ent-dextilidine and bisnortilidine

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

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

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

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

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

The opioid analgesic tilidine and its metabolites were detected by high performance liquid chromatography (HPLC) with UV-detection in serum from a 28 year-old woman who ingested 100 ml Valoron (o)N containing 6.94 g of tilidine and about 0.56 g of naloxone with suicidal intention. Data on the toxicokinetics of tilidine in severe poisonings are missing. Therefore we followed serum concentrations of tilidine and metabolites for 48 or 96 h and for the first time calculated basic kinetic parameters in a massive life threatening poisoning. Serum concentration of tilidine 3 h after ingestion was 38.1 mg/l which is about 70 times of the upper therapeutic level in man and about ninefold above toxic concentrations known so far. The concentration of nortilidine, the primary active metabolite at this time was 18.8 mg/l. The terminal elimination half life's of tilidine and nortilidine were explicit, prolonged with 23.9 and 13.9 h respectively. The competitive opiate antagonist naloxone, which is added as a part of the industrially produced preparation Valoron N solution to minimise oral abuse is not able to prevent ventilatory depression in massive overdoses.

Topics: Adult; Chromatography, High Pressure Liquid; Drug Combinations; Female; Humans; Naloxone; Tilidine; Time Factors

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