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A sensitive method for HPLC quantification of bifonazole, an antimycotic drug, in the skin and plasma was developed. The skin samples were homogenized with the use of a physiological solution (1:5) and then centrifuged at 2000 r.p.m. for 20 minutes. Bifonazole was extracted from the homogenates or plasma with methylene chloride. The organic phase was evaporated to dryness under nitrogen at 45 degrees C, the residue was redissolved in methanol and an aliquot of 0.03 ml was injected to the HPLC system for determination of the drug content. A Silasorb C column (30 cm x 4.6 mm, 10 microns) was used. The mobile phase consisted of acetonitrile, 0.12 M sodium acetate and methanol (84:15:1). The flow rate was 1.5 ml/min. The UV absorption was monitored at lambda 254 nm. The calibration plots were linear within the concentration ranges of 1 to 20 micrograms/g. The determination limit was 0.02 microgram/g. The bifonazole pharmacokinetics was studied with the developed method on rats after a single application of 1 per cent drug cream to the skin. The cream was manufactured by two different companies (formulations A and B). The skin and blood samples were collected 0.5, 1, 2, 6, 24 and 48 hours after the bifonazole cream application in a dose of 1 g/kg. The plasma levels of bifonazole were below the detection limit of the method throughout the observation period whereas the skin concentrations could be measured within 0.5-48 hours. Despite the faster skin penetration of bifonazole applied as formulation A the relative extent of the penetration was close to 1 (0.95) and the mean residence times were similar (14.9 and 14.5 hours for formulations A and B respectively). The developed analytical procedure is useful in pharmacokinetic studies with bifonazole.

The ftorazole pharmacokinetics was studied in 14 patients after the oral administration of 40 and 80 mg as a single dose. The ftorazole concentrations in the serum specimens sampled within 8 hours were determined by GLC with an electron-capture detector. A pronounced variability was inherent in the individual concentration-time profiles: the mean values of the serum peak concentrations (Cmax) following the 40 and 80 mg dosing were 30-119 and 55-195 ng/ml respectively. Nonetheless, a dose-proportional increasing of the areas under the concentration-time curve (AUC) was observed. The mean values (SD) of the AUC related to the dose, absorption lag-time, time for reaching Cmax, the Cmax/AUC ratio as an index of the absorption rate, the elimination half-life and mean residence time were 6.64 (2.98) (ng.h/ml), 0.31 (0.17) h, 1.17 (0.55) h, 0.26 (0.05) h-1, 2.40 (0.70) h and 3.06 (0.28) h respectively. The data obtained are indicative of the ftorazole pharmacokinetics linearity in humans.

The binding of sulfadimethoxine by serum proteins of rabbits did not change in the presence of benzylpenicillin and ampicillin, while the binding of sulfalen increased. The 1.2-2-fold decrease in the proportion of sulfalen not bound by blood proteins was accompanied by its acetylation in rabbits. This in its turn resulted in a decreased rate of the drug elimination. The penicillins did not change the kinetics of sulfadimethoxine in rabbits. When the dose of sulfadimethoxine was increased 2 times, the rate of its elimination in rabbits increased, which is likely to be due to increased acetylation of the drug. This may be associated with the increased level of the free sulfadimethoxine fraction in the blood because of the drug lower binding by serum proteins. When the dose of sulfalen was increased 2 times, its kinetics in rabbits did not change.

Two beta-lactam antibiotics with different serum protein binding were studied for penetration into the tissues of rats with aseptic inflammation. It was found that the pharmacokinetics of the drugs in the blood serum differed only in the elimination rate. The levels of the free fraction of cephaloridin were much higher than those of carbenicillin. The maximum concentrations of free cephaloridin in the inflammation exudate, intact and inflamed tissues and the areas under its pharmacokinetic curves were higher than those of carbenicillin. The elimination rate of both the drugs was the same for all the tissues studied.

Penetration of antibiotics into infected inflammation foci depended on the level of their binding to serum proteins. Low binding ampicillin provided the highest levels of the free antibiotic in both serum and the inflammation foci. At the same time coefficients of antibiotic penetration into purulent infiltrates and infected tissues were close and amounted approximately to 70-80 per cent. Antibiotic elimination from the infection foci was retarded as compared to that from serum.

Combined use of benzylpenicillin or ampicillin with sulfalen or sulfadimethoxine resulted in a decreased binding of the antibiotics to the blood serum proteins and slower elimination of penicillins from the experimental rabbits. It is quite possible that the decreased levels of the antibiotic binding to the proteins caused their slower elimination rates, which was realized by increasing the volume of the drug distribution mainly at the expense of the peripheral compartment and decreased excretion with the urine.

The effect of sulfalen and furosemide on benzylpenicillin kinetics in blood serum, intact tissues and aseptic inflammation foci was studied on rats. It was shown that under the action of sulfalen and furosemide protein binding of benzylpenicillin lowered by 30 per cent. The changes in the antibiotic kinetics after combined use with sulfalen and furosemide were of the same type: markedly increased concentrations in blood serum and tissues and retarded elimination.

Penetration of cefazolin and methicillin into the tissues of rats with aseptic inflammation was studied. Free cefazolin was shown to be present in blood serum and tissues in higher concentrations than methicillin. The level of cefazolin penetration in all the tested tissues was higher than that of methicillin. Elimination of the antibiotic from the focus of the aseptic inflammation was markedly retarded as compared to that from blood serum. It was suggested that the tissue binding of the antibiotics influenced the rate of their elimination from the tissues.

Combined use of sulfalen and sulfadimethoxine with benzylpenicillin and ampicillin resulted in increased binding of sulfalen to serum proteins of man. Acetylsalicylic acid promoted a decrease in the sulfanilamide binding to the serum proteins. The observed changes in the sulfanilamide binding to proteins of human blood serum were due to increased or decreased affinity of the drugs to the protein molecules.

Penetration of 2 penicillins with different indices of serum protein binding in the tissues of rats with aseptic inflammation was studied. The pharmacokinetics of both penicillins in the blood serum (total preparation) did not differ. However, the level of the ampicillin free fraction was much higher than that of oxacillin. In the inflammation exudate and inflamed tissues, the maximum concentrations of free ampicillin and the area below its pharmacokinetic curve were also higher than those of oxacillin. The rate of elimination of both antibiotics from the exudate was the same. The period of half elimination of the drugs from the exudate and inflamed tissue was significantly higher than the period of their half elimination from the blood serum. High positive correlation between the ampicillin levels in the blood serum and inflamed and intact tissues was shown. As for oxacillin, positive correlation between its levels in the blood serum and inflamed tissue was observed.