[2-Amino-oxazoles as potential H-bonding agents in virostatic research. 4. Pharmacokinetics and pharmacologic-toxicologic profile of 2-guanidino-4,5-dipropyloxazole hydrochloride]. / 2-Amino-oxazole als potentielle H-Brückenbildner in der Virostatika-Forschung. 4. Mitteilung: Pharmakokinetik und pharmakologisch-toxikologisches Wirkprofil von 2-Guanidino-4,5-dipropyloxazol-hydrochlorid.

Out of the group of 2-amino-oxazoles 1 was found to be the most potent antiviral compound. Following p.o. or s.c. administration to rats, the 14C-labeled 1 was quickly and completely absorbed. The TRA was eliminated mainly via the kidneys and the liver with half-lives between 32 and 42 h. The acute pharmacodynamic effects of 1 were decrease of blood pressure, bradycardia, and inhibition of both gastric emptying and acid secretion. On smooth muscles spasmolytic and alpha-anti-adrenergic actions were predominant. After single administration the following MTD's were determined: 30 (mouse), 20 (rat), 10 mg/kg i.v. (pig), and 500 (mouse, rat), greater than 100 mg/kg p.o. (pig), respectively. In a subchronic toxicity study in rats, oral doses of 1 between 15 and 240 mg/kg given daily for 4 weeks were tolerated without any severe alterations related to the drug.

Influence of leukemia P388 on plasma concentration-time profiles of bendamustine in B6D2F1 mice.

It was the aim of this study to investigate whether leukemia P388 being an important murine transplantation tumor may alter the plasma concentration-time profiles of the alkylating antineoplastic agent bendamustine (1) in mice. In an advanced tumor stage the rapid decline of 1 plasma levels was found to be retarded in tumor-bearing in comparison to tumor-free animals both after i.v. and p.o. drug administration. These changes cannot be explained by the neoplasia-related depression of drug metabolism whereas the 1-containing ascitic fluid may be a possible reason for the prolonged drug levels in plasma. After p.o. administration of 1, the bioavailability of the drug was found to be increased in the leukemia-bearing animals.

Influence of ion-pair formation on the pharmacokinetic properties of drugs. Pharmacokinetic interactions of bretylium and hexylsalicylic acid in rabbits.

The simultaneous i.v. administration of equimolar doses of bretylium and hexylsalicylic acid results in an increase in plasma area under the curve value of both substances in comparison with their separate administration. The higher plasma levels of both compounds were associated with a reduced renal excretion and an increased biliary elimination. However, the increase in biliary excretion did not compensate for the reduced elimination of bretylium and hexylsalicylic acid via the kidney. The results presented in this paper give further evidence that ion-pairing in-vivo may result in altered pharmacokinetics of drugs particularly due to changes in biliary or renal excretion.

[Pharmacokinetics of bendamustin (Cytostasan) in B6D2F1-mice]. / Pharmakokinetik von Bendamustin (Cytostasan) an B6D2F1-Mäusen.

The pharmacokinetics of bendamustine, (1; Cytostasan), an alkylating antineoplastic agent of the N-lost group, was investigated in B6D2F1 mice. After i.v. injection of the maximally tolerated dose of 50 mg/kg a rapid decrease of the unchanged drug in plasma (MRT 21.9 min) and slowly decreasing levels of mono-, dihydroxy and beta-hydroxy-1 were observed. Variations of the age of the animals as well as of the dose administered did not alter the short MRT of 1. 1 is excreted via the kidneys to a considerable extent showing a similar metabolite pattern in urine as in plasma. The absorption of the drug from the gastrointestinal tract is incomplete resulting in an absolute bioavailability of about 40%.

Influence of melanoma B16 on the pharmacokinetics of mitoguazone in mice.

In this study, the influence of different stages and transplantation routes of the experimentally widely used solid tumor melanoma B16 on the pharmacokinetics of the antineoplastic agent mitoguazone was investigated in B6D2F1 mice. It could be shown that changes of the pharmacokinetic parameters as well as the distribution pattern of this drug were clearly influenced and dependent on the tumor stage but not by the tumor inoculation route. Advanced melanoma (d16) led to a sharp decrease in the terminal elimination half-life as well as to decreased spleen levels and increased initial liver concentrations of the drug. With respect to the results obtained in leukemia P388-bearing mice it can be concluded that the tumor stage as well as the tumor model are to be considered as important factors in which way and to which extent a tumor may alter the pharmacokinetics of antineoplastic agents.

