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Peter Thomann - One of the best experts on this subject based on the ideXlab platform.
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Pharmacokinetics of norTilidine and naloxone after administration of Tilidine/naloxone solution or Tilidine/naloxone sustained release tablets.
Drug Research, 2011Co-Authors: Ulrich Brennscheidt, Klaus-ulrich Seiler, Peter ThomannAbstract: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 × 50 mg Tilidine) and Valoron N retard tablets (2 × 100 mg Tilidine) under steady state conditons, 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.
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pharmacokinetics of norTilidine and naloxone after administration of Tilidine naloxone solution or Tilidine naloxone sustained release tablets
Drug Research, 2011Co-Authors: Ulrich Brennscheidt, Klaus-ulrich Seiler, Peter ThomannAbstract: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 × 50 mg Tilidine) and Valoron N retard tablets (2 × 100 mg Tilidine) under steady state conditons, 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.
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Pharmacokinetics of Tilidine and naloxone in patients with severe hepatic impairment.
Drug Research, 2011Co-Authors: Ulrich Brennscheidt, Peter Thomann, Ulrike Brunnmüller, Dietfried Proppe, Klaus-ulrich SeilerAbstract:The objective of the present study was to evaluate the pharmacokinetics of Tilidine (CAS 20380-58-9), naloxone (CAS 465-65-6) and Tilidine metabolites after administration of a single oral dose of a solution containing 100 mg Tilidine hydrochloride and 8 mg naloxone hydrochloride (equivalent to 1.44 ml Valoron© N solution) to patients with severe hepatic impairment. The investigation was carried out as an open single-dose study in 8 patients suffering from liver cirrhosis. Patients qualified for study enrollment if they had a Child-Pugh score of ≥7 and a mono-ethyl-glycine-xylidide (MEGX) 15-min test value Tilidine, norTilidine and unconjugated naloxone pharmacokinetic parameters showed a high variability between patients. Compared to previous results obtained in healthy volunteers, maximum plasma concentration (Cmax) of norTilidine was reduced by 44%, whereas elimination half-life (t1/2) was prolonged by factor 2. The area under the curve (AUC) showed a slight reduction of approximately 20%. For total naloxone, no relevant change was observed. However, in contrast to the results obtained in healthy subjects, unconjugated naloxone could be measured in plasma from patients with cirrhosis, possibly due to a reduced glucuronidation capacity of the liver in these patients. In conclusion, severe hepatic impairment has a relatively minor influence on the exposure (AUC) to the active metabolite of Tilidine (i.e., norTilidine). However, a straightforward interpretation of the results was confounded by pronounced variability in norTilidine pharmacokinetics. In individual patients with severely affected liver function, satisfactory analgesia with Tilidine/naloxone oral solution might not be achieved because of insufficient formation of norTilidine and insufficient inactivation of naloxone.
Helmut Hoffmannmenzel - One of the best experts on this subject based on the ideXlab platform.
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topical review on the abuse and misuse potential of tramadol and Tilidine in germany
Substance Abuse, 2013Co-Authors: Lukas Radbruch, Gerd Glaeske, Stefan Grond, Frank Munchberg, Norbert Scherbaum, Elisabeth Storz, Kathrin Tholen, Petra Zagermannmuncke, W Zieglgansberger, Helmut HoffmannmenzelAbstract:BACKGROUND: Tramadol and Tilidine (in combination with naloxone) are used as weak opioid analgesics in Germany. Tramadol is not scheduled in the German Narcotic Drugs Act. Tilidine is scheduled, whereas Tilidine in fixed combinations with naloxone is exempt from some of the provisions of the Narcotic Drugs Act. Recent reports on misuse of both substances led to an evaluation of their potential for misuse, abuse, and dependency by the expert advisory committee established by the German Federal Government, resident at the Federal Institute for Drugs and Medical Devices. METHODS: A subcommittee formulated key questions and identified available data sources for each of these questions. Additional information was solicited where necessary, including a survey among a panel of pharmacists, a survey in an addiction clinic, analysis of prescription patterns, and information from the boards of pharmacists of the federal states and the Federal Bureau of Criminal Investigation. RESULTS: Analgesic efficiency in the treatment of acute and chronic pain has been proven for both tramadol and Tilidine/naloxone. For tramadol, high evidence has been confirmed in systematic reviews, and tramadol is listed in national and international guidelines on acute and chronic pain management. Animal and human studies found a low potential for misuse, abuse, and dependency for both substances. Information from 2 tramadol safety databases allowed calculation of the incidence of abuse or dependency as 0.21 and 0.12 cases per million defined daily dosages (DDDs), with lower incidences in recent years. For Tilidine/naloxone, the incidence was calculated as 0.43 cases per million DDDs for oral solution and 0.18 for slow-release tablets. In an online survey among German pharmacies as well as in the reports from state pharmacy boards, fraud attempts were repeated more frequently with Tilidine/naloxone than with tramadol in the last 2 years. The Federal Bureau of Criminal Investigations reported prescription fraud only with Tilidine/naloxone and predominantly in the region of Berlin. Dependency on tramadol or Tilidine/naloxone is reported only rarely from addiction counseling centers. One third of the patients surveyed in an addiction clinic reported experiences with tramadol or Tilidine/naloxone, but mostly with duration of less than 4 weeks and with a medical prescription based on a reasonable indication. Also, occasional illegal use of opioid analgesics as a substitute of heroin was reported. An evaluation of pooled data from statutory health insurance companies found 2.5% of persons receiving at least 1 prescription of tramadol or the combination of Tilidine and naloxone in 2009 (1.6% with tramadol and 1.0% with Tilidine/naloxone). High usage with more than 180 DDDs per year was found in 8.6% of patients treated with tramadol and 17.2% of patients with Tilidine/naloxone. CONCLUSIONS: In conclusion, the subcommittee of the expert advisory committee found a low potential for misuse, abuse, and dependency for tramadol, and a low prevalence in clinical practice. Considerable less information is available for the combination of Tilidine and naloxone. However, the cumulation of evidence indicated a higher risk of misuse, abuse, and dependency for Tilidine/naloxone solution, but not for slow-release tablets.
