[Hormonal and biochemical characterization of breast cyst fluid in gross cystic mastopathy]. / A nagycisztás mastopathia cisztafolyadékának hormonális és biokémiai jellemzése.

A total of 93 breast cyst fluids (BCF) obtained by needle aspiration of women suffering from gross cystic mastopathy was hormonally investigated. The mean age of the patients was 45 years (range 27-65). Estradiol (E2), progesterone (PROG), testosterone (TE), prolactin (PROL), estriol (E3), dehydroisoandrosterone and its sulfate (DHA, DHA-S) levels were investigated in the BCF and in the respective sera. Tumour marker beta-HCG and CA 15-3 as well as cations (K+, Na+) were determined, too. E2, E3, PROG, TE, PROL, DHA, DHA-S and K+ showed significant accumulation in the BCF compared to the serum values. The K+/Na+ ratio proved to be a useful tool to divide cysts into type I (> or = 1), type II (< 1 but > or = 0.1) and type III (< 0.1) subgroups. In case of type I BCF, higher E2, DHA, DHA-S and PROL levels could be detected, while PROG and TE contents proved to be the highest in type II cysts. These findings indicate that the type I BCF is a marker for "active" GCD of the breast and suggest that it may be associated with increased breast cancer risk. It is suggested therefore when macrocysts are aspirated, sex steroids, steroid hormone precursors and cations in the BCF should be examined routinely, and women with type I cysts should be controlled carefully.

The role of comparative pharmacokinetics in the planning of human dose escalation: the experience with diacetyldianhydrogalactitol.

The pharmacokinetics of diacetyldianhydrogalactitol (DADAG) was compared in mice, rats, and humans. The ratios of human therapeutic dose (ThD) to the LD10 were 8 and 5 in mice and rats, respectively. The ratios of the corresponding AUCs of DADAG were 20 and 17, whereas those of dianhydrogalactitol (DAG), the main, active metabolite of DADAG, were 8 in both species. The lower human-to-rodent ratio for DAG was due to the fact that twice as much DAG was formed in the animals. Other factors contributing to the larger AUC in man were the 3-5 times smaller distribution volume found in humans as well as the lower hexitol sensitivity of human bone marrow cells. We conclude that in addition to the distance between the AUCs of the LD10 and of the human starting dose, interspecies pharmacokinetic differences should also be considered in planning the rate of dose escalation.

Pharmacokinetic studies of [14C]-flumecinol in humans.

The pharmacokinetics of 14C-labelled 3-trifluoro-methyl-alpha-ethylbenzhydrol (flumecinol, RGH-3332, Zixoryn), a hepatic enzyme inducer, has been studied in 6 male healthy volunteers after a single oral dose of 100 mg (11.1 Mbq; 300 microCi). Flumecinol concentration in plasma was determined (0-96 h) by capillary gas-liquid chromatography. Total radioactivity was assayed by liquid scintillation counting. The peak concentration of unchanged flumecinol in the plasma (130.2 +/- 37.7 ng/ml S.D.) was detected 2.1 h after dosing. The maximum total radioactivity concentration (1414.4 +/- 158.9 ng eq./ml) was found at 2.3 h. The ratio of the plasma radioactivity level to unchanged flumecinol indicated a rapid metabolic transformation and a marked first-pass effect in man. A two-compartment open model was constructed to describe the pharmacokinetics of the drug. The unchanged drug was eliminated from plasma with a biological half-life of 20.7 +/- 1.8 h giving a total body clearance value of 100.9 +/- 33.8 l/h. The volume of distribution of flumecinol was found to be 41.4 +/- 18.4 l/kg. However, the biological half-life of total radioactivity was much longer (35.2 +/- 11.9 h) than that of the decrease of unchanged drug. The value of total body clearance (4.1 +/- 0.6 l/h) and volume of distribution (3.2 +/- 1.6 l/kg) were found to be much lower than that of unchanged flumecinol. Radioactivity excreted with urine was 78.8 +/- 5.9% and with faeces 12.0 +/- 5.3% during 120 h.

Pharmacokinetics and metabolism of dianhydrogalactitol DAG in patients: a comparison with the human disposition of dibromodulcitol DBD.

Dianhydrogalactitol (DAG), labelled with 3H, was administered in single intravenous or oral doses to six patients (three in each group) with cancer. Kinetic parameters were calculated for the unchanged DAG and its biotransformation products. Elimination of the drug by metabolism and excretion was described by a catenary model. In order to elucidate the role of DAG as a mediator of the alkylating action of the cytostatic drug dibromodulcitol (DBD), the pharmacokinetic parameters of DAG and DBD were compared. The mean residence time for pharmacologically active molecules in the body was six times shorter for DAG (1.9 hr) than for DBD (11.4 hr). Alkylating action and metabolic degradation proceeded about 8-9 times faster for DAG than for DBD. The process of DBD alkylation implies a slow solvolytic conversion of the parent drug into the more reactive bromoepoxide and DAG. The preformed DAG would be rapidly consumed by intracellular alkylation and degradation, while unchanged DBD could form a depot in the cells and exert its cytostatic activity through the epoxides released in situ by solvolytic activation. Thus DBD entering the cells in unchanged form may have a more important role in its therapeutic effects than had been assumed earlier.

