NCBI Bookshelf. A service of the National Library of Medicine, National Institutes of Health.
IARC Working Group on the Evaluation of Carcinogenic Risks to Humans. Pharmaceutical Drugs. Lyon (FR): International Agency for Research on Cancer; 1990. (IARC Monographs on the Evaluation of the Carcinogenic Risks to Humans, No. 50.)
1. Chemical and Physical Data
1.1. Synonyms
Chem. Abstr. Services Reg. No.: 29069-24-7
Chem. Abstr. Name: Pregna-1,4-diene-3,20-dione, 21-(4-{4-[bis(2-chloroethyl)amino]phenyl}-1-oxybutoxy)-11,17-dihydroxy-(11β)-
Synonyms: Prednisolone, 21-(4-{para[bis(2-chloroethyl)-αβ-amino]phenyl}-butyrate); 11β,17,21-trihydroxypregna-1,4-diene-3,20-dione-21-(1-{para-[bis-(2-chloroethyl)amino]phenyl}butyrate); Leo 1031; NSC 134087
1.2. Structural and molecular formulae and molecular weight
1.3. Chemical and physical properties of the pure substance
From Windholz (1983), unless otherwise specified
- Description: Crystals from methanol-waterMelting-point: 163–164°COptical rotation:
Solubility: Practically insoluble in water; soluble in ethanol, acetone, chloroform and methanol (Reynolds, 1989)
1.4. Technical products and impurities
Trade names: Mostarine; Sterecyt; Stéréocyt
2. Production, Occurrence, Use and Analysis
2.1. Production and occurrence
Prednimustine can be produced by the esterification of chlorambucil with prednisolone (Fex et al., 1970). It is synthesized in Sweden.
Prednimustine is not known to occur naturally.
2.2. Use
Prednimustine is a cytostatic agent. It has been used in the treatment of various malignancies, including chronic lymphatic leukaemia and non-Hodgkin's lymphomas, at daily oral doses of 140–200 mg for three to five days or continuously at 20–30 mg per day (Reynolds, 1989; Szanto et al., 1989). It has also been tested for use in the treatment of breast cancer (Loeber et al., 1983; Rankin et al., 1987).
2.3. Analysis
Prednimustine has been quantified in plasma by high-performance liquid chromatography (Newell et al., 1979). It has also been quantified after hydrolysis to chlorambucil, by gas chromatography-mass spectrometry (Jakhammer et al., 1977) and high-performance liquid chromatography (Workman et al., 1987).
3. Biological Data Relevant to the Evaluation of Carcinogenic Risk to Humans
3.1. Carcinogenicity studies in animals
(a) Oral administration
Rat: Four groups of 30 female Sprague-Dawley rats, 100 days of age, received prednimustine [purity unspecified] at 12 mg/kg bw in a vehicle consisting of carboxymethylcellulose, Tween 80 and glucose in water by gavage once, twice, 4.5 or nine times per month for 18 months. The last group had significantly reduced survival. A group of 120 female rats received the vehicle alone by gavage nine times per month for 18 months. A significant increase (p < 0.01; Peto test: Peto et al., 1980) in the incidence of squamous-cell carcinomas of the external auditory canal was observed (controls, 0/30; once per month, 0/30; twice per month, 1/30; 4.5 times per month, 2/30; nine times per month, 2/30). No increase in the incidence of other tumours was observed (Berger et al., 1985, 1986).
(b) Carcinogenicity of metabolites
Chlorambucil has been evaluated in the IARC Monographs (IARC, 1975, 1981, 1987).
3.2. Other relevant data
(a) Experimental systems
(i) Absorption, distribution, excretion and metabolism
Following a subcutaneous injection of radiolabeled prednimustine at 20 mg/kg bw to female Wistar rats, radioactivity appeared gradually in blood plasma over 48 h. The levels of chlorambucil and phenylacetic mustard in plasma were below 5 μM. Radioactivity levels in all tissues studied were lower than those in plasma; in the small intestine, activity peaked at 2–4 h after administration. No or little radioactivity was detected in bone marrow (Newell et al., 1981).
When radiolabeled prednimustine was injected intravenously to baboons, low urinary and biliary excretion was observed. The radioactivity in blood and kidney decreased with time, but it was stable in the liver over the observation period of 6 h. In muscle, prostate, lung, spleen and seminal vesicles, however, radioactivity levels rose after 4 and 6 h (Kirdani et al., 1978).
Prednimustine is hydrolysed completely in vitro by rat plasma esterases to chlorambucil and prednisolone (Wilkinson et al., 1978). A cholesterol ester of chlorambucil, originating from prednimustine by acyltransferase-catalysed transesterification, was detected when prednimustine was incubated with human, rat or dog plasma in vitro. The same ester was identified in plasma of dogs after intravenous injection in vivo (Gunnarsson et al., 1984).
