Abstract
Melphalan is commonly used as a cytotoxic agent in isolated limb perfusion for locally recurrent malignant melanoma. The time course of melphalan concentrations in perfusate and tissues during a 60-min melphalan perfusion and 30-min drug-free washout in the single-pass perfused rat hindlimb was examined using a physiologically based pharmacokinetic model. The rat hindlimbs were perfused with Krebs-Heinseleit buffer containing 4.7% bovine serum albumin (BSA) or 2.8% dextran 40 at a constant rate of 3.8 ml/min. The concentration of melphalan in perfusate and tissues was determined by high-performance liquid chromatography. The tissue concentrations of melphalan were significantly higher with the perfusate containing dextran than BSA during the 60-min perfusion. During the washout period, the melphalan concentration in the perfusates decreased rapidly in first few minutes, followed by a slower monoexponential decline. The estimated half life ( t1/2) for melphalan removal from skin and fat was 59 ± 2 min for both BSA and dextran perfusates. However, the estimated t1/2 for melphalan removal from muscle was 79 and 96 min for BSA and dextran washout perfusates, respectively. The predicted concentration-time profiles obtained for melphalan with BSA and dextran perfusates appear to correspond closely to the observed data. This study showed that the uptake of melphalan into perfused tissues is impaired by the use of perfusates in which melphalan is highly bound. Melphalan washout from muscle, but not skin and fat, was facilitated by the use of perfusates in which melphalan is highly protein bound.
Footnotes
-
Send reprint requests to: Dr. Michael S. Roberts, Department of Medicine, University of Queensland, Princess Alexandra Hospital, Brisbane, Queensland, Australia 4102.
-
↵1 This work was supported by the Queensland Cancer Fund. M.S.R. was supported by Australian National Health & Medical Research Council and the Queensland and Northern New South Wales Lions Kidney & Medical Research Foundation.
- Abbreviations:
- PK
- pharmacokinetics
- IPRH
- isolated perfused rat hindlimb
- ILP
- isolated limb perfusion
- fu
- fraction unbound
- BSA
- bovine serum albumin
- HPLC
- high-performance liquid chromatography
- RBC
- red blood cell
- Received July 23, 1996.
- Accepted April 28, 1997.
- The American Society for Pharmacology and Experimental Therapeutics
JPET articles become freely available 12 months after publication, and remain freely available for 5 years.Non-open access articles that fall outside this five year window are available only to institutional subscribers and current ASPET members, or through the article purchase feature at the bottom of the page.
|