Ethyl 2-(dimethylamino)-1-phenylcyclohex-3-ene-1-carboxylate

Endpoint summary

Key value for chemical safety assessment

Bioaccumulation potential:

no bioaccumulation potential

Additional information

No studies on the toxicokinetics of ethyl 2-(dimethylamino)-1-phenylcyclohex-3-ene-1-carboxylate were available. Five studies are available in which the pharmacokinetics of tilidine hydrochloride ((+-)-ethyl trans-2-(dimethylamino)-1-phenyl-3-cyclohexene-1-carboxylate hydrochloride), a structural analogue of ethyl 2-(dimethylamino)-1-phenylcyclohex-3-ene-1-carboxylate, are described.

The pharmacokinetics of nortilidine, a metabolite of tilidine, was studied in 18 male healthy subjects after oral application of tilidine/naloxone solution or tilidine/naloxone retard tablets, respectively (Brennscheidt 2000). Investigations were performed of a) dose linearity after application of 25 mg, 50 mg and 100 mg tilidine solution, b) dose equivalence of a solution (4 x 50 mg tilidine/nalaxone) and retard tablets (2 x 100 mg tilidine/nalaxone) under steady state conditions, and c) the equivalence of different dose strengths of tilidine/nalaxone 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 4 tilidine/naloxone solution and tilidine/naloxone retard tablets. There is also an equivalence of different dose strengths of tablets (4x50 mg, 2x100 mg and 200 mg tilidine/tablet). The mean area under the curve was 219, 394, 885, 1309, 1248, 1748, 1727, and 1758 ng*h/mL for Trial A 25 mg, Trial A 50 mg, Trial A 100 mg, Trial B retard tablets, Trial B oral solution, Trial C 4x50 mg, Trial C 2x100 mg and Trial C 200 mg, respectively. All half lifes were similar, ranging from 5.2 to 6.8 h.

The pharmacokinetics of tilidine, nortilidine and bisnortilidine were studied in nine healthy subjects following single intravenous (10 min infusion) and oral 50 mg tilidine-HCl dose as well as following multiple 50 mg tilidine-HCl oral doses (Vollmer 1989). Systemic availability of the parent substance was 6% and of the active metabolite nortilidine 99%. The terminal half-life of nortilidine was 3.3 h following single oral administration, 4.9 h following intravenous administration and 3.6 h following multiple dosing. Following intravenous infusion, concentration of unchanged substance were found which were 30 times higher than following oral administration. Bisnortilidine was eliminated with half-live 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 nortilidine and 5% as bisnortilidine following both routes of administration.

Investigations following oral administration of 14C-labelled DL-trans-2-Dimethylamino-1-phenyl-cyclohex-3-ene-trans-1-carboxylate hydrochlorid (Gö 1261 C, Valoron®) to four male volunteers showed that Valoron is rapidly and completely absorbed by the oral route (Vollmer 1970). Maximal blood and plasma levels were achieved 90 min after administration of the labelled compound. Radioactivity levels of the cerebrospinal fluid reached approximately one tenth of serum levels. Valoron is rapidly metabolized and excreted. About 90% is eliminated via urine and the other 10% is eliminated via feces. The half-life of the product via urine excretion is approximately 11 h.

Metabolism and excretion of ethyl-DL-trans-2-dimethylamino-1-phenyl-cyclohex-3-ene-trans-1-carboxylate-hydrochloride (Tilidine-HCl) were investigated in SIV-50 rats, Beagle dogs and one human volunteer (Vollmer 1977). Following oral administration 51, 77 and >90 % of the applied radioactivity was eliminated via urine for rats, dogs and the human, respectively. After intravenous administration in rats this elimination was 47.1%. The half-life of renal elimination was 8 h in rats and the human. The elimination was faster in dogs. In all species ca. 17% of the urinary radioactivity could be extracted with ether at alkaline pH values as so called unpolar metabolites, after oral administration. After intravenous administration, in rats, this was ca. 25%. The largest part of the administered substance was excreted as a metabolite in all species. Less than 0.2% of the urinary radioactivity corresponded to unchanged tilidine and 2-3% to nortilidine and bis nortilidine each. In addition, a number of other metabolites were detected in the ether extract, each corresponding to < 2% of the administered dose. The higher proportion of unchanged tilidine in the urine of the i.v. rat test in comparison to the i.g. test (3.4% and < 0.1 %, resp., of applied dose) indicated a first-pass effect during absorption. Elimination rate and composition of the renal metabolites were almost identical with both routes of administration. Incubation tests with different enzymes indicated that the major part of the polar urinary metabolites consists of glucuronides, at least in the rat and in man.

Absorption, distribution, metabolism and excretion of ethyl-DL-trans-2-dimethylamino-1-phenyl-cyclohex-3-ene-trans-1-carboxylate-hydrochloride (tilidine-HCl, Gö 1261 C, active ingredient of Valoron®) were investigated in rats and dogs using the radioactively labelled substance (Vollmer 1976). Rats received the substance via oral, intravenous and intraduodenal administration. Dogs only received the oral administration. Following oral administration, tilidine-HCl is rapidly and completely absorbed from the duodenum. During absorption, tilidine undergoes a marked first-pass effect, which was observed in rats. In plasma several metabolites are found, part of them occurring in higher concentration than the unchanged substance. The metabolites are also formed rapidly after intravenous administration, unchanged tilidine being found in higher concentrations than any of the metabolites at all times measured. 14C distribution studies showed a relatively high concentration of the radioactivity in the excretory organs, liver, kidneys and the gastro-intestinal tract. In the brain, muscle tissue and blood much lower concentrations were found. The concentrations measured in fetal organs corresponded to those in muscle tissue of the maternal animals and are therefore much lower than in most maternal organs. The elimination of the fetal organs is at the same rate as from maternal organs. Tilidine is rapidly and completely eliminated with the excrements, nearly exclusively in form to metabolic products. 50 and 78% of this elimination is via the kidneys in rats and dogs, respectively. The relatively high fecal elimination in rats is based on the biliary metabolites. Following intraduodenal and intravenous administration in rats, in animals of which the enterohepatic circulation was interrupted, about 80% of the dose is eliminated with bile.