[Pharmacokinetic study of dibromodulcitol in children with brain tumors]. / A dibrómdulcit farmakokinetikai vizsgálata agytumoros gyermekekben.

Systemic pharmacokinetics of high-dose (500 mg/m2), orally administered dibromodulcitol (Elobromol) were studied in 16 chemotherapeutic courses administered to 5 patients. Cerebrospinal fluid dibromodulcitol levels were also analysed in two patients. Bromoepoxydulcitol, dianhydrodulcitol are cytotoxic, whereas bromoanhydrodulcitol, andhydroepoxydulcitol are inactive metabolites detectable during the biotransformation of dibromodulcitol. The HPLC method, developed by our team, is suitable for the determination of both dibromodulcitol and its main metabolites (dianhydrodulcitol and bromoanhydrodulcitol). Our publication is the first in the literature to describe the pharmacokinetic properties of these three hexite-derivatives in pediatric patients. With the exception of one patient, concentration-time curves were analysed by the one-compartment model. From the 30th minute following administration, dibromodulcitol was detectable in all plasma samples for at least 12 hours, its concentration however was usually undetectable by the 24th hour. Though highly variable in value, dianhydrodulcitol concentrations were detectable during all but one therapeutic courses. The following peak concentrations were observed: dibromodulcitol: 3.46-30.63 microM; dianhydroldulcitol: 1.70-6.17 microM; bromoanhydrodulcitol: 0-5.63 microM. The correlation of area under the curve for bromoanhydrodulcitol and dibromodulcitol was exponential up to 200 microMxh with no additional increase detectable above this limit; the distribution of dianhydrodulcitol values were described by a maximum-curve. The possibility of enterohepatic recirculation could not be excluded for any of the compounds studied. Each of the three hexitol derivatives were detectable in the cerebrospinal fluid even if the concentration of the individual metabolite remained undetectable in plasma. The cerebrospinal fluid concentrations of dibromodulcitol were almost constant in the period from 2.5 to 8 hours following administration.(ABSTRACT TRUNCATED AT 250 WORDS)

Assay for mitolactol and its bifunctional alkylating metabolites in plasma.

A method involving precolumn derivatization and high-performance liquid chromatography is described for the measurement of mitolactol levels in plasma. The basis of the assay is the reaction at pH 7.4 and 50 degrees C of mitolactol with diethyldithiocarbamate to form 1,6-bis(diethyldithiocarbamoyl)-2,3,4,5-tetrahydroxyhexane. This derivative is then extracted into chloroform, resolved by normal-phase chromatography, and detected by UV (254 nm) absorbance. The method quantitates the sum of mitolactol and its active bifunctional metabolites, bromoepoxydulcitol and dianhydrogalactitol, in plasma down to concentrations of 0.5 microM. The pharmacokinetic parameters of the drug in mice have been determined following the intraperitoneal injection of either 20 or 100 mg/kg of body weight. Absorption from the peritoneal cavity was largely complete by 5 min. Parameters obtained include a first-order elimination constant, k = 0.92 X 10(-2) min-1 and an apparent volume of distribution, Vd = 0.78 L/kg. For a 100-mg/kg dose, the area under the concentration-time curve was 49 mM X min, and the mean peak drug concentration was reached at 40 min following intraperitoneal injection. Concentrations of mitolactol in total plasma and in plasma ultrafiltrates were identical, indicating that the drug is not (less than 4%) reversibly bound to plasma proteins.