Rat liver-mediated degradation of dibromodulcitol.

The rate and extent of dibromodulcitol (DBD) conversion by 9000 g rat liver supernatant with an NADPH-generating system (S-9 mix) were studied using 3H-labelled drug. Results indicated that S-9 mix seemed to exert an initial protective effect delaying the solvolysis of DBD for about 30 min at 37 degrees C followed by rapid degradation into exclusively pharmacologically inactive products. Thus S-9 mix contained merely DBD as an effective agent; it amounted to less than 40% of the total radioactive compounds by 120 min. In the control mixtures the sovolytically produced effective drug content, i.e. the sum of DBD, 1,2-anhydro-6-bromo-6-deoxygalactitol (BrEpG), 1,2-5,6-dianhydrogalactitol (DAG) was 63%. Our results suggest the involvement of liver enzymes in the detoxification of DBD into inactive products. Therefore the antitumour effect of DBD cannot be attributed to its active BrEpG and DAG alone. The drug in its unchanged form may contribute to a somewhat greater extent to its cytostatic action than was believed before.

The distribution of [3H]-dibromodulcitol in the central nervous system of patients with brain tumour.

The uptake of [3H]-dibromodulcitol ( [3H]-DBD) into glioblastomas, white matter and cerebrospinal fluid was studied in 10 patients. Single-tissue samples were taken from different subjects at 4, 15 and 24 hr after [3H]-DBD administration. The level of 3H-compounds in the central nervous system was similar after a single (400 mg/m2), or 3 smaller daily oral doses of 150-180 mg/m2 of [3H]-DBD. The distribution of radioactivity was uniform in the tumour, white matter and muscle. Between 3 and 15 hr after administration of DBD the concentration of radioactivity did not change significantly and was between 5 and 13 micrograms of DBD/g tissue wet wt. At the same time the level in the cerebrospinal fluid (CSF) remained between 1 and 4 micrograms/ml. Meanwhile, the average concentration of radioactivity in the plasma fell from 11 to 3 micrograms/ml. The elimination half-life of the labelled compounds from the tissues was about 1 day as judged from the limited number of non-serial data obtained 4 and 24 hr after the last dose of repeated drug administration.

Metabolism and pharmacokinetics of dibromodulcitol (DBD, NSC-104800) in man--II. pharmacokinetics of DBD.

Dibromodulcitol (DBD), labelled with [3H] at position C-1, was administered orally to 6 patients in a single dose of 15 mg/kg. Kinetic parameters were calculated for the effective drug (DBD + BrEpG + DAG), protein-bound hexitol moieties and free metabolites. Approximate values were estimated for the oral bioavailability of DBD. Disposal of the drug by metabolism and excretion was described by a simplified catenary model. The results indicated that 8-20% of the drug became firmly bound to macromolecules, probably by alkylation. The slow rate of alkylation in vivo (half-life 14 hr) may imply conversion of DBD into epoxides and their alkylating interaction with the target nucleophiles. The long retention of the firmly bound hexitol moieties in the body may be an indicator of the cumulative potency of DBD and must be taken into consideration by developing dosage schedules.

Chemical reactivity and intracavitary application of alkylating sugar alcohol derivatives.

Lycurium [1,4-di-(methylsulfonyloxy-ethylamino)-1,4-didesoxy-erythrioldimethylsulfonate; R-74; NSC-122402] undergoes rapid hydrolysis in aqueous solutions. The concentration of the alkylating compound(s), demonstrated by the 4-(4'-nitrobenzyl)pyridine reaction, decreases approximately by 80% in 10 min following the dissolution of the drug in saline. In patients peak plasma concentration of radioactivity after the intracavitary injection of 14C-labelled Lycurim is observed between 4 and 6 h. It is assumed, therefore, that only a negligible amount of pharmacologically active alkylating compounds reaches the circulation after intracavitary application. This conclusion is supported by clinical experience showing that intracavitary administration of the same amount of Lycurim causes much milder systemic side-effects than intravenous injection. A dose escalation study was started to determine the applicability of Lycurim in the form of high volume intraperitoneal instillation ('belly bath') for the treatment of ovarian cancer.

Uptake of labeled dianhydrogalactitol into human gliomas and nervous tissue.

The distribution of iv administered 3H-dianhydrogalactitol (DAG) in the plasma, cerebrospinal fluid (CSF), brain, and tumor tissue was studied in 11 patients. DAG entered the CSF and was slowly eliminated, with a half-life of 20 hours. Unchanged DAG accounted for about 6%-30% of the total radioactivity in the CSF. All the tumors accumulated the drug to a higher extent than the intact white matter, except the one meningioma studied. The highest uptake was observed in the relatively benign astrocytic tumors.