Ulrich Brennscheidt - One of the best experts on this subject based on the ideXlab platform.
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Pharmacokinetics of norTilidine and naloxone after administration of Tilidine/naloxone solution or Tilidine/naloxone sustained release tablets.
Drug Research, 2011Co-Authors: Ulrich Brennscheidt, Klaus-ulrich Seiler, Peter ThomannAbstract: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 × 50 mg Tilidine) and Valoron N retard tablets (2 × 100 mg Tilidine) under steady state conditons, 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.
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pharmacokinetics of norTilidine and naloxone after administration of Tilidine naloxone solution or Tilidine naloxone sustained release tablets
Drug Research, 2011Co-Authors: Ulrich Brennscheidt, Klaus-ulrich Seiler, Peter ThomannAbstract: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 × 50 mg Tilidine) and Valoron N retard tablets (2 × 100 mg Tilidine) under steady state conditons, 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.
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Pharmacokinetics of Tilidine and naloxone in patients with severe hepatic impairment.
Drug Research, 2011Co-Authors: Ulrich Brennscheidt, Peter Thomann, Ulrike Brunnmüller, Dietfried Proppe, Klaus-ulrich SeilerAbstract:The objective of the present study was to evaluate the pharmacokinetics of Tilidine (CAS 20380-58-9), naloxone (CAS 465-65-6) and Tilidine metabolites after administration of a single oral dose of a solution containing 100 mg Tilidine hydrochloride and 8 mg naloxone hydrochloride (equivalent to 1.44 ml Valoron© N solution) to patients with severe hepatic impairment. The investigation was carried out as an open single-dose study in 8 patients suffering from liver cirrhosis. Patients qualified for study enrollment if they had a Child-Pugh score of ≥7 and a mono-ethyl-glycine-xylidide (MEGX) 15-min test value Tilidine, norTilidine and unconjugated naloxone pharmacokinetic parameters showed a high variability between patients. Compared to previous results obtained in healthy volunteers, maximum plasma concentration (Cmax) of norTilidine was reduced by 44%, whereas elimination half-life (t1/2) was prolonged by factor 2. The area under the curve (AUC) showed a slight reduction of approximately 20%. For total naloxone, no relevant change was observed. However, in contrast to the results obtained in healthy subjects, unconjugated naloxone could be measured in plasma from patients with cirrhosis, possibly due to a reduced glucuronidation capacity of the liver in these patients. In conclusion, severe hepatic impairment has a relatively minor influence on the exposure (AUC) to the active metabolite of Tilidine (i.e., norTilidine). However, a straightforward interpretation of the results was confounded by pronounced variability in norTilidine pharmacokinetics. In individual patients with severely affected liver function, satisfactory analgesia with Tilidine/naloxone oral solution might not be achieved because of insufficient formation of norTilidine and insufficient inactivation of naloxone.
Gerd Mikus - One of the best experts on this subject based on the ideXlab platform.
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Pre-systemic elimination of Tilidine: localization and consequences for the formation of the active metabolite norTilidine.
Basic & Clinical Pharmacology & Toxicology, 2014Co-Authors: Christine Eichbaum, Kristin Mathes, Jürgen Burhenne, Christoph Markert, Antje Blank, Gerd MikusAbstract: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.
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Contribution of CYP2C19 and CYP3A4 to the formation of the active norTilidine from the prodrug Tilidine.
British Journal of Clinical Pharmacology, 2012Co-Authors: Barbara Grün, Johanna Weiss, Klaus-dieter Riedel, Ulrike Merkel, Gerd MikusAbstract:WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT • 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. WHAT THIS STUDY ADDS • 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. AIMS 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. METHODS 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. RESULTS 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. CONCLUSIONS 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.
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In vitro identification of the cytochrome P450 isozymes involved in the N-demethylation of the active opioid metabolite norTilidine to bisnorTilidine
Naunyn-Schmiedeberg's Archives of Pharmacology, 2012Co-Authors: Isabel Wustrow, Gerd Mikus, Klaus-dieter Riedel, Johanna WeissAbstract: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.
