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 than 100‐fold more photocytotoxic than Photofrin and many other drugs. The reasons for this are not yet known but are likely to be associated with the mechanism of uptake of the drug and its intratumoral and intracellular localization. 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 doses of sensitizer and administration solvent (diluant) gives rise to a protein‐binding pattern quite different to that of Photofrin and other hydrophobic drugs as judged by density‐gradient ultra centrifugation. Analysis of the binding immediately after addition to human plasma has shown that lipoprotein binding accounts for only a minor proportion of the sensitizer, which is mainly associated with a high‐density protein fraction that is not coincident with serum albumin. The m‐THPC protein complex does not fluoresce significantly even on dilution. This binding pattern is highly dependent on administration conditions and storage. Over a period of 6–8 h at 37°C the m‐THPC that is associated with this unidentified fraction redistributes to the plasma lipoproteins. Plasma collected from rats after intravenous administration of m‐THPC also contains this low fluorescent complex, showing that this phenomenon is not limited to human plasma and also occurs in vivo. It is postulated that the m‐THPC bound to the unknown protein fraction is highly aggregated and that it is likely to be taken up into tissues in this 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 plasma pharmacokinetics of the drug.