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Gabapentin, an analog of gamma-aminobutyric acid, exhibits anticonvulsant properties in both animal models and humans. Gabapentin pharmacokinetics was studied in laboratory animals using HPLC and radiometry. Oral bioavailability was 40% in monkeys administered 25 mg/kg, 79% in mice and rats receiving 50 mg/kg, and 80% in dogs administered 50 mg/kg. Binding to plasma proteins was < 3%. Maximum blood or plasma concentrations generally occurred within 2 hr of an oral dose. In rats and monkeys, increases in maximum plasma concentrations and/or areas under the curve were less than dose-proportional following oral administration, most likely because of saturable absorption. However, intravenous pharmacokinetics in rats were linear over the dosage range of 4-500 mg/kg. Mean intravenous elimination half-life was 1.7 hr in rats, 2.9 hr (14C only) in dogs, and 3.0 hr in monkeys. In rats and dogs, repeated administration did not alter gabapentin or 14C pharmacokinetics. Additionally, gabapentin did not induce hepatic cytochrome P450 monooxygenases in rats. There were no age- (rats only) or gender-associated changes in pharmacokinetic parameters. [14C]Gabapentin was extensively distributed to tissues. In the dog, gabapentin was metabolized to N-methylgabapentin (approximately 34% of dose); whereas metabolism in mouse, rat, and monkey was minimal (< 5%). The principal route of excretion was via urine. In summary, as an antiepileptic drug, gabapentin exhibited desirable pharmacokinetic properties, such as linear elimination kinetics, not highly bound to plasma proteins, not extensively metabolized, and not an inducer of hepatic cytochrome P450.

A sensitive and specific GLC method is described to determine therapeutic levels of tilidine and its two main metabolites, nortilidine and bisnortilidine, in plasma and urine. The method involves the extraction of the compounds and an internal standard with cyclohexane from alkalinized samples, followed by back-extraction into 1 N HCl. The hydrochloric acid solution is evaporated to dryness. After liberation of the free bases with ammonia, the residue is subjected to GLC analysis with a nitrogen-phosphorus detector and a 1.8-m (6-ft) glass column packed with 1% CRS 101 and 1.5% LAC-4-R-886 on Gas Chrom Q. Sensitivity in plasma and urine is approximately 1 ng/ml for a 5-ml sample.

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.

Absorption, distribution, metabolism and excretion of the potent analgesic ethyl-DL-trans-2-timethylamino-1-phenyl-chclohex-3-ene-trans-1-carboxylate-hydrochloride (tilidine-HCl, Gö 1261 C, active ingredient of Vloron) were investigated in rats and dogs, using the radioactively labelled substance. Following oral administration, tilidine-HCl is rapidly and completely absorbed from the duodenum. During absorption, tilidine undergoes a marked first-pass effect. In plasma several metabolites are found, part of them occurring in higher concentrations than the unchanged substance. The metabolites are also formed rapidly after parenteral administration, unchanged tilidine being found in higher concentrations than any of the metabolites at all times measured. Following both routes of administration, the Met. I (nortilidine), also possessing a strong analgesic activity, reaches similar plasma levels. 14C distribution studies in rats showed a relatively high concentration of the radioactivity in the excretory organs, liver and kidneys. In brain, muscle tissue and blood much lower 14C concentrations are found. The concentrations measured in the foetal organs correspond to those in the muscle tissue of the mother animals and are, therefore, much lower than in most maternal organs. The radioactivity is eliminated from the foetal organs at the same rate as from the maternal organs. Tilidine is rapidly and completely eliminated with the excrements, nearly exclusively in the form of metabolic products. Rats eliminate 50% of the given radioactivity via the kidneys. The relatively high fecal elimination is based on the biliary metabolites. Following intraduodenal and intravenous administration to rats with an interrupted enterohepatic circulation, about 80% of the dose is eliminated with bile. The biliary metabolites are partly reabsorbed. In dogs, approx. 80% of the applied radioactivity is eliminated with urine.

This paper describes the pharmacokinetic studies of 1-(aminomethyl)-cyclohexane acetic acid (gabapentin, Gö 3450, CI-945) conducted with the 14C-labelled substance following intravenous and intragastric administration to rats and dogs and oral administration to humans. Gabapentin is well absorbed in rats, dogs and in humans, with maximum blood levels, reached within 1-3 h after peroral administration. Following i.v. administration to rats, similar blood and brain levels of gabapentin are observed after a short distribution phase, whereby concentrations in cerebrum and cerebellum are comparable. The highest concentrations are found in the pancreas and kidneys and the lowest values in adipose tissue. No binding of gabapentin to human plasma proteins or human serum albumin is observed. The distribution coefficient (octanol/buffer pH 7.4) is 7.5 X 10(-2). In man, no biotransformation of gabapentin is observed. In rats, biotransformation is only minor. In dogs, however, a remarkable formation of N-methyl-gabapentin is found. Elimination half-lives range between 2-3 h in rats, 3-4 h in dogs, and 5-6 h in man. Gabapentin is nearly exclusively eliminated via the kidneys. Renal elimination was up to 99.8% in rats and approx. 80% in man following oral administration. The blood level-time course after i.v. administration to rats can well be described by a three-compartment open model. Experiments in rats and dogs demonstrate that pharmacokinetics are not sex-dependent and are not changed after multiple dosage. Pharmacokinetics are shown to be linear in the range tested of 4 to 500 mg/kg i.v. in rats.

We report a specific and sensitive method for determination of the individual optical isomers of nortilidine, a main metabolite of tilidine, with the aid of a nitrogen-sensitive detector. With N-trifluoroacetyl-L-leucyl chloride as chiral reagent, the diastereomeric derivatives of the nortilidine enantiomers could be separated and quantified in the nanogram range. Under these conditions, the enantiomers of bisnortilidine, another main metabolite of tilidine, were also separated. Investigations in rats with the enantiomers of tilidine and nortilidine indicated that no racemization occurs during N-demethylation in the organism. After oral and intravenous administration of 50 mg of tilidine.HCI to a human volunteer, identical concentrations of nortilidine enantiomers were found in the plasma.