High-pressure liquid chromatographic evaluation of cyclic paracetamol-acetylsalicylate and its active metabolites with results of a comparative pharmacokinetic investigation in the rat.

Like benorilate, its correlated open ester, MR 897, a cyclic ester between acetylsalicylic acid and paracetamol, gives rise to acetylsalicylic acid, salicylic acid and paracetamol by enzymatic hydrolysis. An analytical method was developed, which detects parent drugs and active metabolites, in order to compare the pharmacokinetic and metabolic behaviour of the two products. The method was specifically validated for quantitative analysis of salicylic acid and paracetamol, which are the main systemic metabolites of both MR 897 and benorilate. Extraction from plasma or tissue homogenate was carried out in two steps with diethyl ether and acetate. Recovery of the analytical substances ranged from 82.7% for paracetamol to 98.5% for salicylic acid. The results of a comparative pharmacokinetic investigation of MR 897 and benorilate in the rat confirm higher bioavailability and a more favourable plasma level profile with MR 897.

Gas chromatographic evaluation of the antimycotic democonazole for pharmacokinetic and bioavailability studies in man and animals.

A new gas chromatographic method for quantitative determination of 1-[2,4-dichloro-beta-[2-(p-chlorophenoxy)ethoxy] styryl]imidazole (demonoconazole), employing an electron capture detector, was developed. All analytical parameters were satisfactory within the range between 5 ng and 1 micrograms per ml of plasma, which means 20 pg-2 ng as absolute sensitivity. This method therefore is specific and sensitive enough for the quantitative determination of the drug in biological samples for pharmacokinetic and bioavailability studies to be performed in animals and human beings.

Gas-liquid chromatographic evaluation of bencyclane in biological samples for pharmacokinetic and bioavailability investigations: comparison of two analytical methods.

Analytical conditions that allow bencyclane, a vasodilator, to be evaluated in biological samples for pharmacokinetic and bioavailability investigations are reported. Two gas chromatographic methods were developed, one employing a flame-ionization detector, reaching a sensitivity of 0.5-1 micrograms/ml, and the other employing a thermionic specific detector and reaching a sensitivity of 10 ng/ml. The extraction recovery, reproducibility and specificity were all satisfactory with both methods. The former method is suitable for chemical quality controls and the latter has a sufficient sensitivity and reproducibility for determination of the drug in biological samples as required in pharmacokinetic investigations.

Gas--liquid chromatographic evaluation of lofemizole in biological samples for pharmacokinetic investigations. Comparison of two analytical methods.

The present paper reports the analytical conditions allowing lofemizole, a new non-steroidal anti-inflammatory drug, to be evaluated in biological fluids for pharmacokinetic and bioavailability investigations. The first approach led to an N-methyl derivative of lofemizole which could be successfully analysed by gas--chromatography employing a flame-ionization detector, reaching a sensitivity of 2 micrograms/ml. The second approach led to the N-(2-chlorobenzoyl) derivative of lofemizole which was suitable for pharmacokinetic investigation using gas--liquid chromatography with electron-capture detection, and reaching a much higher sensitivity of 10 ng/ml of plasma. Recovery of the extraction, reproducibility and specificity were all satisfactory with both methods. Since the first method employing flame-ionization detection was suitable for pharmacokinetic investigations in animal species, this paper describes both methods on a comparative basis.

MR 714, a new aryloxypropionic non-steroidal antiinflammatory agent. Chemical and pharmacokinetic properties and preliminary pharmacotoxicological data.

2-(4-(2',4'-Difluorophenyl)-phenoxy)propionic acid (MR 714) is endowed with an interesting analgesic and antiinflammatory activity, while any remarkable gastro-ulcerogenic action is virtually absent. From a toxicological point of view, MR 714 orally administered to mice showed a LD50 of 848 mg/kg; an observation of general behaviour proved that the drug is free of any remarkable effect on general behaviour, food and water intake, or diuresis after single or repeated administration. An autoptic examination after single oral doses (25, 50, 100 and 200 mg/kg) or repeated oral doses (100 mg/kg/day over 5 days) did not show any adverse modification and also the Ames test didn't allow any mutagenic action to be detected. From a pharmacokinetic point of view, MR 714 given p.o. to rats was absorbed excellently and plasma levels showed a peak after 4-6 h, followed by a plateau lasting 24-36 h at a dose of 50 or 100 mg/kg and considerably less at a dosage of 25 mg/kg. This lower dose allowed a dominant half-life (t1/2) of plasma levels of 13 h to be determined. Excretion occurred only via the bile in conjugated form (acylglucuronide) which reverted easily into the parent drug. The resultant enterohepatic circulation contributes to a substantial maintenance of plasma levels and hence long-lasting activity. Among the organs examined, the uterus showed the highest ratio of organ/plasma concentration; this evidence points to a possible clinical application of MR 714 in the treatment of dysmenorrhoea. From a chemical point of view, the aryloxypropionic structure may be regarded as an interesting novelty in the field of structure-activity relationship studies on non-steroidal antiinflammatory agents.

Gas-liquid chromatographic evaluation of fenquizone in biological samples for pharmacokinetic investigations.

Extractive alkylation was carried out on fenquizone, a sulphonamide diuretic, in order to devise a suitable method for its determination in pharmacokinetic and bioavailability studies. After extraction as a tetramethyl derivative, fenquizone was evaluated by gas-liquid chromatography with a 63Ni electron-capture detector, which enables a limit of detection of 2 ng/ml of plasma or urine to be achieved. Linearity was verified in a range of 50- 10,000 pg for each injection with a fenquizone/internal standard ratio ranging from 4:1 to 1:4. Determination is very rapid, as one analysis only takes 5 min. The preliminary results of the pharmacokinetic study performed in a volunteer human subject after a single oral administration of the drug are presented in this paper in terms of the plasma levels and the cumulative urinary excretion.