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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.

The new choleretic ethyl (Z-3-ethyl-4-oxo-5-piperidino-thiazolidin-2-ylidene) acetate (piprozoline, Gö 919, Probilin) is absorbed well and rapidly in rats, dogs and humans. Maximum 14C plasma concentrations are found 1-2 h after oral administration of the labelled substance to fasting animals and human volunteers. When administered to test persons after breakfast, the absorption is delayed but the absorbed amount is unaffected. Elimination of the radioactivity from the plasma occurs in two phases; 24 h after administration the radioactivity concentration has dropped to 5-8% of the maximum levels. Piprozoline is almost completely metabolized during absorption. The primary metabolic step is the enzymatic hydrolysis of the ester bond to the corresponding acid (metabolite I). At the time of maximum plasma concentration most of the plasma radioactivity corresponds to metabolite I, which also possesses choleretic activity. Approx. 65% of the radioactive dose is eliminated renally in all three species, approx. 60% being excreted within the first 24 h. Approx. 40-60% of the urinary radioactivity can be ascribed to metabolite I, both in its free form and conjugated with glucuronic acid. No unchanged substance is found in the urine. A comparison of the pharmacokinetic and metabolic behaviour of piprozoline in rats, dogs and humans showed that it was similar in all three species.

A sensitive and specific method for the determination of the diuretic Ethyl (Z)-(3-methyl-4-oxo-5-piperidino-thiazolidin-2-ylidene) acetate (etozolin, Elkapin) and its pharmacologically active main metabolite, (Z)-(3-methyl-4-oxo-5-piperidino-thiazolidin-2-ylidene) acetic acid (ozolinone), at therapeutic concentrations in plasma is described. The method is based on high performance liquid chromatography and the use of two structurally similar internal standards. Etozolin and its metabolite are extracted from the plasma into dichloromethane at pH 9 and pH 5, respectively, and the resulting residues are analyzed on a silica gel column. The elution peaks are detected by UV absorption at 281 nm. The sensitivity for both compounds is 20 ng/ml plasma. The precision of the method is about +/- 5%. The applicability to pharmacokinetic studies of etozolin is shown.

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.

The pharmacokinetic profile of D-3-acetoxy-cis-2,3-dihydro-5-(2-dimethylamino-ethyl)-2-(p-methoxy-phenyl)-1, 5-benzothiazepin-4(5H)-one hydrochloride (diltiazem . HCl) following i.v. and p.o. administration has been studied in six healthy subjects using a new sensitive GLC method. The volunteers received an i.v. infusion of 20 mg in 20 min, a peroral solution of 120 mg and two 60-mg tablets (Dilzem) in a randomized sequence. The plasma level time courses of the unchanged compound following infusion and peroral solution were simultaneously evaluated by nonlinear regression analysis. The best model was chosen by means of statistical criteria. In all subjects the experimental data could be adequately described by an open three-compartment model with zero order input following infusion and first order absorption following p.o. solution. Using this procedure the following common disposition parameters were obtained for both routes of administration: t1/2 alpha = 0.1 h, t1/2 beta = 2.1 h, t1/2 gamma = 9.8 h (harmonic means derived from individualized fits), Vc = 0.9 +/- 0.4 l/kg, Vss = 5.2 +/- 2.4 l/kg, Cltot = 11.5 +/- 1.8 ml/min/kg. Compared to the beta-phase the terminal gamma phase represents a smaller contribution to the total AUC. The blood/plasma distribution ratio was found to be 1.00 +/- 0.08 (N = 4), the mean hepatic extraction ratio was 0.54. Peak levels appeared 0.6 +/- 0.3 h after the p.o. solution. The mean absolute bioavailability of diltazem based on the individual AUC infinity 0 of the p.o. solution and the infusion was 0.44 +/- 0.10. Following tablet administration, delayed maximum levels were found after 2.8 +/- 0.9 h. Comparing the AUC infinity 0 of tablets and p.o. solution, there was no significant difference between both dosage forms.

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.

