Habilitationsschrift--Heidelberg. / At head of title: Aus dem physiologischen Institut zu Heidelberg. Includes bibliographical foot-notes.

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Melphalan (the synthetic product of nitrogen mustard and L-phenylalanine) is an alkylating agent and is the drug of choice in the treatment of multiple myeloma. The bioavailability of melphalan is variable but factors affecting its absorption and the mechanism(s) by which the drug crosses the intestinal epithelium are not known. A sensitive assay for melphalan in plasma (down to a concentration of 2ng.ml^-1) has been developed. The method, involving solid phase extraction and derivatisation with o-phthalaldehyde followed by reversed-phase high-performance liquid chromatography, was applied to the study of melphalan pharmacokinetics in multiple myeloma patients. Bioavailability ranged from 0.16 to 1.37 in nine fasting patients and peak plasma concentrations of melphalan ranged from 8.0 to 170 ng.ml^-1 and occurred 0.5 to 2.0 hours after an oral dose of 10mg. When melphalan was taken with food (three patients) a mean reduction of 40% in bioavailability was observed. Significant correlations (P< 0.05) were observed between bioavailability and melphalan plasma concentrations in single samples drawn at 0.5, 1.0 and 2.0 hours. There was no significant correlation between renal function and melphalan absorption, distribution or elimination. A second peak was observed in the distribution phase of six of the eleven plasma concentration-time curves when melphalan was administered intravenously. The secondary peak may be attributed to either melphalan redistribution or enterohepatic circulation. An <i>in vitro</i> method (modified Ussing technique) was developed to investigate melphalan transport across rat and human small intestine. There was no evidence for the Na⁺-coupled (active) transport of melphalan in these tissues. The rate of melphalan transfer was non-saturable and values of apparent mass transfer coefficients were comparable with the diffusional contribution to the intestinal transport of amino acids The results indicate that passive diffusion is the major process responsible for the transfer of melphalan across intestinal epithelium.

Thesis (Ph.D.)--University of Nebraska-Lincoln, 2008. / Title from title screen (site viewed Mar. 10, 2009). PDF text: 100 p. : ill. ; 708 K. UMI publication number: AAT 3330677. Includes bibliographical references. Also available in microfilm and microfiche formats.

Thesis (doctoral)--Københavns universitet.

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