron N is a compound which consists of the prodrug tilidine (CAS 20380-58-9), from which the active metabolite nortilidine is formed by demethylation in the liver, and the opiate antagonist naloxone (CAS 465-65-6), which prevents the abuse of the analgesic by opiate dependents. The pharmacokinetics of nortilidine and naloxone were studied in 18 male healthy subjects after oral application of tilidine/naloxone solution or tilidine/naloxone retard tablets, respectively. The following report gives the results on investigations of a) dose linearity after application of 25 mg, 50 mg and 100 mg Valoron N solution, b) dose equivalence of Valoron N solution (4 x 50 mg tilidine) and Valoron N retard tablets (2 x 100 mg tilidine) under steady state conditions, and c) the equivalence of different dose strengths of Valoron N retard tablets (50 mg, 100 mg, 200 mg tilidine/tablet). The results obtained in these studies demonstrate a dose linear kinetic for nortilidine after the application of 25 mg to 100 mg tilidine. Furthermore, there is dose equivalence between the tilidine/naloxone solution and tilidine/naloxone retard tablets, which permits the replacing of the solution with the retard tablets. Because of the equivalence of different dose strengths of Valoron N tablets, patients are able to exchange low dosed Valoron N retard tablets for higher-dosed ones (50 mg, 100 mg and 200 mg tilidine/tablet), if necessary. With their constant release of tilidine and the possibility for individual dosage, the retard tablets are efficient analgesics that improve pain therapy considerably for patients with chronic pain.

Topics: Adult; Area Under Curve; Cross-Over Studies; Delayed-Action Preparations; Drug Combinations; Half-Life; Humans; Male; Middle Aged; Naloxone; Narcotic Antagonists; Regression Analysis; Tilidine

An oral solution available as ethanol-free droplets of the fixed drug combination tilidine-HCl 50 mg/naloxone-HCl 4 mg (CAS 27107-79-5 and CAS 465-65-6, respectively; Tilidin-ratiopharm plus Tropfen) was investigated in 12 healthy volunteers together with an ethanol-containing reference preparation for comparable bioavailability. The study was conducted in an open, randomized, two-way cross-over design applying single doses of 20 droplets (equivalent to 50 mg tilidine-HCl/4 mg naloxone-HCl) of either formulation in the fasting state. The drug plasma profiles were monitored for a period of 48 h by means of LC-MS/MS for tilidine and its active metabolite nortilidine, whereas GC-MS was employed in order to determine naloxone and its phase I metabolite, 6-beta-naloxole. Maximum concentrations (Cmax) achieved were 22.28 ng/ml (tilidine) and 92.78 ng/ml (nortilidine) for the test preparation. Corresponding values for the reference preparation were 24.95 ng/ml (tilidine) and 100.73 ng/ml (nortilidine). The extent of drug absorption (AUC0-infinity) amounted to 38.83 ng h/ml and 467.63 ng h/ml for the prodrug tilidine and the metabolite nortilidine of the test preparation and corresponded well to 43.81 ng h/ml and 493.85 ng h/ml of the reference. Regarding the rate of drug absorption, essentially identical tmax and Rabs values for both tilidine and nortilidine of either preparation in addition pointed to well comparable liquid formulations and equipotent analgesia may be inferred from opioid pharmakokinetic profiles. Pharmacokinetics of the opioid antagonist naloxone and 6-beta-naloxole were also determined and resulted in well coinciding profiles for both preparations. Thus despite the fact that only minimum oral naloxone bioavailabilities were observed, plasma level monitoring of naloxone and 6-beta-naloxole allowed for demonstration of systemic exposure of opioid antagonistic compounds throughout a period of 2-3 h after oral drug administration. Due to the limited number of subjects involved, the primary aim of the study did not consist in demonstration of drug bioequivalence. Rather a comparable bioavailability between preparations was assumed if AUC and Cmax point estimators of 90% confidence intervals would be contained within a 0.80-1.20 range. The study outcome revealed that all four investigated analytes met this requirement, whilst nortilidine pharmacokinetic parameters even fulfilled commonly accepted bioequivalence criteria, i.e. inclusion of 90% confi

Topics: Adult; Analgesics, Opioid; Area Under Curve; Biological Availability; Chromatography, Thin Layer; Female; Gas Chromatography-Mass Spectrometry; Humans; Male; Mass Spectrometry; Middle Aged; Naloxone; Narcotic Antagonists; Reference Standards; Tilidine