Thymoxamine is rapidly and completely absorbed in man. Rapid biotransformation is observed after intravenous and oral administration of 40 mg 14C-thymoxamine HCl. No unchanged compound is found in the body. More than 90% of plasma and urine radioactivity could be ascribed to six metabolites: the desacetyl compound (metabolite I), the monodemethylated metabolite I (metabolite II), the sulfate conjugates of I and II (metabolites III and IV) and the glucuronides of I and II (metabolites V and VI). The unconjugated metabolites are observed in plasma only after intravenous administration. Similar patterns for polar metabolites are found in plasma and urine for both routes of administration. The sulfate fraction amounts to about 50-60% and the glucuronide fraction to about 30-40% of the radioactivity, the conjugates of metabolite I being more abundant than those of metabolite II. The elimination of the metabolites is rapid, the half-life of radioactivity elimination being 1.5 h during the first 12 hours and 12 h thereafter. 80% of the radioactivity dose is recovered in the urine within 4 hours. Recovery after four days amounts to 99.8% (i.v.) and 97.7% (oral). The results are discussed with regard to the application of the drug in man, taking into account that not only the unconjugated metabolites but also the sulfate conjugates are pharmacologically active.

1 The pharmacokinetic characteristics and bioavailability of isoxicam were investigated in healthy male volunteers following various routes of administration. Plasma concentrations were determined up to 96 or 120 h following each administration using a selective h.p.l.c. method. 2 Twelve subjects received an i.v. and an i.m. injection of 150 mg and an oral dose of 200 mg (two capsules) in a three-way crossover design. 3 The plasma concentration-time curves after intravenous administration followed two compartmental characteristics with a rapid initial distribution phase and a predominant terminal elimination phase. The area under the distribution phase contributed only 0.4% to the total AUC. Mean disposition parameters were: t1/2, lambda 1 = 3.3 min t1/2, lambda z = 28 h, Vc = 5.61, Vdarea = 12.71, CL = 5.1 ml min-1. 4 Following other routes of administration, the isoxicam plasma profile could be adequately described by a one compartment model. 5 After the i.m. dose, isoxicam was rapidly and completely absorbed: within 15 min 40% of the peak concentrations were attained. Maximum plasma concentrations of 11.7 micrograms ml-1 were reached after an average of 3 h. 6 After oral administration isoxicam was completely bioavailable. Mean peak concentrations of 12.3 micrograms ml-1 were obtained within 10 h. 7 The bioavailability of suppositories containing 200 mg of active substance was investigated in another 10 volunteers relative to capsules (2 X 100 mg). The formulations tested were bioequivalent with respect to the amount absorbed. 8 Comparison of AUCs (normalized for dose and body weight) resulting from all treatments, did not show significant differences among the various formulations.(ABSTRACT TRUNCATED AT 250 WORDS)

Thymoxamine is rapidly and completely absorbed in rats. It is a prodrug which does not enter the systemic circulation in its unchanged form. After either oral or intravenous administration it undergoes rapid and intense metabolism involving four biotransformation reactions: Enzymatic hydrolysis to the corresponding phenol (metabolite I), Monodemethylation to metabolite II, Sulfate conjugation of I and II (metabolites III and IV) and Conjugation of I and II with glucuronic acid (metabolites V and VI). With these 6 metabolites identified approximately 95% of the radioactivity can be accounted for in plasma, urine and bile. Whereas the systemic availability of I and II is low, III and IV show high bioavailability. Metabolites I to IV are pharmacologically active, while III and IV are less potent than I and II. The radioactivity distribution in tissues is different after oral and intravenous administration consistent with the higher portion of unconjugated metabolites in the body after administration by parenteral route. Although 60% of the labelled compounds is eliminated via bile, the radioactive compounds are almost completely excreted in the urine after both routes of administration. This demonstrates complete reabsorption of the biliary metabolites. Secondary peaks of radioactivity in plasma and organs at 4 hours are explained by the participation of the metabolites in the enterohepatic circulation.

This paper describes the determination of metabolic profiles of 14C marked ethyl (Z-3-ethyl-4-oxo-5-piperidino-thiazolidin-2-ylidene) acetate (piprozoline, Gö 919, Probilin) in rat, dog and human urine and rat bile with the aid of an HPLC-radioactivity detector system following the direct injection of large quantities onto an analytical C-18 column. Metabolite 1 and two glucuronic acid conjugates of metabolite I were determined quantitatively, isolated and identified. Following HPLC separation, the specific detection of radioactivity permits the determination of metabolic profiles without prior clean-up so that unstable metabolites can also be analyzed.

