The pharmacokinetic characteristics of prednisolone & of chlorambucil & its beta-oxidized metabolite, phenylacetic mustard (PAM) were studied in plasma after the oral admin of 200 mg prednimustine (Sterecyt) & a regimen consisting of 20 mg prednisolone plus 20 mg chlorambucil, respectively. A total of 12 cancer patients completed this trial. The drugs were given in a cross-over study as single doses, & serial plasma samples were collected for 32 h. Chlorambucil & PAM were assayed by a gas chromatographic/mass spectrometry method & prednisolone, by radioimmunoassay. The median relative availability of the prednisolone & chlorambucil moiety in prednimustine was 19% & 16%, respectively. Prednisolone, as well as chlorambucil & PAM, appeared later & at a significantly lower concn in plasma after treatment with prednimustine as compared with the mixture of chlorambucil & prednisolone. We also found that the elimination phase of chlorambucil & PAM in plasma is prolonged after the admin of prednimustine as compared with chlorambucil per se. In contrast, the elimination of the prednisolone moiety of prednimustine & that following the admin of a plain prednisolone tablet did not seem to differ. The modified plasma profile of the alkylating components following prednimustine admin may be important for the clinical efficacy of prednimustine.
This report describes the physicochemical & pharmacokinetic parameters of 7 chlorambucil esters, which were compared with those of chlorambucil. These esters were designed as chlorambucil prodrugs to incr the brain penetration & concn vs time profile of chlorambucil within the CNS for potential treatment of brain tumors. They include four aliphatic esters from 1-8 carbon chains in length (chlorambucil-methyl, -propyl, -hexyl, & -octyl esters) & 3 aromatic esters, including the phenylmethyl, phenylethyl & prednisolone ester of chlorambucil, prednimustine. The esters were lipophilic & possessed log octanol:water partition coefficients (log P values) that ranged from 4.05 to >8.0. All retained alkylating activity, which was reduced compared with that of chlorambucil. In addition, all were metabolized in vivo in the rat to yield chlorambucil alone. Measurement of the in vitro rate of ester hydrolysis of the cmpds to yield chlorambucil in rat plasma demonstrated that short-chain aliphatic & aromatic chlorambucil esters were rapidly broken down to their parent compound. The plasma half-lives of the compounds increased with the increasing length & complexity of their ester chain. This may have been related to an incr in the binding of the long-chain esters to plasma proteins, protecting the ester from nonspecific plasma esterases, & to a reduced affinity of plasma esterases to these esters. Pharmacokinetic analysis of chlorambucil-hexyl, -octyl, & -prednisolone esters by HPLC demonstrated that following their iv admin in the rat (in doses equivalent to equimolar chlorambucil, 10 mg/kg), they yielded only low concns of active compounds in plasma & brain. The brain:plasma ratio of these was low & similar to that of chlorambucil, & no ester demonstrated anticancer activity superior to that obtained after the admin of equimolar chlorambucil (5 mg/kg i.v., days 1-5) against brain-sequestered Walker 256 carcinosarcoma in the rat.
The purpose of this investigation was to evaluate the ability of the cysteinyl-rich protein metallothionein (MT) to protect cells against the cytotoxic effects of prednimustine, an ester of chlorambucil & prednisolone. The cells studied were MT-rich substrains of murine fibroblasts (C1 1D100) & human epithelial cells (HE100), both demonstrated in an earlier report to exhibit an approx 3-fold incr in resistance to chlorambucil compared to their parent lines (C1 1D & HE) ... . Both in cloning & in growth rate studies the MT-rich strains proved to be significantly more resistant also to prednimustine. E.g. in cloning studies D0 for C1 1D cells (D0= the dose of drug reducing survival to 1/e) was 8.7 ug/ml prednimustine, whereas D0 for C1 1D100 was 12.4 ug/ml, representing an approx 1.5-fold incr in resistance, P<0.001, t-test. Other cloning studies revealed that prednimustine had a significantly higher cell killing activity in the resistant cells than equimolar concns of its components, single or in combination. Following treatment with 3H, (14)C-prednimustine (3H in the prednisolone moiety, (14)C in the chlorambucil moiety) & subsequent gel filtration, about 40% of the cytosolic chlorambucil eluted with MT. However, no intact prednimustine was recovered in the MT fractions. The data indicate that the MT-rich cells possess increased resistance to prednimustine due to a sequestration by MT of the alkylating moiety. Since the interaction probably does not take place until after hydrolysis, it is possible that the intact conjugate may bypass this cellular defence mechanism.
Basic treatment: Establish a patent airway. Suction if necessary. Watch for signs of respiratory insufficiency and assist ventilations if needed. Administer oxygen by nonrebreather mask at 10 to 15 L/min. Monitor for pulmonary edema and treat if necessary ... . Monitor for shock and treat if necessary ... . Anticipate seizures and treat if necessary ... . For eye contamination, flush eyes immediately with water. Irrigate each eye continuously with normal saline during transport ... . Do not use emetics. For ingestion, rinse mouth and administer 5 ml/kg up to 200 ml of water for dilution if the patient can swallow, has a strong gag reflex, and does not drool ... . Cover skin burns with dry sterile dressings after decontamination ... . /Poison A and B/
Intracellular concns of prednimustine (PM), chlorambucil (CLB), phenylacetic acid mustard (PAAM) & prednisolone (P) were measured in different experimental tumor cell lines that had been incubated with either PM or CLB + P. For intracellular analytical determination, we modified a high-pressure liquid chromatographic method for the detection of these substances in plasma. Intact PM could be detected in the intracellular compartment of the incubated tumor cells. PM-incubated cells from PM-injected rats exhibited a higher intracellular concn-time integral (PAAM) & longer concn-time profiles for drugs with alkylating capacity than did cells exposed to the CLB + P mixture or to CLB. PAAM was not detectable after incubation of cells with PM, whereas in CLB-incubated cells the AUC of PAAM exceeded that of the parent drug CLB. Our in vitro results therefore favour the concept of a facilitated intracellular uptake & an increased antiproliferative effect for PM versus CLB & CLB + P.
A single oral soln dose (40 mg/sq m) of (14)C-prednimustine was administered to each of four cancer patients. Plasma, urine, & feces were collected at appropriate times & analyzed for total radioactivity. Plasma samples were analyzed for prednimustine. Peak plasma levels of radioactivity (1-3 ug (14)C-prednimustine equivalents) occurred at 1.5-3 hr in 3 patients & at 5-6 hr in one patient. No intact prednimustine was detected in the plasma; this means that if present, it would be at a concn of 0.02 ug/ml or less & would account for <1% of the total drug-related material at the time of peak plasma levels. Solvent-extractable metabolites had a plasma half-life of about 8 hr or less. By 24 hr essentially all the plasma radioactivity appeared to be covalently bound, & it was eliminated slowly with an estimated terminal elimination half-life of about 10 days. Rapid urinary excretion occurred in the first 24 hr, & 40%-60% of the dose was recovered in the urine in 72 hr. Although prednimustine was well absorbed, the ester was subject to extensive presystemic metab & was not present in the systemic circulation after oral admin.