(ii) Toxic effects
In an acute lethality study, survival of Wistar rats given prednimustine at 128 mg/kg bw subcutaneously was 70% after 21 days. The drug was less toxic than chlorambucil and less toxic than chlorambucil and prednisolone given in combination (Harrap et al., 1977).
In subacute toxicity experiments, the mortality caused by daily oral administrations of prednimustine for four weeks to Sprague-Dawley rats was low compared to that induced by chlorambucil and prednisolone given together. Mortality in prednimustine-treated animals was about 10% at dose levels of 32 and 64 mg/kg bw. Dose-related lymphopenia was observed, and spleen and adrenal weights were reduced (Fredholm et al., 1978).
No symptom of toxicity was observed during a life-time carcinogenicity study with prednimustine given to Sprague-Dawley rats at 12 mg/kg bw one to nine times per month for 18 months (Berger et al., 1986).
Prednimustine caused a dose-dependent decrease in survival in Chinese hamster V79-4 cells; it was at least three times as toxic as chlorambucil throughout the dose range (Hartley-Asp et al., 1986). Dose-dependent cell death was also observed in the hormone-sensitive S49 mouse lymphoma cell line after incubation for 24 h with prednimustine at 10−8 M up to 5 × 10−7 M prednimustine (Harrap et al., 1977).
(iii) Effects on reproduction and prenatal toxicity
No data were available to the Working Group.
(iv) Genetic and related effects
No data were available to the Working Group.
(b) Humans
(i) Pharmacokinetics
When prednimustine was given orally at doses up to 200 mg, no unchanged drug could be detected in blood (Newell et al., 1979; Ehrsson et al., 1983; Gaver et al., 1983; Newell et al., 1983; Oppitz et al., 1989) or in urine (Kirdani et al., 1978). When prednimustine was given orally at 20 mg, no chlorambucil or phenylacetic mustard was detected in the circulation (Newell et al., 1979, 1983); however, when a higher dose (100 or 200 mg) was given, chlorambucil was detected in blood (Ehrsson et al., 1983; Oppitz et al., 1989). After a dose of 200 mg, phenylacetic mustard was also identified in the circulation (Oppitz et al., 1989), and, after an oral dose of 100 mg, free prednisolone was detected (Sayed et al., 1981). The concentrations of chlorambucil and its metabolites and of prednisolone detected in the circulation after an oral dose of prednimustine were lower than those after equimolar doses of chlorambucil and prednisolone given separately (Sayed et al., 1981; Ehrsson et al., 1983; Oppitz et al., 1989). After a single oral dose of prednimustine, the peak values of chlorambucil and phenylacetic acid mustard in the serum were reached later and the disappearance half-time was longer than after administration of chlorambucil and prednisolone separately (Ehrsson et al., 1983; Oppitz et al., 1989). Three to six hours after a single oral dose of 40 mg/m2 radiolabelled prednimustine, 50% of the plasma radioactivity could be extracted into organic solvents; the extractable proportion decreased with time and was <10% after 12–18 h. The terminal half-time of ten days for prednimustine-derived radioactivity in plasma could be attributed to these covalently bound metabolites (Gaver et al., 1983).
When a trace amount of double-labelled prednimustine (14C in the bischloroethyl group, 3H at positions 6 and 7 of the steroid part) was administered intravenously, 14C and 3H in the urine cochromatographed partially during the first hour after the injection but were fully separated thereafter, indicating that intact prednimustine is excreted in the urine only immediately after injection (Kirdani et al., 1978).
(ii) Adverse effects
Leukopenia and thrombocytopenia seem to be dose-dependent and may limit the dose that can be used. Nausea and vomiting are frequent (Könyves et al., 1975; Loeber et al., 1983; Rankin et al., 1987; Szanto et al., 1989).
(iii) Effects on reproduction and prenatal toxicity
No data were available to the Working Group.
(iv) Genetic and related effects
No adequate studies were available to the Working Group.
3.3. Case reports and epidemiological studies of carcinogenicity to humans
No data were available to the Working Group.
4. Summary of Data Reported and Evaluation
4.1. Exposure data
Prednimustine has been used as a cytostatic drug, mainly for the treatment of malignancies of lymphatic tissue.
4.2. Experimental carcinogenicity data
Prednimustine given by oral administration to rats induced a low but significant increase in the incidence of squamous-cell carcinomas of the external auditory canal.
4.3. Human carcinogenicity data
No data were available to the Working Group.
4.4. Other relevant data
In humans, prednimustine causes leukopenia and thrombocytopenia; in experimental animals, it causes lymphopenia. It is hydrolysed to chlorambucil and prednisolone in vivo. (See Appendix 1.)
