Author: Fontanon, C. ; Madelmont, J. C. ; Baudry, J. P. ; Labarre, P. ; Chollet, P. ; Tisserant, A. ; Cussac, C. ; Godeneche, D. ; Dupuy, J. M. ; Veyre, A.

The pharmacokinetics of perrimustine and cystemustine, 2 novel-2-chloroethylnitrosoureas (CENUs) were investigated in patients with various cancer diseases.The unique protocol followed in this study consisted of a 15-min i.v. perfusion of a 45 mg/m² dose of perrimustine every 4 wk and a 60 or 90 mg/m² dose of cystemustine every 2 wk.A sensitive and specific method was developed using solid phase extraction and HPLC anal., which allowed measurement of the drug concentration levels until at least 3 h after the beginning of administration of the injection.The rate of disappearance of the 2 drugs from the blood was fitted to either a monoexponential or a biexponential model.When detected, the half-lives of the distribution phase were less than 10 min.Regardless of the pharmacokinetic model used, the elimination half-lives were about 50 min.The interindividual variations of the pharmacokinetic parameters, as reflected by the variation coefficients (10 to 47%), were lower than those reported in the literature for this class of unstable anticancer drugs.The procedure described here allows one to safely conduct perrimustine and cystemustine pharmacokinetic studies with the purpose of further investigation in a greater number of patients to determine whether any correlation exists between pharmacokinetics, efficacy and/or toxicity.

01 Jan 1993·Drug Metabolism and Disposition

Main urinary metabolites of two cysteamine-containing 2-(chloroethyl) nitrosoureas in rats.

Author: Moreau, M. F. ; Madelmont, J. C. ; Labarre, P. ; Rapp, M. ; Papon, J. ; Godeneche, D. ; Veyre, A.

Urine is the major route of excretion of N'-(2-chloroethyl)-N-[2-(methylsulfinyl)ethyl]-N'-nitrosourea (CMSOEN₂), N'-(2-chloroethyl)-N-[2-(methylsulfonyl)ethyl]-N'-nitrosourea (CMSO₂EN₂), and their metabolites in the rat.Labeling the two compounds with ¹⁴C in three different positions facilitated their metabolic study in animals.The ¹⁴C-Et species were chosen in order to investigate the presence of unchanged compounds and that of the denitrosated forms.With the same ¹⁴C label position, the authors showed that isolated metabolites derived from this part of the mol. were degradation products of alkylated glutathione and/or cysteine.They are common to both CMSOEN₂ and CMSO₂EN₂, namely thiodiacetic acid and its sulfoxide, the sum of which represents about half of urinary radioactivity.N-Acetylcarboxymethylcysteine and N-acetylhydroxyethylcysteine, accounting for ∼ 6% to 7% of the eliminated ¹⁴C radioactivity, were also characterized.However, four minor metabolites corresponding to less than 10% of the excreted radioactivity remained unidentified.With the [¹⁴C]cysteamine and [¹⁴C]carbonyl labels related to the isocyanate moiety behavior, the authors indirectly showed that more than 60% to 70% of the excreted metabolites were carbamoylation products of endogenous substrates.Small amounts of the free amines 2-methylsulfinylethylamine and/or 2-methylsulfonylethylamine, representing 15%-16% of the eliminated radioactivity, were also detected.The total data confirm the predominant function of glutathione and/or cysteine in the detoxifying system of the chloroethyl moieties and reveal the unexpected but important role played by carbamoylation reactions in the metabolic fate of the drug isocyanate moieties.

01 Jun 1992·Anti-Cancer DrugsQ4 · MEDICINE

Phase I trial of Perrimustine, a new cysteamine (2-chloroethyl) nitrosourea

Q4 · MEDICINE

Article

Author: Madelmont, J C ; Kim-Triana, B ; Musset, M ; Misset, J L ; Godenèche, D ; Mathé, G

The recently synthesized nitrosourea, N-[N'-chloro-2-ethyl-N'-nitrosocarbamoyl]-S-methyl cysteamine sulfoxide (Perrimustine), is water soluble and has a high alkylating activity, similar to that of the widely used nitrsoureas BCNU and CCNU, and a low carbamoylating activity. Preclinical studies with a broad spectrum of murine tumors indicate that this new compound may be clinically useful. The maximally efficient dose range (MEDR) in L1210 bearing mice was 45 mg/m2 (subcurative dose) to 67 mg/m2 (subtoxic dose). The present phase I trial used an intrapatient escalation schedule, so that each patient entering the study received a potentially active dose. The first dose injected was 1:100 of the MEDR suboptimal dose to check for anaphylactic sensitivity. Patients were then given increasing doses at increasing time intervals until toxicity was observed. The highest dose was given on day 150-230. The main toxic effect was myelosuppression [five out of the 24 patients evaluated: one grade 4 thrombocytopenia, two grade 3 thrombocytopenia; anemia and leucopenia were milder (grade 1 to 2 on OMS scale)]. Of the 19 patients evaluated for clinical response, one showed response after the 45 mg/m2 dose (disappearance of the cerebral metastasis with persistence of hepatic localizations in a patient with melanoma) and the disease was stabilized in two cases (a pleural mesothelioma and a renal carcinoma with lung metastases) after 26 and 37 weeks, with total cumulative doses per m2 of 232 and 196 mg, respectively.

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