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.

A sensitive assay for the pharmacokinetic investigation of a rapidly hydrolyzing alkylating agent Lycurim (ritrosulfan; R-74; NSC-122 402).

Lycurim [1,4-di(2'-methanesulfonyloxyethylamino)-1,4-dideoxymesoerythri tol dimethane sulfonate] is rapidly hydrolyzed in aqueous media to inactive products according to a second-order reaction. The respective rate constants are: k1 = 9.82 X 10(-2) and k2 = 1.76 X 10(-2) mumol/ml/min. The concentrations of the parent compound and alkylating intermediate(s) were measured by chemical trapping with N,N-diethyldithiocarbamic acid (DDTC). The rate of this reaction is substantially higher: k1 = 2.61 X 10(-1) and K2 = 4.76 X 10(-2) mumol/ml/min. By using 35S-labeled DDTC, alkylating compounds in concentrations as low as 0.04 microgram/ml could be detected in spiked plasma samples. After intracavitary application of 60 mg Lycurim no alkylating activity could be demonstrated in the plasma of patients at any time point.

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.

Toxicity, antitumour and haematological effects of 1,2-anhydro-6-bromogalactitol and d-mannitol: a comparison with the related dibromo- and dianhydro-derivatives.

1,2-Anhydro-6-bromo-6-deoxygalactitol (BrEpG) and its D-mannitol analogue (BrEpM) intermediary metabolites in the conversion of dibromodulcitol (DBD) and dibromomannitol (DBM) into dianhydrogalactitol (DAG) and dianhydromannitol (DAM) have been prepared. The three types of derivative of each hexitol have been compared in their toxicities towards mice, tumour inhibitory activities against the Walker carcinosarcoma and haematological effects in rats. The bromoepoxides showed intermediate potency in all tests. The galactitol derivatives were always more potent than their mannitol counterparts. The mannitol derivatives were selectively myelosuppressive, being twice as toxic towards granulocytes as towards lymphocytes. The lymphotoxic activity of DBM, in particular, relative to its other toxic effects was particularly mild. These differences have been ascribed principally to the more rapid reactivity of DAG compared with DAM towards target nucleophiles, modulated by the influence of the bromine substituent on the transport properties of the dibromo- and bromoepoxy-derivatives.

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.