Identification and partial characterization of an unusual distribution of the photosensitizer meta-tetrahydroxyphenyl chlorin (temoporfin) in human plasma

Temoporfin (m-THPC) is an extremely powerful photosensitizing drug, more th an 100-fold more photocytotoxic than Photofrin and many other drugs. The re asons for this are not yet known but are likely to be associated with the m echanism of uptake of the drug and its intratumoral and intracellular local ization. Uptake itself is likely to be dependent upon the plasma binding of the drug following administration. In the current work, we have shown that the addition of m-THPC to human plasma in vitro at clinically relevant dos es of sensitizer and administration solvent (diluant) gives rise to a prote in-binding pattern quite different to that of Photofrin and other hydrophob ic drugs as judged by density-gradient ultracentrifugation, Analysis of the binding immediately after addition to human plasma has shown that lipoprot ein binding accounts for only a minor proportion of the sensitizer, which i s mainly associated with a high-density protein fraction that is not coinci dent with serum albumin, The m-THPC protein complex does not fluoresce sign ificantly even on dilution, This binding pattern is highly dependent on adm inistration conditions and storage, Over a period of 6-8 h at 37 degrees C the m-THPC that is associated with this unidentified fraction redistributes to the plasma lipoproteins, Plasma collected from rats after intravenous a dministration of m-THPC also contains this low fluorescent complex, showing that this phenomenon is not limited to human plasma and also occurs in viv o, It is postulated that the m-THPC bound to the unknown protein fraction i s highly aggregated and that it is likely to be taken up into tissues in th is form. This unusual uptake may possibly be associated with the very high activity of m-THPC and also to the recent finding of a second peak in the p lasma pharmacokinetics of the drug.