Detection of 13C labelled compounds by gas chromatography coupled to atomic emission detection--application to caffeine metabolites.

This paper illustrates the use of gas chromatography coupled to atomic emission detection (GC-AED) and of the stable isotope tracer 13C for the determination of drug metabolites. After administration of a parent drug labelled with 13C and extraction of the metabolites from the biological fluids, a 13C chromatographic profile is determined using the specific detection of the 13C atomic emission and subtraction of the 13C natural abundance. Thus, only the compounds which are metabolites with a 13C enrichment over the natural abundance are detected. [1,3,7 trimethyl-13C3]xanthine which is extensively metabolized by the liver is used as an example.

Effect of probenecid on isofezolac kinetics.

The interaction between isofezolac and probenecid has been studied with the aid of a specific HPLC assay for isofezolac in plasma and urine. 8 healthy adult volunteers received a single 40 mg oral dose of isofezolac before and after 3 days of loading with 0.5 probenecid t.i.d. There was an increase in the maximum plasma isofezolac concentration from 2.44 to 3.38 micrograms X ml-1 when probenecid was given. The AUC of isofezolac in plasma increased from 6.73 to 11.28 micrograms X h X ml-1. After the last dose in a 7 day treatment with 40 mg isofezolac t.i.d., there was an increase in the maximum plasma isofezolac level from 2.84 to 4.96 micrograms X ml-1 when probenecid was given. The rate of absorption of isofezolac was not affected. An increase in the AUC of isofezolac in plasma was observed from 11.74 to 26.34 micrograms X h X ml-1. The major effect of probenecid on isofezolac metabolism was a 50% reduction in total isofezolac (free + conjugates) excreted inurine. Because of this interaction, patients given isofezolac combined with probenecid will have a higher steady-state plasma level of isofezolac than when probenecid is not administered.

[The bioavailability of ketoprofen (Profenid) administered orally in combination with a gastric protector (aluminum phosphate, Phosphalugel)]. / Etude de la biodisponibilité du kétoprofène (Profénid) administré par voie orale en association avec un protecteur gastrique (phosphate d'alumine, Phosphalugel).

Bioavailability of ketoprofen associated with aluminum phosphate was studied. Subjects were studied after an initial dose given without gastric protection, after ingestion of a single dose given with aluminum phosphate and, lastly, after four days of continuous treatment with this product. Results of plasma peak level and its time of occurrence, area under the curve, half-life and elimination constant establish that bioavailability of ketoprofen is not changed by association with aluminum phosphate. It is therefore unnecessary to modify dosages in such combination treatment. Lastly, there is no change in ketoprofen absorption liable to alter its efficacy.

Bioavailability of ketoprofen in man with and without concomitant administration of aluminium phosphate.

The purpose of this study was to determine whether a concomitant single dose of antacid (aluminium phosphate), or multiple doses of this antacid, administered prior to and with ketoprofen would alter the bioavailability of this non steroidal anti-inflammatory agent. The possible effects of aluminium phosphate were evaluated following administration of ketoprofen alone (Phase I), co-administration of antacid and ketoprofen (Phase II), and antacid for four days before administration of ketoprofen with co-administration on the day of the study (Phase III). There were no significant differences between treatment means for peak plasma concentration, time to peak plasma concentration, and area under the plasma concentration-time curve. The observed differences were due only to individual effects. The results indicate a lack of interaction between ketoprofen and the antacid aluminium phosphate (Phosphalugel).

Determination of ketoprofen in biological fluids by reversed-phase chromatography.

A sensitive and specific high-performance liquid chromatographic method was developed for the determination of ketoprofen [2-(3-benzoylphenyl)propionic acid] in plasma and urine. The method includes an extraction of the drug and the internal standard [2-(4-benzoylphenyl)butyric acid] into ether from acidified plasma. The organic phase is evaporated, and the residue is dissolved in the mobile phase (acetonitrile-0.02 M phosphate buffer, pH 3) (45:55). A 20-microliter aliquot is analyzed on a reversed-phase column. The accuracy is within 1.5% for therapeutic concentrations, and the coefficients of variation are 5.5 and 3.4% for 2 and 10 micrograms/ml, respectively. For the urine assay, the accuracy is within 3%, and the cofficients of variation are 1.9 and 1.7% for 3 and 50 micrograms/ml, respectively. This method was applied successfully to the determination of ketoprofen in humans for pharmacokinetic studies.

Determination of isofezolac in biological fluids by reversed-phase liquid column chromatography.

A rapid, sensitive, and specific reversed-phase high-performance liquid chromatography assay was developed for the determination of 1,3,4-triphenylpyrazole-5-acetic acid (isofezolac) in plasma and urine. The assay involves extraction into diethyl ether from plasma buffered at pH 4.4. The organic phase is evaporated and the residue, dissolved in the mobile phase [acetonitrile-water-0.2 M phosphate buffer (pH 3) (65 : 15 : 20)] is chromatographed at a flow-rate of 1.5 ml/min. The drug is detected by its UV absorption (detection limit 100 ng/ml) or its very intense fluorescence (detection limit 10 ng/ml). Absolute analytical recoveries for isofezolac varied from 92.9 to 100.4%. The accuracy is ca. 1%. Each separation requires about 6 min. This method was applied successfully to the determination of isofezolac in humans for pharmacokinetic studies.

[Determination of ketoprofen in plasma using high-performance liquid chromatography. Comparison with gas--liquid chromatography (author's transl)]. / Dosage du kétoprofène dans le sang par chromatographie liquide haute performance. Comparaison avec la chromatographie en phase gazeuse.

A new method of determination of ketoprofen 2-(3-benzoyl phenyl) propionic acid in plasma using high-performance liquid chromatography (HPLC) is described. After extraction by diethyl either in acidic medium, ketoprofen and the internal standard, 2-(4-benzoyl phenyl) butyric acid, are methylated with gaseous diazomethane and their concentrations measured by HPLC using in LiChrosorb Si 60 (5 micrometer) column and dichloromethane-hexane (60:40) as the mobile phase. The absolute retention times of the internal standard and ketoprofen are 11.6 and 12.8 min, respectively. The precision of the methods is +/- 4% and the lower detection limit ranges from 0.06 to 0.10 microgram/ml. The results obtained by HPLC show a very good correlation with those obtained by gas--liquid chromatography. The proposed method is sensitive, reproducible and rapid and very suitable for ketoprofen determination in pharmacokinetic studies.