Preliminary clinical and absorption studies with prednimustine in patients with mammary carcinoma

Könyves, I.; Nordenskjöld, Bo; Forshell, Gustaf Plym; Schryver, A. De; Westerberg-Larsson, H.

doi:10.1016/0014-2964(75)90082-1

Cited by 32 publications

(11 citation statements)

References 4 publications

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“…These data suggest that prednimustine is poorly absorbed from the gastrointestinal tract. In agreement with this suggestion is the observation that following the oral administration of radiolabelled prednimustine (20-100 mg) to mammary carcinoma patients, there is extensive and highly variable faecal excretion (0.3-55.2% dose administered) (Konyves et al, 1975). This latter study estimated only the parent compound and hence further drug-derived material may have been present in the faeces, i.e.…”

Section: Discussionsupporting

confidence: 61%

Studies on the pharmacokinetics of chlorambucil and prednimustine in man.

Newell¹,

Calvert²,

Harrap³

et al. 1983

Brit J Clinical Pharma

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1 Chlorambucil (10 mg) and prednimustine (20 mg), the prednisolone ester of chlorambucil, were administered orally on separate occasions to six patients. 2 Chlorambucil was rapidly absorbed such that the parent compound was observed in the plasma 30 min after administration. 3 A preliminary comparison of chlorambucil levels following oral and intravenous administration, and after repeat oral dosage indicated that chlorambucil was well (greater than 70%) and consistently absorbed. 4 Following prednimustine no parent drug or alkylating metabolites (chlorambucil or phenyl acetic mustard) could be detected in the plasma. 5 In studies with intravenously administered chlorambucil plasma levels of the parent drug were described by a two‐compartment open model with first‐order kinetics. Significant levels of the cytotoxic metabolite phenyl acetic mustard were detected. 6 It is concluded that: a. the bioavailability of orally administered prednimustine is much lower than that of chlorambucil. Thus the use of prednimustine in routine combination therapy is not recommended. b. due to the lower therapeutic index of phenyl acetic mustard in experimental systems, the production of this metabolite in man may be disadvantageous. Thus research aimed at producing chlorambucil analogues, which cannot be metabolised, seems justified.

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Section: Discussionsupporting

confidence: 61%

Studies on the pharmacokinetics of chlorambucil and prednimustine in man.

Newell¹,

Calvert²,

Harrap³

et al. 1983

Brit J Clinical Pharma

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“…Our data do not support the assumption of a simple presystemic hydrolysis of the substance, in which case chlorambucil and pred nisolone AUC should be similar after stoichiometrically equivalent dosing of the conjugate and the com ponents. While there is some evidence that prednimus tine might be absorbed only incompletely from the gastrointestinal tract [17,18], a different explanation was suggested by Gunnarsson et al [11], They pro posed the formation of a cholesterol ester of chloram bucil by transestérification of the chlorambucil moiety of prednimustine. catalyzed by lecithin-cholesterol acyltransferase.…”

Section: Discussionmentioning

confidence: 99%

“…While chlorambucil, its metabolite, phenylacetic acid mustard, and prednisolone are easily detected, intact prednimustine could not be observed in plasma after oral administration of the drug in previous pharmacokinetic studies [5,8,17,18,28,[31][32][33][34], Some studies indicate that prednimustine is incompletely absorbed by the gastrointestinal tract. While the bio availability of chlorambucil and prednisolone is more than 70% [7.…”

Section: Discussionmentioning

confidence: 99%

“…with 3 of 7 subjects excreting 35 55% of the labeled prednimustine in the feces [18], Kirdani et al [17] found a lower fraction in the feces ranging from 2 to 28%; using prednimustine labeled with 3H at positions 6 and 7 of the steroid moiety and with l4C at 4 positions of the bis-chloroethyl group of the chlorambucil moiety, approximately 60% of the label associated with the prednisolone and 50% of the label associated with the chlorambucil moieties were ex-crcted in the urine, with additional radioactivity ap pearing in feces. The route of administration (oral versus intravenous) did not distinctly affect the per centage of radioactivity excreted.…”

Section: Discussionmentioning

confidence: 99%

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Comparative Pharmacokinetics of Chlorambucil and Prednimustine after Oral Administration

Loos

Musch²,

Malek³

et al. 1991

Oncology

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The pharmacokinetics of chlorambucil, phenylacetic acid mustard (the β-oxidation product of chlorambucil), and prednisolone were investigated in a cross-over study after oral administration of chlorambucil (30 mg) + prednisolone (50 mg) versus prednimustine (300 mg), the ester of chlorambucil and prednisolone. Intact prednimustine could not be detected in plasma at any time. After administration of prednimustine, the plasma concentration-time curves of chlorambucil, phenylacetic acid mustard, and prednisolone showed a retarded profile compared to the administration of the single components. The mean bioavailability was 14% for chlorambucil, 21% for phenylacetic acid mustard, and 22% for prednisolone, when given as prednimustine, compared to the administration of free compounds in stoichiometrically equivalent doses. When given in the oral dosages mentioned above, the average dose-intensity was 62% for chlorambucil, 95% for phenylacetic acid mustard, and 72% for prednisolone, indicating sufficient therapeutic concentrations of the detectable agents.

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“…Given (a) the low bioavailability of chlorambucil when administered as prednimustine (ca. 20%, Ehrsson et al, 1983;Newell et al, 1983), and (b) the highly variable and in some patients extensive faecal excretion of unchanged prednimustine (Konyves et al, 1975), it would appear to be a relatively poor prodrug. These observations lead to the recommendation that for diseases where chlorambucil and prednisolone therapy are indicated the two agents should continue to be given separately (Newell et al, 1983).…”

Section: The Clinical Pharmacology Of Chlorambucil and Prednimustinementioning

confidence: 99%