Influence of leukemia P388 on the pharmacokinetics of mitoguazone in B6D2F1 mice.

The aim of the present study was to investigate the influence of different stages of leukemia P388 on the pharmacokinetics of the antineoplastic agent mitoguazone in mice. It could be shown that, independent of the tumor stage investigated, the total clearance of mitoguazone is slightly reduced reflecting a moderate increase of AUC in the serum of leukemia-bearing animals. Furthermore, in an advanced tumor stage the drug levels in kidneys, liver, spleen and serum were found to be elevated to some extent in comparison to tumor-free controls in contrast to an earlier stage of leukemia. In conclusion, the tumor stage has to be considered as an important factor to which extent a neoplasia may alter the pharmacokinetics of drugs used for anticancer chemotherapy.

Distribution of cisplatin in tumor-free versus tumor-bearing B6D2F1 mice.

In healthy as well as in leukemia P388- or melanoma B16-bearing B6D2F1 mice the platinum concentrations in liver, serum and kidneys were determined after i.v. administration of 10 mg/kg cisplatin. In a tumor stage related to about 40% of the mean survival time (MST) no differences in platinum distribution between tumor-bearing and healthy animals could be observed. In the tumor stage related to about 70% of the MST, elevated platinum levels in serum of both tumor models and in kidneys only in melanoma-bearing but not in leukemia-bearing mice could be found. These results confirm those of other authors that tumor stages less than 50% of the MST exert no marked influence on the distribution pattern of cisplatin in rodents. Moreover, in advanced tumor stages distributional differences of antineoplastic agents may be expected between healthy and tumor-bearing mice as well as between animals bearing different neoplasias.

Influence of age on antileukemic action, subacute toxicity and tissue distribution of ambazone in B6D2F1 mice.

The influence of age of experimental animals on the antileukemic activity, toxicity and distribution of ambazone, a new potential antineoplastic agent, was studied in 2- and 12-month-old B6D2F1 mice. The predominant effect observed was a significant reduction of the antileukemic action of this compound in old-aged mice. Together with a slight increase in several toxicity parameters this caused a marked reduction of the therapeutic index in 12-month-old mice compared to younger individuals. Furthermore, a general tendency to increased ambazone levels in liver, kidneys and thymus of old-aged mice was observed. Our data therefore provide further evidence that age has to be taken into consideration as one factor that may account for the variety of drug response frequently observed during clinical therapy with anticancer agents.

[Kinetics of the transformation of dihydroambazone into ambazone]. / Kinetik der Umwandlung von Dihydroambazon in Ambazon.

The oxidation of dihydroambazone (1) by oxygen is dependent on the pH-values of the solutions used. This transformation can be inhibited and excluded, respectively, by ascorbic acid using defined concentrations. The oxidation product ambazone (2) was determined spectroscopically at different pH-values. The rate of transformation in serum depends on the temperature and can also be inhibited with ascorbic acid.

Influence of the ion-pair-formation on the pharmacokinetic properties of drugs. Part 5: Influence of ion-pair-formation on elimination of bretylium and hexylsalicylic acid in rats.

Following i.v. administration of the hydrophilic drug bretylium (1) and the lipophilic hexylsalicylic acid (2) in rats the plasma levels of 2 were increased due to an increased intestinal reabsorption of 2. Under these conditions the biliary eliminated amount of 2 was 8 times higher than that following the administration of 2 alone. The eneteroheptic circulation of 2 was found to be interrupted following i.v. administration of 1 and 2 and additional oral administration of an anionic exchanger. Then the plasma levels of 2 were not influenced by 1. On other hand the plasma levels of 2 appear to be too low in order to influence those of 1.