The structures of six metabolites were elucidated using rat urine after intragastric administration of 14C-thymoxamine by means of enzyme incubations, mass spectrometry and synthesis of metabolites: desacetylthymoxamine, N-demethyl-desacetylthymoxamine, the corresponding sulfates and glucuronides. The nature of the conjugates was confirmed by biosynthesis, i.e., co-administration of unlabelled thymoxamine and 35S-sulfate or 14C-glucose. The system high performance liquid chromatography-radioactivity detection was used for interspecies comparison. All biotransformation pathways are seen in rat and man. In dog and cat demethylation is a very minor reaction. Glucuronidation is not observed in the cat.

Investigations on the metabolism of the new diuretic ethyl (Z)-(3-methyl-4-oxo-5-piperidino-thiazolidin-2-ylidene) acetate (Gö 687, etozolin, Elkapin) were carried out with urine of rat, dog and man as well as rat bile after enteral administration of the 14C-labelled substance. Seven metabolites were isolated with either the aid of high-pressure liquid chromatography (HPLC) or extraction and thin-layer chromatography. Mass spectroscopy was applied to determine the structures of the metabolites, partly by use of authentic reference substances. Because of the instability of most of the metabolites, some of them showing strong polarity, the described investigations on the metabolic profiles and the enrichment and purification of some metabolites could only be carried out with the HPLC-radioactivity detector system, which requires no clean-up for the samples. The metabolisation process of etozolin is qualitatively equal in rat, dog and man; it is characterized by 3 steps: 1. enzymatic cleavage of the ester group, which leads to the also diuretically active main metabolite (metabolite I) in the plasma of all 3 species; 2. glucuronidation of the resulting metabolite I, leading to metabolites II and III, which are diastereoisomeric esters of the two enantiomeric forms of metabolite I with beta-D-glucuronic acid. 50--60% of the urinary radioactivity can be described with these two metabolisation steps in all 3 species; 3. Oxidation of the piperidine moiety to metabolites IV--VII.

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.

Studies of hexobarbital sleeping time in rats showed that only a very high dosage of ethyl(Z)-(3-ethyl-4-oxo-5-piperidino-thiazolidin-2-ylidene)-acetate (piprozoline, Gö 919, Problin) (500 mg/kg) produced a weak interaction with the metabolism of hexobarbital; no signs of any induction of the oxidative enzyme system were observed until 4 days after pre-treatment with 3 X 250 mg/kg. Determinations of the in vitro activity of hepatic microsomal enzymes after several days pre-treatment of male Wistar rats with 2 X 250 mg piprozoline/kg per day showed that piprozoline has only a slight inductive effect on some of the enzymes of the oxidative system. Some of the glucuronidation reactions tested showed marked increases.

Binding of 3H-dihydroalprenolol (3H-DHA) to beta-adrenoceptors in homogenates from rat and rabbit lung was homogeneous and of high affinity (KD = 0.6 and 1.1 nmol/l at 20 degrees C; 1.1 and 2.2 nmol/l at 37 degrees C). The beta 1-selective antagonists betaxolol, metoprolol, bevantolol and acebutolol displaced 3H-DHA in a biphasic manner. From these data, the beta-adrenoceptor subtype distribution in rat lung homogenates was estimated to be 80% beta 2 (at 20 and 37 degrees C) as compared to 25% beta 2 in rabbit lung homogenates. In general, binding of beta-adrenoceptor antagonists (selective and nonselective) was slightly (less than 2 X) weaker in rabbit than in rat lung homogenates. In rat lung, binding of cardioselective beta-blockers to beta 1-receptors seemed to be more temperature-sensitive than binding to beta 2-receptors or binding of nonselective beta-blockers. Levobunolol, a potent non-cardioselective beta-blocker in pharmacological experiments, displaced 3H-DHA in a homogeneous manner (indicative of non-selectivity). In rat lung homogenates KD values were 0.8 nmol/l at 20 degrees C and 2.1 nmol/l at 37 degrees C. Similar values were found for the metabolites dihydrolevobunolol and hydroxylevobunolol. Surprisingly, d-bunolol, the dextrarotatory enantiomer of bunolol, showed a biphasic displacement curve, the fraction of high affinity sites being 83% in rat lung homogenates and 23% in rabbit lung. This ratio of sites is expected for a beta 2-adrenoceptor preferring ligand. High affinity binding (i.e. supposedly binding to beta 2-receptors) was about 50 times weaker than binding of levobunolol, in agreement with known stereospecificity of beta-adrenoceptor binding.