Clinical pharmacology of oral psoralen drugs

Proper oral PUVA therapy includes the application of a psoralen drug and the administration of light, and both of these have to be adjusted to each other in regard to dose and timing. As psoralens are rather insoluble, it is difficult to produce pharmaceutical formulations which ensure safe and predictable absorption. A strong, saturable first pass effect occurs after oral intake of psoralens, resulting in a wide variability in plasma levels and thus also in phototoxicity. Phototoxicity seems to be slightly delayed compared to plasma levels in the absorption phase, but then persists much longer than plasma levels. Therefore irradiation should be done at or shortly after tmax of plasma levels. "Skin levels" seem to parallel plasma levels rather than the time course of cutaneous photosensitivity, which indicates that they do not represent drug concentration at the true site of action. Metabolism and first pass of TMP are very fast and thus oral intake does not result in significant plasma levels. Phototoxicity may, however, occur if TMP is administered as a solution. The present paper discusses clinically relevant aspects of psoralen drug pharmacokinetics, including absorption, distribution, metabolism and excretion. The shortcomings in the development of regimens for oral psoralen photochemotherapy are pointed out, and suggestions for further developments are given. Based on the pharmacokinetic data, recommendations are given for an improved performance of clinical psoralen photochemotherapy.