[Mitoguazone (methylglyoxal bis(guanylhydrazone))--its status and prospects]. / Mitoguazon (Methylglyoxal-bis-guanylhydrazon)--Stand und Perspektiven.

Because of its severe side effects, initial clinical trials of the antineoplastic compound mitoguazone (Methyl-GAG, M-G) were ceased in the middle of 1960s. One decade later pharmacokinetically guided dose schedules as well as new experimental data on the antiproliferative mechanism of action stimulated new clinical studies. First results indicated that M-G had single-agent activity against various tumors such as acute leukemia and malignant lymphoma connected with acceptable tolerance. M-G seems to be effective especially in combination with other antineoplastic drugs. Its final evaluation may be reserved to further randomized trials. Recently, the psoriasis vulgaris is expected to be an additional field of the application of M-G. In this minireview data on synthesis, preclinical pharmacology, pharmacokinetics, biochemical effects and toxicology of M-G are given. Furthermore, clinical findings on M-G concerning its pharmacokinetic behaviour, antitumor and antipsoriatic activities are described.

Age-dependent antileukemic action and suppression of immune response by 1,4-benzoquinone-guanylhydrazone-thiosemicarbazone (ambazone) in mice.

The antineoplastic activity of 1,4-benzoquinone-guanylhydrazone-thiosemicarbazone (ambazone) against murine leukemia P388 was found to be markedly reduced in 12- and 18-month-old mice as compared to young animals. The immune response against sheep red blood cells (SRBC), a T cell-dependent antigen, was also strongly diminished in tumor-free old mice and was further suppressed after ambazone treatment. Since the antileukemic effect of ambazone disappeared more or less in congenitally athymic nude mice, in neonatally thymectomized or silica-pretreated animals, it has been concluded that the action of the compound seems to be limited to young adult immunocompetent tumor-bearing hosts. Therefore immunosenescence, primarily of T cell functions of old tumor-bearers, may represent a decisive factor influencing the antileukemic, especially curative effect of ambazone in aged animals. A combined treatment with ambazone and immunomodulators (thymalin or a splenopentin derivative) failed to improve the antileukemic effect in young and old leukemia P388-bearing mice.

Pharmacokinetics of 14C-ambazone in rats.

In rats, the pharmacokinetics of 14C-ambazone after i.v. and oral administration was studied. The results demonstrate that the compound is incompletely absorbed from the gastrointestinal tract, penetrates rapidly and to a high degree into various tissues and is preferentially eliminated via the kidneys. After i.v. administration of 50 mg/kg b.m. disposition half-life in whole blood is about 6-7 h. The extent of absorption from the gastrointestinal tract is about 40%.

Use of alternative dose schedules for the determination of sublethal doses of potential antiviral drugs in mice.

In mice the ratio between maximally tolerated sublethal doses (MTD) after single and repeated administration of benzoxazolyl-2-formyl-S-ethyl-isothiosemicarbazone (ZIMET 111/74) was found to be different after s.c., p.o. or i.p. administration. Comparing the treatment schedules with relatively high or low initial doses, no differences of the total MTD were found. Using MTD after single drug administration (MTDs) as initial doses for repeated administration, the subsequent doses had to be reduced in a different manner for s.c. and p.o. administration to avoid lethality. As a result of these investigations a rule is proposed for compounds with similar mode of action and comparable pharmacokinetics to ZIMET 111/74 to calculate dose schedules for antiviral in vivo screening related to acute as well as to subacute toxicity data.

Distribution of 14C-ambazone in normal and leukemia P 388-bearing mice.

There is some evidence in the literature that the pharmacokinetics of anticancer agents can be influenced by the presence of a tumor. Therefore several authors recommend pharmacokinetic studies of such drugs to be performed also in tumor-bearing animals (2, 5, 7). The aim of the present study was to evaluate the influence of different stages and routes of inoculation of leukemia P 388 in B6D2F1-hybrid mice on the tissue distribution of ambazone, a new potential antineoplastic drug. It could be emphasized that the drug levels in liver, kidneys and thymus were higher in advanced tumor-bearing than in control animals whereas in the spleen and in whole blood the opposite was true. The differences can be explained partially by changes in the erythrocyte binding of ambazone.