5-Aminolevulinic acid (ALA) is a precursor of protoporphyrin IX (PpIX) that is being evaluated for use in photodiagnosis and phototherapy of malignant and nonmalignant disorders. Previous clinical studies using topical, oral, and intravesical administration have been conducted in attempts to determine the optimal route of administration for ALA. The purpose of these studies was to examine the systemic pharmacokinetics and elimination of ALA, the bioavailability of ALA after oral and intravesical doses, and the factors that affect ALA concentrations in the bladder during intravesical treatment. The disposition of ALA was evaluated in six healthy volunteers receiving single intravenous and oral doses (100 mg) and eight patients at high risk for recurrent bladder cancer receiving an intravesical dose (1.328 g) of ALA. The mean (ϮS.D.) plasma area under the plasma concentration-time curve from time 0 to infinity of PpIX (0.20 Ϯ 0.11 g ⅐ h/ml) after intravenous administration of ALA was not significantly different from that observed after oral administration of ALA (0.15 Ϯ 0.11 g‫ء‬h/ml; P ϭ 0.49). ALA terminal half-life was approximately 45 min after intravenous or oral administration. The oral bioavailability of ALA was approximately 60%. After intravesical administration, urine production was largely responsible for decreases in ALA concentration in the bladder, with less than 1% being absorbed into the systemic circulation. In summary, oral and intravenous administration of ALA at these doses results in modest plasma levels of PpIX. Regional administration (i.e., intravesical) of ALA resulted in a significant pharmacokinetic advantage, with urinary bladder being exposed to concentrations approximately 20,000-fold higher than systemic circulation.

The method of surface-detected fluorescence has been used to monitor the emission intensity from 5-aminolaevulinic acid (ALA)-induced protoporphyrin IX (PpIX) in lesions and corresponding adjacent normal skin. Three types of lesions were examined: psoriatic plaques, actinic keratosis and basal cell carcinoma. This study included a total of 14 human volunteers on whom ALA-induced PpIX formation and clearance was monitored for a total of 48 h post-ALA application. Both an ALA dose-ranging study, as well as a comparison of results between normal and lesional tissue at a fixed ALA dose, were carried out. For the dose range examined (10-30%), there was no ALA dose dependency of the PpIX fluorescence for any of the lesions tested. Although all three lesions tested did show enhanced PpIX fluorescence as compared with normal skin, there was considerable lesion-to-lesion variability. Thick psoriatic plaques seem to give longer PpIX retention times than those of thin lesions. Limitations of the surface-detected fluorescence methodology are discussed.

Exogenous provision of 5-aminolevulinic acid (ALA) to many tissues results in the accumulation of sufficient quantities of the endogenous photosensitizer protoporphyrin IX (PpIX) via the heme biosynthetic pathway, to produce a photodynamic effect when exposed to activating light. Therefore, ALA may be considered the only current photodynamic therapy (PDT) agent in clinical development that is a biochemical precursor of a photosensitizer. Topical ALA application, followed by exposure to activating light (ALA PDT), has been reported effective for the treatment of a variety of dermatologic diseases including cutaneous superficial and nodular basal cell carcinoma, Bowen's disease, actinic (solar) keratoses, and T cell lymphoma. Local internal application of ALA has also been used for selective endometrial ablation in animal model systems and, in human clinical studies, it has shown selective formation of PpIX within the endometrium. PpIX induced by ALA application has also been used as a fluorescence detection marker for photodiagnosis (PD) of cancer and dysplastic conditions of the urinary bladder and other organs. Systemic, oral administration of ALA has been used for ALA PDT of superficial head and neck cancer, various gastrointestinal cancers, and the condition known as Barrett's esophagus. This paper reviews the current clinical and development status of ALA PDT and PD.

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