Sequential First‐Pass Metabolism of Nortilidine: The Active Metabolite of the Synthetic Opioid Drug Tilidine

et al. 2009

Brit J Clinical Pharma

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 m-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. AIMSTo investigate in vivo the influence of the potent CYP2C19 and CYP3A4 inhibitor voriconazole on the pharmacokinetics and analgesic effects of tilidine. METHODSSixteen 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). RESULTSVoriconazole caused a 20-fold increase in exposition of tilidine in serum [AUC 1250.8 h * ng ml, 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 , 95% CI 138, 213; P < 0.016), mainly due to the shorter withdrawal time 0.75 h after tilidine administration. CONCLUSIONSVoriconazole 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.

Section: Figurementioning

confidence: 99%

Inhibition of the active principle of the weak opioid tilidine by the triazole antifungal voriconazole

Grün

Krautter

et al. 2009

Brit J Clinical Pharma

“…Recently, it was demonstrated that tilidine is a substrate of cytochrome P450 (CYP) isozymes, especially CYP3A4 and CYP2C19 [7]. Tilidine undergoes a so‐called sequential metabolism; two‐thirds of an administered dose is converted to nortilidine, while about 50% of the formed nortilidine is further metabolized to bisnortilidine before leaving the metabolizing organ [8]. In a recently published study, the simultaneous inhibition of CYP3A4 and CYP2C19 by voriconazole resulted in a 20‐fold increase of tilidine exposure [9].…”

Section: Introductionmentioning

confidence: 99%

Contribution of CYP2C19 and CYP3A4 to the formation of the active nortilidine from the prodrug tilidine

Grün

Merkel

et al. 2012

Brit J Clinical Pharma

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 m-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. AIMSTo 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. METHODSFourteen 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. RESULTSTilidine 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 CONCLUSIONSThe 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.

“…More than 90% of the parent compound is metabolised in the liver, thus giving an absolute bioavailability of less than 10% (Vollmer 1988). In accordance to this, it has been reported that at least two thirds of tilidine is metabolised to the active metabolite nortilidine, but only 33% of the dose is systemically available due to further metabolism to bisnortilidine prior to leaving the metabolising organ (Hajda et al 2002). Clinical implications could arise in the interaction of tilidine with other compounds.…”

Section: Discussionmentioning

confidence: 81%

“…Hence the analgesic effect is mediated by the activation of μ-opioid receptors via the metabolite nortilidine being the primary agonist (Vollmer et al 1989). After oral intake tilidine is completely absorbed and rapidly metabolised to nortilidine, bisnortilidine and polar metabolites which are yet unknown (Vollmer and Hodenberg 1977;Hajda et al 2002). The extraction ratio of tilidine to nortilidine adds up to two thirds of the original dose, however only one third is systemically available due to the intensive first pass effect (Hajda et al 2002).…”

Section: Introductionmentioning

confidence: 99%

“…After oral intake tilidine is completely absorbed and rapidly metabolised to nortilidine, bisnortilidine and polar metabolites which are yet unknown (Vollmer and Hodenberg 1977;Hajda et al 2002). The extraction ratio of tilidine to nortilidine adds up to two thirds of the original dose, however only one third is systemically available due to the intensive first pass effect (Hajda et al 2002). We have previously demonstrated that the first N-demethylation step most likely occurs via the cytochrome P450 isozymes (CYP) 3A4 and CYP2C19 (Weiss et al 2008), which led to the hypothesis that inhibition of CYP3A4 and CYP2C19 would cause a decreased analgesic effect of tilidine.…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

In vitro identification of the cytochrome P450 isozymes involved in the N-demethylation of the active opioid metabolite nortilidine to bisnortilidine

Wustrow

Naunyn-Schmiedeberg's Arch Pharmacol

Mikus

et al. 2012

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.