The synthetic opioid tilidine is often used in chronic pain treatment. However, the activation via metabolism in patients with concomitant medication and reduced liver or kidney function is not thoroughly investigated. We therefore studied pain treatment efficacy, health-related quality of live and the metabolism of tilidine in patients with chronic pain.. In all, 48 patients, who were on a stable dose of oral prolonged release tilidine for at least 7 days, were included in this observational multicenter study. Liver and kidney function were assessed in routine blood samples, concentrations of tilidine, nortilidine and bisnortilidine were determined using a validated LC/MS/MS method. Comedication was registered and patients experience with regard to quality of life, pain, gastrointestinal symptoms and adverse events was assessed in standardised questionnaires.. On average a daily dose of 180 mg tilidine was taken. Dose normalized plasma concentrations of the active metabolite nortilidine ranged between 1.6 ng/ml and 76.5 ng/ml (mean 29.2 ± 25.1 ng/ml). Ratios between tilidine and nortilidine were on average 0.28 (median = 0.13, standard deviation = 0.67). Patients were on 1 to 14 different concomitant medications. About 66% of the patients had sufficient pain treatment. Almost no opioid-induced constipation was observed. Only few patients had decreased kidney or liver function which did not result in elevated nortilidine concentrations.. Pain treatment using tilidine resulted in variable nortilidine concentrations which are obviously not strongly influenced by comedication or reduced liver or kidney function. Only a few side effects were observed with almost no opioid-induced constipation.

Topics: Adult; Aged; Aged, 80 and over; Chronic Pain; Delayed-Action Preparations; Drug Interactions; Drug Therapy, Combination; Female; Humans; Kidney Function Tests; Liver Function Tests; Male; Middle Aged; Quality of Life; Tilidine

Segmental hair analysis has been used for monitoring changes of consumption habit of drugs. Contamination from the environment or sweat might cause interpretative problems. For this reason, hair analysis results were compared in hair samples taken 24 h and 30 days after a single tilidine dose. The 24-h hair samples already showed high concentrations of tilidine and nortilidine. Analysis of wash water from sample preparation confirmed external contamination by sweat as reason. The 30-day hair samples were still positive for tilidine in all segments. Negative wash-water analysis proved incorporation from sweat into the hair matrix. Interpretation of a forensic case was requested where two children had been administered tilidine by their nanny and tilidine/nortilidine had been detected in all hair segments, possibly indicating multiple applications. Taking into consideration the results of the present study and of MALDI-MS imaging, a single application as cause for analytical results could no longer be excluded. Interpretation of consumption behaviour of tilidine based on segmental hair analysis has to be done with caution, even after typical wash procedures during sample preparation. External sweat contamination followed by incorporation into the hair matrix can mimic chronic intake. For assessment of external contamination, hair samples should not only be collected several weeks but also one to a few days after intake. MALDI-MS imaging of single hair can be a complementary tool for interpretation. Limitations for interpretation of segmental hair analysis shown here might also be applicable to drugs with comparable physicochemical and pharmacokinetic properties.

Topics: Adult; Chromatography, Liquid; Forensic Toxicology; Hair; Humans; Infant; Male; Middle Aged; Narcotics; Spectrometry, Mass, Electrospray Ionization; Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization; Tandem Mass Spectrometry; Tilidine

Tilidine exhibits the highest consumption of opioids in Germany. The prodrug is hepatically metabolised in a sequential N-demethylation reaction. Its primary metabolite nortilidine is a selective μ-opioid receptor agonist which can penetrate the blood-brain barrier. Cytochrome P450 isozymes (CYP) 3A4 and CYP2C19 were previously identified as isozymes mediating the formation of nortilidine. This study was set up to identify the enzymes and kinetics of the subsequent N-demethylation to bisnortilidine, thus being able to understand clinical interactions. Human liver microsomes and recombinant CYPs were used to investigate the metabolism of nortilidine to bisnortilidine. Nortilidine and bisnortilidine were quantified using liquid chromatography tandem mass spectrometry. Inhibitor screening kits were used to quantify the inhibition of CYP3A4, CYP2C19, CYP2B6 and CYP2D6 by bisnortilidine. Nortilidine metabolism to bisnortilidine followed the Michaelis-Menten kinetics with K (m) = 141.6 ± 15 μM and V (max) = 46.2 ± 3 nmol/mg/h. Inhibitors of CYP3A4, CYP2C19 and CYP2B6 inhibited this reaction. Assays with recombinant CYPs verified that the N-demethylation is catalysed by CYP3A4, CYP2C19 and CYP2B6. Our results also demonstrated that the metabolism from tilidine to nortilidine is not only mediated by CYP3A4 and CYP2C19, but also by CYP2B6. Moreover, bisnortilidine is a weak inhibitor of CYP3A4 and CYP2B6, a strong inhibitor of CYP2D6, but not an inhibitor of CYP2C19. Our study demonstrated that nortilidine is metabolised via the same CYP isozymes as the prodrug tilidine, whereas the formation of bisnortilidine appears to be the rate-limiting step in the metabolism of tilidine. Pharmacokinetic interactions can be expected with inhibitors or inducers of CYP3A4, CYP2C19 or CYP2B6.

