Prednimustine

SRP: At the time of review, criteria for land treatment or burial (sanitary landfill) disposal practices are subject to significant revision. Prior to implementing land disposal of waste residue (including waste sludge), consult with environmental regulatory agencies for guidance on acceptable disposal practices.

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.

Prednimustine

Group 3: Not classifiable as to its carcinogenicity to humans

Volume 50: (1990) Pharmaceutical Drugs

1990

1989

Chlorambucil was linked to prednisolone to improve the therapeutic & toxic properties of this potent alkylating agent, which is known to induce second tumors in humans. To compare the carcinogenic potency of the linked cmpd with that of the respective individual agents & of their unlinked mixture, prednimustine (I), chlorambucil (II), prednisolone (III), chlorambucil plus prednisolone (IV), or vehicle were administered to groups of 120 female Sprague-Dawley rats for 18 months. The following doses were administered 9, 4, 5, 2 times, or once a month/subgroup of 30 rats: I, 12 mg/kg; II, 3 mg/kg; III, 3 mg/kg; IV, 3 mg/kg. After natural death of animals, median survival times were analyzed, & % of malignant tumors were recorded. An increased tumor risk was found in the following organs compared with those of vehicle-treated controls: I, external auditory canal (EAC); II, mammary gland (MG), central & peripheral nervous tissue (CPNT), hematopoietic & lymphatic tissue (HLT), & EAC; III, none; & IV, MG, CPNT, & EAC. There is evidence of carcinogenic activity of prednimustine compared with untreated controls, but the cancer-inducing potential of the linked cmpd is distinctly lower than that of the unlinked mixture of chlorambucil plus prednisolone or that of chlorambucil.

In the rat prednimustine, the prednisolone ester of chlorambucil, is much less toxic than equimolar doses of chlorambucil, when administered subcutaneously (SC). This is due to differences in alkylating agent pharmacokinetics. Prednimustine injected SC produced low plasma concns (<5 microM) of the alkylating metabolites chlorambucil & phenyl acetic mustard, which were maintained for 48 hr. No unhydrolysed prednimustine could be detected. Chlorambucil, in contrast, was rapidly absorbed, peak levels (40 microM) occurring within 2 hr, after which chlorambucil & phenyl acetic mustard plasma levels decreased with half-lives of 2.4 hr & 2.9 hr respectively. The toxicity of chlorambucil could be similarly reduced by administering either the methyl ester of chlorambucil or by giving chlorambucil in a multiple-treatment low-dose schedule. Neither of these treatments inhibited the Yoshida alkylating agent-resistant tumour, however, whereas prednimustine or a combination of chlorambucil & prednisolone produced significant tumour growth inhibition. Prednisolone did not alter chlorambucil pharmacokinetics. Thus the reduced toxicity of prednimustine is due to chlorambucil esterification & the subsequent alteration in pharmacokinetics, whilst inhibition of alkylating agent-resistant tumours results from the combination of chlorambucil & prednisolone.

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/

Advanced treatment: Consider orotracheal or nasotracheal intubation for airway control in the patient who is unconscious, has severe pulmonary edema, or is in respiratory arrest. Positive pressure ventilation techniques with a bag valve mask device may be beneficial. Monitor cardiac rhythm and treat arrhythmias as necessary ... . Start an IV with D5W /SRP: "To keep open", minimal flow rate/. Use lactated Ringer's if signs of hypovolemia are present. Watch for signs of fluid overload. Consider drug therapy for pulmonary edema ... . For hypotension with signs of hypovolemia, administer fluid cautiously. Watch for signs of fluid overload ... . Treat seizures with diazepam (Valium) ... . Use proparacaine hydrochloride to assist eye irrigation ... . /Poison A and B/

L - Antineoplastic and immunomodulating agents

QL - Antineoplastic and immunomodulating agents

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.

A class of drugs that differs from other alkylating agents used clinically in that they are monofunctional and thus unable to cross-link cellular macromolecules. Among their common properties are a requirement for metabolic activation to intermediates with antitumor efficacy and the presence in their chemical structures of N-methyl groups, that after metabolism, can covalently modify cellular DNA. The precise mechanisms by which each of these drugs acts to kill tumor cells are not completely understood. (From AMA, Drug Evaluations Annual, 1994, p2026)

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.

Prednimustine (Leo 1031), a conjugate of prednisolone & chlorambucil, was administered to humans & baboons & the metabolic fate of the cmpd ascertained. Compared to the excretion of prednisolone, prednimustine is excreted more slowly & less quantitatively, with a significant part of the cmpd being retained in the body. Hydrolysis of the prednimustine molecule appears to take place quantitatively after oral admin, but a substantial part of prednimustine appears to remain intact after its iv admin. Fecal excretion of radioactivity was minor compared to the urinary route. The biliary excretion in the baboon was relatively insignificant. Localisation within the lung & spleen of the baboon points to a potential therapeutic use of this drug in neoplastic conditions affecting these organs.