Pharmacokinetics of tilidine and metabolites in man.

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.

GLC method for the quantification of metabolites of thymoxamine in human plasma.

A sensitive gas-chromatographic method for quantification of the pharmacologically active metabolites I-IV of thymoxamine in plasma is described. 4-(Hydroxythymyl)-(2'methylbutylaminoethyl)ether, a compound similar to metabolite I, is used as an internal standard. Metabolites I and II the internal standard are extracted with cyclohexane from alkalinized plasma followed by back-extraction into 0.1 N hydrochloric acid. After evaporating the hydrochloric acid solution, the sample is silylated with BSTFA and analyzed by gas-chromatography on a CRS 101/Carbowax 4000 column using a thermoionic detector. For subsequent determination of metabolites III and IV, the extracted plasma is hydrolyzed under conditions in which the phenol sulfates but not the glucuronide conjugates undergo cleavage. The resulting phenols (metabolite I and II) are analyzed as described above. The sensitivity threshold for all 4 compounds is approximately 5 ng/ml plasma based on a 2 ml plasma sample.

Determination of gemfibrozil in plasma by high performance liquid chromatography.

A sensitive and specific method for the determination of 5-(2,5-dimethylphenoxy)-2,2-dimethyl-pentanoic acid (gemfibrozil, Gevilon) at therapeutic concentrations in plasma is described. The method is based on high performance liquid chromatography and the use of ibuprofen as internal standard. Gemfibrozil and the internal standard are extracted from acidified plasma into cyclohexane and the resulting residue is analyzed on a commercial reversed phase column with acetonitrile/water 1:1 and 0.2% phosphoric acid as mobile phase. The eluted peaks are detected by UV-absorption at 225 nm. The sensitivity is approx. 50 ng/ml plasma using a 0.5-ml sample. The applicability to pharmacokinetic studies of gemfibrozil is demonstrated.

Assay of etozolin and its main metabolite, ozolinone, in plasma by high performance liquid chromatography.

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.

GLC determination of tilidine, nortilidine, and bisnortilidine in biological fluids with a nitrogen-sensitive detector.

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.

Gas-chromatographic determination of nanogram amounts of enantiomers of nortilidine, a main metabolite of tilidine, in biological specimens.

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.

[TLC-method for quantitative densitometric determination of piprozoline and its main metabolite using internal standards (author's transl)]. / Dünnschichtchromatographische Methode zur quantitativen, densitometrischen Bestimmung von Piprozolin und dessen Hauptmetabolit mit Hilfe interner Standards

A determination method is described for ethyl (Z-3-ethyl-4-oxo-5-piperidino-thiazolidin-2-ylidene)acetate (piprozoline, Gö 919, Probilin) and its main metabolite (Gö 3284) extracted from the sample to be analyzed at different pH-values, after the addition of two internal standards to the sample. The extracts are then recombined and applied to TLC plates. After developing twice in a cyclohexane/isopropanol mixture, the substances are determined densitometrically on the plates at 275 nm. By comparing the peak area ratios (substance/internal standard) the peaks were quantitated after plotting a calibration curve. The lower sensitivity limit was approx. 100 ng after extraction of a 1 ml sample.