Topics: Cytochrome P-450 Enzyme Inhibitors; Cytochrome P-450 Enzyme System; Enzyme Inhibitors; Humans; Isoenzymes; Microsomes, Liver; Tilidine

The opioid tilidine is a prodrug which is hepatically metabolized to active nortilidine and bisnortilidine. Due to the increasing abuse of tilidine by drug users and the lack of a specific immunoassay, we developed an analytical method for the quantification of tilidine, nortilidine, and bisnortilidine in urine suitable for screening. In a following step, this method was used to establish data on excretion kinetics of the substances in order to evaluate the time window of detection after a single oral dose of tilidine/naloxone and also was applied to authentic urine samples from correctional facilities. Urine samples were mixed with internal standard solution and extracted on a weak cation exchanger at pH 6 using a Symbiosis Pico system. The chromatographic separation was achieved within a 3.5-min run time on a Phenylhexyl column (50 × 2.0 mm, 5 μm) via gradient elution (methanol and 0.2% formic acid) at a flow rate of 0.50 mL/min. The ESI-MS/MS was performed on a QTrap 3,200 in positive multiple reaction monitoring mode using two mass transitions per analyte. Validating the method resulted in a lower limit of quantification of 1.0 μg/L followed by a linear calibration range to 100 μg/L for each analyte (r(2) > 0.99). The analytical method allowed the detection of a single dose of a commercially available tilidine solution up to 7 days after administration. Using this highly sensitive method, 55 of 3,665 urine samples were tested positive.

Topics: Automation; Chromatography, Liquid; Humans; Limit of Detection; Reference Standards; Reproducibility of Results; Solid Phase Extraction; Tandem Mass Spectrometry; Tilidine

Tilidine is one of the most widely used narcotics in Germany and Belgium. The compound's active metabolite nortilidine easily penetrates the blood-brain barrier and activates the mu-opioid receptor. Thus far, the enzymes involved in tilidine metabolism are unknown. Therefore, the aim of our study was to identify the cytochrome P450 isozymes (CYPs) involved in N-demethylation of tilidine in vitro. We used human liver microsomes as well as recombinant CYPs to investigate the demethylation of tilidine to nortilidine and quantified nortilidine by liquid chromatography-tandem mass spectrometry. Inhibition of CYPs was quantified with commercial kits. Moreover, inhibition of ABCB1 and ABCG2 was investigated. Our results demonstrated that N-demethylation of tilidine to nortilidine followed a Michaelis-Menten kinetic with a K(m) value of 36 +/- 13 microM and a v(max) value of 85 +/- 18 nmol/mg/h. This metabolic step was inhibited by CYP3A4 and CYP2C19 inhibitors. Investigations with recombinant CYP3A4 and CYP2C19 confirmed that the demethylation of tilidine occurs via these two CYPs. Inhibition assays demonstrated that tilidine and nortilidine can also inhibit CYP3A4, CYP2C19, CYP2D6, ABCB1, but not ABCG2, whereas inhibition of CYP2D6 and possibly also of CYP3A4 might be clinically relevant. By calculating the metabolic clearance based on the in vitro and published in vivo data, CYP3A4 and CYP2C19 were identified as the main elimination routes of tilidine. In vivo, drug-drug interactions of tilidine with CYP3A4 or CYP2C19 inhibitors are to be anticipated, whereas substrates of CYP2C19, ABCB1, or ABCG2 will presumably not be influenced by tilidine or nortilidine.

Topics: Analgesics, Opioid; Aryl Hydrocarbon Hydroxylases; ATP Binding Cassette Transporter, Subfamily B; ATP Binding Cassette Transporter, Subfamily B, Member 1; ATP Binding Cassette Transporter, Subfamily B, Member 2; ATP-Binding Cassette Transporters; Biotransformation; Chromatography, High Pressure Liquid; Cytochrome P-450 CYP2C19; Cytochrome P-450 CYP2D6; Cytochrome P-450 CYP2D6 Inhibitors; Cytochrome P-450 CYP3A; Cytochrome P-450 CYP3A Inhibitors; Drug Interactions; Enzyme Inhibitors; Humans; In Vitro Techniques; Kinetics; Microsomes, Liver; Recombinant Proteins; Tandem Mass Spectrometry; Tilidine

Singular coronary arteries are a rare feature appearing in approximately 0.05% of the population. The clinical relevance of those anomalies varies a lot. The wide range of descriptions reaches from asymptomatic cases to sudden cardiac death. This will be discussed in a case report concerning a 31-year-old woman who was found dead in her apartment. Due to drugs that were found next to her, a suicide was assumed. The autopsy yielded an aplastic right coronary artery and a left coronary artery with an anomalous origin of the circumflex branch as well as a myocardial scar. The autopsy findings and the results of the toxicological examinations are presented and discussed in view of the cause of death.

