Hydrolysis and Protein Binding of Melphalan

Chang, Su-Youne; Alberts, David S.; Farquhar, David; Melnick, L.; Walson, Philip D.; Salmon, SE

doi:10.1002/jps.2600670530

Cited by 75 publications

(31 citation statements)

References 7 publications

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“…In contrast melphalan is continually degraded by hydrolysis in aqueous environments, and the fraction of melphalan which 'leaks' from the isolated limb to the systemic circulation will partition within a much larger volume of distribution (intravascular and interstitial fluid). Furthermore some of the melphalan taken up by the tissues (of the perfused leg and the rest of the body) may be protected from hydrolysis by associating with tissue proteins (Chang et al, 1978a;Ehrsson & Lonroth, 1982) and released later, when the melphalan concentration gradients are reversed after perfusion. Thus a significant fraction of the administered melphalan dose could 'leak' and be 'washed out' from the perfusate to systemic circulation, yet produce only low systemic plasma concentrations.…”

Section: Discussionmentioning

confidence: 99%

The pharmacokinetic advantages of isolated limb perfusion with melphalan for malignant melanoma

Scott

Kerr²,

Blackie³

et al. 1992

Br J Cancer

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Summary We describe melphalan pharmacokinetics in 26 patients treated by isolated limb perfusion (ILP). Group A (n = 11) were treated with a bolus of melphalan (1.5 mg kg-'), and in a phase I study the dose was increased to 1.75 mg kg-'. The higher dose was given as a bolus to Group B (n = 9), and by divided dose to Group C (n = 6).Using high performance liquid chromatography (HPLC) the concentrations of melphalan in the arterial and venous perfusate (during ILP) and in the systemic circulation (during and after ILP) were measured. Areas under the concentration time curves for perfusate (AUCa, AUCV) and systemic (AUCS) data were calculated. In all three groups the peak concentrations of melphalan were much higher in the perfusate than in the systemic circulation. The pharmacokinetic advantages of ILP can be quantified by the ratio of AUCa/AUCS, median value 37.8 (2.1-131).AUCG and AUC, were both significantly greater in Group B than in Group A (P values <0.01, Mann-Whitney). In Groups B and C acceptable 'toxic' reactions occurred but were not simply related to melphalan levels.Our phase I study has allowed us to increase the dose of melphalan to 1.75 mg kg-', but we found no pharmacokinetic advantage from divided dose administration.The rationale for isolated limb perfusion (ILP) in the management of cancer depends on the generation of high levels of effective anticancer agent confined to the tumourbearing limb, thereby avoiding unacceptable systemic toxicity.It is clearly important to establish whether the complex and expensive technique of ILP genuinely achieves its major aim i.e. maximum levels of melphalan in the tumour-bearing limb and minimum systemic exposure.ILP is effective in the management of locally advanced malignant melanoma, and may be an effective adjuvant to surgery for thick, high risk primary lesions. Having reviewed our early experience of patients treated by ILP, it was confirmed that, because of the absence of melphalan-induced toxicity, there was scope for a phase I (dose escalating) clinical study.The study of pharmacokinetics is concerned with the absorption, distribution, biotransformation and excretion of drugs (Goodman et al., 1985). For a given dose these factors govern the concentration of drug at the site of action and they determine how the concentration varies with time.We have studied melphalan pharmacokinetics in the context of a phase I study of ILP.The aims of our studies were:(1) to measure melphalan concentrations in perfusate during ILP, and compare these with the levels in the systemic circulation during and after perfusion, (2) to study the pharmacokinetics of melphalan in ILP, as the dose was increased in a phase I study, (3) to compare the pharmacokinetics of bolus dose with divided dose administration.Patients, materials and methods Patient groupsOnly patients having external iliac perfusion for malignant melanoma were included in the study. The starting dose of melphalan was 1.5 mg kg' body weight, which is the maximum dose recommended in the protocols on which our t...

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Section: Discussionmentioning

confidence: 99%

The pharmacokinetic advantages of isolated limb perfusion with melphalan for malignant melanoma

Scott

Kerr²,

Blackie³

et al. 1992

Br J Cancer

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“…The breakdown of L-PAM in vivo is believed to be primarily by hydrolysis and alkylation (Evans et al, 1982). Furthermore, the hydrolysis of L-PAM has been shown to be temperature sensitive with slower rates being obtained at lower temperatures, both in water (Chang et al, 1978) and in plasma (Hinchliffe et al, 1983). Alternatively, these inhibitors may actually interfere with these processes or affect some other metabolic route.…”

Section: Discussionmentioning

confidence: 99%

Changes in the response of the RIF-1 tumour to melphalan in vivo induced by inhibitors of nuclear ADP-ribosyl transferase

Horsman¹,

Brown²,

Hirst³

et al. 1986

Br J Cancer

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Summary The effect of inhibitors of nuclear ADP-ribosyl transferase (ADPRT) on the cytotoxicity of melphalan (L-PAM) in the RIF-l tumour in vivo was investigated. A large single dose of nicotinamide (1000mgkg-') enhanced the tumour cell killing by L-PAM as measured by tumour cell survival. This enhancement was maximum when nicotinamide was administered within 1 h before injecting the L-PAM. When given at this time, the nicotinamide had a dose-modifying effect on all L-PAM doses tested, giving rise to a mean enhancement ratio (ER) of 2.2. Nicotinamide did not appear to inhibit the recovery from L-PAM induced potentially lethal damage. L-PAM (6mgkg-1) produced a transient drop in mouse body temperature. This effect was both increased and prolonged by nicotinamide. In addition the inhibitor also delayed the clearance of L-PAM from the plasma of C3H mice, such that the half-life of the chemotherapeutic agent was extended from 41 min to 143 min. The effect of combining L-PAM with nicotinamide doses below 1000mgkg-' was also investigated. The results showed that as the nicotinamide dose was decreased, the enhancement of the effects on body temperature, pharmacokinetics and white blood cell counts were reduced. However, a concomitant loss in the enhancement of tumour cell killing was also observed. Similar results were obtained using 3-aminobenzamide, a more efficient inhibitor of ADPRT.

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“…Binding of nitrogen mustards to serum proteins, and in particular to albumin, has been reported by several groups (Chang et al 1978;Ehrsson et al 1981;Ehrsson and Lo¨nroth 1982;Greig et al 1987;Gera et al 1989;Lo¨f et al 1997). Unfortunately, in these studies no binding sites were elucidated and in some cases even the type of binding (covalent or non-covalent) could not be established.…”

Section: Introductionmentioning

confidence: 86%

Covalent binding of nitrogen mustards to the cysteine-34 residue in human serum albumin

Noort¹,

Hulst²,

Jansen

2002

Archives of Toxicology

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Hydrolysis and Protein Binding of Melphalan

Cited by 75 publications

References 7 publications

The pharmacokinetic advantages of isolated limb perfusion with melphalan for malignant melanoma

The pharmacokinetic advantages of isolated limb perfusion with melphalan for malignant melanoma

Changes in the response of the RIF-1 tumour to melphalan in vivo induced by inhibitors of nuclear ADP-ribosyl transferase

Covalent binding of nitrogen mustards to the cysteine-34 residue in human serum albumin

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