4.5. Evaluation1
There is inadequate evidence for the carcinogenicity of prednimustine in experimental animals.
No data were available from studies in humans on the carcinogenicity of prednimustine.
Overall evaluation
Prednimustine is not classifiable as to its carcinogenicity to humans (Group 3).
5. References
- Berger M.R., Habs M., Schmähl D. Comparative carcinogenic activity of prednimustine, chlorambucil, prednisolone and chlorambucil plus prednisone in Sprague-Dawley rats. Arch. Geschwulstforsch. 1985;55:429–442. [PubMed: 4083998]
- Berger M.R., Habs M., Schmähl D. Long-term toxicology effects of prednimustine in comparison with chlorambucil, prednisolone, and chlorambucil plus prednisolone in Sprague-Dawley rats. Semin. Oncol. 1986;13 Suppl. 1:8–13. [PubMed: 3952521]
- Ehrsson H., Wallin I., Nilsson S.-O., Johansson B. Pharmacokinetics of chlorambucil in man after administration of the free drug and its prednisolone ester (Prednimustine, Leo 1031). Eur. J. clin. Pharmacol. 1983;24:251–253. [PubMed: 6840176]
- Fex H.J., Hogberg K.B., Könyves I. Corticosteroid p-bis(2-chloroethyl)-aminophenylcarboxylates as antitumor agents. Chem. Abstr. 1970;73:391.
- Fredholm B., Gunnarsson K., Jensen G., Müntzing J. Mammary tumour inhibition and subacute toxicity in rats of prednimustine and of its molecular components chlorambucil and prednisolone. Acta Pharmacol. toxicol. 1978;42:159–163. [PubMed: 580343]
- Gaver R.C., Deeb G., Pittman K.A., Issel B.F., Mittelman A., Smyth R.D. Disposition of orally administered 14C-prednimustine. Cancer Chemother. Pharmacol. 1983;11:139–143. [PubMed: 6640823]
- Gunnarsson P.O., Johansson S.-Å., Svensson L. Cholesterol ester formation by transesterification of chlorambucil: a novel pathway in drug metabolism. Xenobiotica. 1984;14:569–574. [PubMed: 6506771]
- Harrap K.R., Riches P.G., Gilby E.D., Sellwood S.M., Wilkinson R., Könyves I. Studies on the toxicity and antitumour activity of prednimustine, a prednisolone ester of chlorambucil. Eur. J. Cancer. 1977;13:873–881. [PubMed: 908348]
- Hartley-Asp B., Gunnarsson P.O., Liljekvist J. Cytotoxicity and metabolism of prednimustine, chlorambucil and prednisolone in a Chinese hamster cell line. Cancer Chemother. Pharmacol. 1986;16:85–90. [PubMed: 3948307]
- IARC (1975) IARC Monographs on the Evaluation of Carcinogenic Risk of Chemicals to Man, Vol. 9, Some Aziridines, N-, S-, and O-Mustards and Selenium, Lyon, pp. 125–134. [PubMed: 1234596]
- IARC (1981) IARC Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Humans, Vol. 26, Some Antineoplastic and Immunosuppressive Agents, Lyon, pp. 115–136. [PubMed: 6944255]
- IARC (1987) IARC Monographs on the Evaluation of Carcinogenic Risks to Humans, Suppl. 7, Overall Evaluations of Carcinogenicity: An Updating of IARC Monographs Volumes 1 to 42, Lyon, pp. 144–145. [PubMed: 3482203]
- Jakhammer T., Olsson A., Svenson L. Mass fragmentographic determination of prednimustine and chlorambucil in plasma. Acta pharm. suec. 1977;14:485–496. [PubMed: 596165]
- Kirdani R.Y., Murphy G.P., Sandberg A.A. Some metabolic aspects of a nitrogen mustard of prednisolone. Oncology. 1978;35:47–53. [PubMed: 652263]
- Könyves I., Nordenskjöld B., Plym Forshell G., de Schryver A., Westerberg-Larsson H. Preliminary clinical and absorption studies with prednimustine in patients with mammary carcinoma. Eur. J. Cancer. 1975;11:841–844. [PubMed: 767114]
- Loeber J., Mouridsen H.T., Christiansen I.E., Dombernowsky P., Mattsson W., Roerth M. A phase III trial comparing prednimustine (LEO 1031) to chlorambucil plus prednisolone in advanced breast cancer. Cancer. 1983;52:1570–1576. [PubMed: 6352005]
- Newell D.R., Hart L.I., Harrap K.R. Estimation of chlorambucil, phenyl acetic mustard and prednimustine in human plasma by high-performance liquid chromatography. J. Chromatogr. 1979;164:114–119. [PubMed: 541393]