Topics: Adult; Analgesics, Opioid; Antidepressive Agents, Tricyclic; Central Nervous System Depressants; Coronary Vessel Anomalies; Female; Forensic Pathology; Humans; Myocardium; Pyrethrins; Tilidine; Trimipramine

A fully validated liquid chromatographic procedure coupled with electrospray ionization-tandem mass spectrometry (LC-ESI-MS/MS) is presented for quantitative determination of the opioids buprenorphine, codeine, fentanyl, hydromorphone, methadone, morphine, oxycodone, oxymorphone, piritramide, tilidine, and tramadol together with their metabolites bisnortilidine, morphine-glucuronides, norfentanyl, and nortilidine in blood plasma after an automatically performed solid-phase extraction (SPE). Separation was achieved in 35 min on a Phenomenex C12 MAX-RP column (4 microm, 150 x 2 mm) using a gradient of ammonium formiate buffer (pH 3.5) and acetonitrile. The validation data were within the required limits. The assay was successfully applied to authentic plasma samples, allowing confirmation of the diagnosis of overdose situations as well as monitoring of patients' compliance, especially in patients under palliative care.

Topics: Analgesics, Opioid; Chromatography, Liquid; Fentanyl; Humans; Morphine Derivatives; Palliative Care; Patient Compliance; Spectrometry, Mass, Electrospray Ionization; Tilidine

Tilidine, alone or combined with naloxone to prevent drug abuse, is used as an oral opioid analgesic. Although the analgesic action of tilidine and its active metabolite nortilidine is reversed by naloxone and therefore believed to involve the activation of the Mu opioid (MOP, OP3, mu) receptor, this has never been studied in recombinant systems. We have measured the selectivity of tilidine and nortilidine for human opioid and opioid-like receptors stably expressed in CHO-K1 cells, using the inhibition of the forskolin (FK)-induced accumulation of cAMP as endpoint. In cells expressing the MOP receptor, tilidine and nortilidine inhibited cAMP accumulation with IC50 of 11 microM and 110 nM, respectively. The agonist effects of nortilidine and [D-Ala2-MePhe4-Gly5-ol]enkephalin (DAMGO) on the MOP receptor were reversed by naloxone with very similar IC50 (1.2 versus 1.8 nM). At concentrations up to 100 microM, tilidine and nortilidine had no agonist effect on the DOP, KOP and NOP receptors. In conclusion, this study on cloned human receptors demonstrates that nortilidine is a selective agonist of the MOP receptor.

Topics: Animals; CHO Cells; Cloning, Molecular; Cricetinae; Dose-Response Relationship, Drug; Receptors, Opioid; Tilidine

We developed an isocratic, selective, and very sensitive HPLC method for the determination of ketamine and its two main metabolites in plasma. The compounds were extracted from plasma by a liquid-liquid extraction with a dichloromethane:ethyl acetate mixture followed by an acidic back-extraction. Separation was achieved on a new stationary phase, Purospher RP-18 endcapped, with a mobile phase containing acetonitrile:0.03 mol/L phosphate buffer (23:77 by vol) adjusted to pH 7.2. Because of the high column efficiency and the significant improvement of peak symmetry, the quantification limit could be down to 5 micrograms/L for ketamine and norketamine (NK). The intraday and interday CVs ranged from 1.7% to 5.8% and 3.1% to 10.2% for all compounds respectively. The method is sensitive enough for monitoring ketamine, NK, and dehydroketamine in plasma during pharmacokinetic studies after an intravenous bolus of a low dose of ketamine.

Topics: Acetates; Calibration; Chromatography, High Pressure Liquid; Humans; Indicators and Reagents; Ketamine; Methylene Chloride; Sensitivity and Specificity; Tilidine

Tilidine is a prodrug from which the active metabolite nortilidine is formed by demethylation. The pharmacokinetics of tilidine (T), nortilidine (NT) and bisnortilidine (BNT) were studied in nine healthy subjects following single intravenous (10 min infusion) and oral 50 mg T-HCl dose as well as following multiple 50 mg T-HCl oral doses. Systemic availability of the parent substance was 6% and of the active metabolite NT 99%. The terminal half-life of NT was 3.3 h following single oral administration, 4.9 h following intravenous administration and 3.6 h following multiple dosing. Following intravenous infusion, concentrations of unchanged substance were found which were 30 times higher than following oral administration. BNT was eliminated with half-lives of 5 h after oral administration and 6.9 h after intravenous administration. Renal elimination of unchanged substance was 1.6% of the dose following intravenous administration and less than 0.1% of the dose following oral administration. Approximately 3% were recovered in urine as NT and 5% as BNT following both routes of administration.

Topics: Administration, Oral; Adult; Chromatography, Gas; Cyclohexanecarboxylic Acids; Half-Life; Humans; Injections, Intravenous; Male; Tilidine