title: Pre-systemic elimination of tilidine: localization and consequences for the formation of the active metabolite nortilidine.
abstract: 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.
authors.affiliation: Department of Clinical Pharmacology and Pharmacoepidemiology, University Hospital Heidelberg, Heidelberg, Germany.
authors.forename: Christine
authors.initials: C
authors.lastname: Eichbaum
authors.forename: Kristin
authors.initials: K
authors.lastname: Mathes
authors.forename: Jürgen
authors.initials: J
authors.lastname: Burhenne
authors.forename: Christoph
authors.initials: C
authors.lastname: Markert
authors.forename: Antje
authors.initials: A
authors.lastname: Blank
authors.forename: Gerd
authors.initials: G
authors.lastname: Mikus
mesh_terms: D000328:Adult; D000480:Alkynes; D000701:Analgesics, Opioid / Q000493:pharmacokinetics*; D048588:Benzoxazines / Q000494:pharmacology; D001628:Beverages; D002853:Chromatography, Liquid / Q000379:methods; D032083:Citrus paradisi; D018592:Cross-Over Studies; D003521:Cyclopropanes; D051544:Cytochrome P-450 CYP3A / Q000378:metabolism*; D005260:Female; D006207:Half-Life; D006801:Humans; D008297:Male; D008875:Middle Aged; D053719:Tandem Mass Spectrometry / Q000379:methods; D013993:Tilidine / Q000031:analogs & derivatives* / Q000493:pharmacokinetics; D055815:Young Adult
chemical_list: D000480:Alkynes; D000701:Analgesics, Opioid; D048588:Benzoxazines; D003521:Cyclopropanes; C062492:bisnortilidine; C062490:nortilidine; D051544:Cytochrome P-450 CYP3A; C510163:CYP3A4 protein, human; D013993:Tilidine; C098320:efavirenz