- Newell D.R., Shepherd C.R., Harrap K.R. The pharmacokinetics of prednimustine and chlorambucil in the rat. Cancer Chemother. Pharmacol. 1981;6:85–91. [PubMed: 7273268]
- Newell D.R., Calvert A.H., Harrap K.R., McElvain T.J. Studies on the pharmacokinetics of chlorambucil and prednimustine in man. Br. J. clin. Pharmacol. 1983;15:253–258. [PMC free article: PMC1427847] [PubMed: 6849759]
- Oppitz M.M., Musch E., Malek M., Rueb H.P., von Unruh G.E., Loos U. Studies on the pharmacokinetics of chlorambucil and prednimustine in patients using a new high-performance liquid chromatographic assay. Cancer Chemother. Pharmacol. 1989;23:208–212. [PubMed: 2924378]
- Peto, R., Pike, M.C., Day, N.E., Gray, R.G., Lee, P.N., Parish, S., Peto, J., Richards, S. & Wahrendorf, J. (1980) Guidelines for simple sensitive significance tests for carcinogenic effects in long-term animal experiments. In: Long-term and Short-term Screening Assays for Carcinogens: A Critical Appraisal (IARC Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Humans, Suppl. 2), Lyon, IARC, pp. 311–426. [PubMed: 6935185]
- Rankin E.M., Harvey C., Knoght R.K., Rubens R.D. Phase II trial of prednimustine as first-line chemotherapy in patients with advanced breast cancer. Cancer Treat. Rep. 1987;71:1107–1108. [PubMed: 3119205]
- Reynolds, J.E.F., ed. (1989) Martindale. The Extra Pharmacopoeia, 29th ed., London, The Pharmaceutical Press, pp. 647–648.
- Sayed A., Van Hove W., Vermeulen A. Prednisolone plasma levels after oral administration of prednimustine®. Oncology. 1981;38:351–355. [PubMed: 7301281]
- Szanto L., Fleischmann T., Eckhardt S. Prednimustine treatment in malignant lymphomas. Oncology. 1989;46:205–207. [PubMed: 2662086]
- Wilkinsson, R., Gunnarsson, P.O., Plym-Forshell, G., Renshaw, J., Harrap, K.R. (1978) The hydrolysis of prednimustine by enzymes from normal and tumour tissues. In: Davis, W. Harrap, K.R., eds, Advances in Tumour Prevention, Detection and Characterization, Amsterdam, Excepta Medica, pp. 260–273.
- Windholz, M., ed. (1983) The Merck Index, 10th ed., Rahway, NJ, Merck & Co., pp. 1109–1110.
- Workman P., Oppitz M., Donaldson J., Lee F.Y.F. High-performance liquid chromatography of chlorambucil analogues. J. Chromatogr. 1987;422:315–321. [PubMed: 3437020]
Footnotes
- 1
For description of the italicized terms, see Preamble, pp. 26–29.
- Cytotoxicity and metabolism of prednimustine, chlorambucil and prednisolone in a Chinese hamster cell line.[Cancer Chemother Pharmacol. 1986]Cytotoxicity and metabolism of prednimustine, chlorambucil and prednisolone in a Chinese hamster cell line.Hartley-Asp B, Gunnarsson PO, Liljekvist J. Cancer Chemother Pharmacol. 1986; 16(2):85-90.
- Comparison of the cytotoxic effect of prednimustine in cultured cells with high or low levels of metallothionein.[Acta Pharmacol Toxicol (Copenh...]Comparison of the cytotoxic effect of prednimustine in cultured cells with high or low levels of metallothionein.Endresen L. Acta Pharmacol Toxicol (Copenh). 1984 Jan; 54(1):49-57.
- Comparative pharmacokinetics of chlorambucil and prednimustine after oral administration.[Oncology. 1991]Comparative pharmacokinetics of chlorambucil and prednimustine after oral administration.Loos U, Musch E, Malek M, Riedel E. Oncology. 1991; 48(4):334-42.
- Review Prednimustine in advanced breast cancer: a review.[Semin Oncol. 1986]Review Prednimustine in advanced breast cancer: a review.Mouridsen HT. Semin Oncol. 1986 Mar; 13(1 Suppl 1):27-31.
- Review [Myoclonus induced by prednimustine].[Neurologia. 1998]Review [Myoclonus induced by prednimustine].Ezpeleta Echávarri D, Muñoz-Blanco JL, Diaz-Otero F, Giménez Roldán S. Neurologia. 1998 Mar; 13(3):154-5.
- Prednimustine - Pharmaceutical DrugsPrednimustine - Pharmaceutical Drugs
- Pharmaceutical DrugsPharmaceutical Drugs
Your browsing activity is empty.
Activity recording is turned off.
See more...