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Inhibition of the active principle of the weak opioid Tilidine by the triazole antifungal voriconazole
British Journal of Clinical Pharmacology, 2009Co-Authors: Barbara Grün, Klaus-dieter Riedel, Stefanie Krautter, Gerd MikusAbstract:WHAT IS ALREADY KNOWN ABOUT THE SUBJECT • Tilidine, a World Health Organization level II analgesic, is a high extraction drug subject to pronounced first-pass metabolism, resulting in a low absolute bioavailability. • The analgesic activity of Tilidine is almost exclusively exerted through its metabolite norTilidine, which easily penetrates the blood–brain barrier and binds to the µ-opioid receptor as a potent agonist. • In vitro, Tilidine has been shown to be metabolized to norTilidine by N-demethylation via CYP3A4 and CYP2C19; furthermore, strong CYP3A4 and CYP2C19 inhibitors inhibited the formation of norTilidine, suggesting that these inhibitors will lead to a reduction of Tilidine efficiency in vivo. WHAT THIS PAPER ADDS • Co-administration of Tilidine and the potent CYP3A4 and CYP2C19 inhibitor voriconazole resulted in a major pharmacokinetic interaction that was partly associated with changes in the analgesic effect. • Voriconazole inhibits both metabolic steps in the sequential metabolism of Tilidine resulting in an increased exposure of the active norTilidine. • The incidence of adverse reactions was also significantly increased. AIMS To investigate in vivo the influence of the potent CYP2C19 and CYP3A4 inhibitor voriconazole on the pharmacokinetics and analgesic effects of Tilidine. METHODS 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). RESULTS 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 tmax 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. CONCLUSIONS 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.
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In vitro metabolism of the opioid Tilidine and interaction of Tilidine and norTilidine with CYP3A4, CYP2C19, and CYP2D6
Naunyn-Schmiedeberg's Archives of Pharmacology, 2008Co-Authors: Johanna Weiss, Evelyn Sawa, Klaus-dieter Riedel, Walter Emil Haefeli, Gerd MikusAbstract: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 μ-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 μM 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.
Klaus-ulrich Seiler - One of the best experts on this subject based on the ideXlab platform.
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Pharmacokinetics of norTilidine and naloxone after administration of Tilidine/naloxone solution or Tilidine/naloxone sustained release tablets.
Drug Research, 2011Co-Authors: Ulrich Brennscheidt, Klaus-ulrich Seiler, Peter ThomannAbstract: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 × 50 mg Tilidine) and Valoron N retard tablets (2 × 100 mg Tilidine) under steady state conditons, 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.
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pharmacokinetics of norTilidine and naloxone after administration of Tilidine naloxone solution or Tilidine naloxone sustained release tablets
Drug Research, 2011Co-Authors: Ulrich Brennscheidt, Klaus-ulrich Seiler, Peter ThomannAbstract: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 × 50 mg Tilidine) and Valoron N retard tablets (2 × 100 mg Tilidine) under steady state conditons, 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.
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Pharmacokinetics of Tilidine and naloxone in patients with severe hepatic impairment.
Drug Research, 2011Co-Authors: Ulrich Brennscheidt, Peter Thomann, Ulrike Brunnmüller, Dietfried Proppe, Klaus-ulrich SeilerAbstract:The objective of the present study was to evaluate the pharmacokinetics of Tilidine (CAS 20380-58-9), naloxone (CAS 465-65-6) and Tilidine metabolites after administration of a single oral dose of a solution containing 100 mg Tilidine hydrochloride and 8 mg naloxone hydrochloride (equivalent to 1.44 ml Valoron© N solution) to patients with severe hepatic impairment. The investigation was carried out as an open single-dose study in 8 patients suffering from liver cirrhosis. Patients qualified for study enrollment if they had a Child-Pugh score of ≥7 and a mono-ethyl-glycine-xylidide (MEGX) 15-min test value Tilidine, norTilidine and unconjugated naloxone pharmacokinetic parameters showed a high variability between patients. Compared to previous results obtained in healthy volunteers, maximum plasma concentration (Cmax) of norTilidine was reduced by 44%, whereas elimination half-life (t1/2) was prolonged by factor 2. The area under the curve (AUC) showed a slight reduction of approximately 20%. For total naloxone, no relevant change was observed. However, in contrast to the results obtained in healthy subjects, unconjugated naloxone could be measured in plasma from patients with cirrhosis, possibly due to a reduced glucuronidation capacity of the liver in these patients. In conclusion, severe hepatic impairment has a relatively minor influence on the exposure (AUC) to the active metabolite of Tilidine (i.e., norTilidine). However, a straightforward interpretation of the results was confounded by pronounced variability in norTilidine pharmacokinetics. In individual patients with severely affected liver function, satisfactory analgesia with Tilidine/naloxone oral solution might not be achieved because of insufficient formation of norTilidine and insufficient inactivation of naloxone.