Clinical Pharmacokinetics of 5-Aminolevulinic Acid in Healthy Volunteers and Patients at High Risk for Recurrent Bladder Cancer

Abstract

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.

5-Aminolevulinic acid combined with ferrous iron induces carbon monoxide generation in mouse kidneys and protects from renal ischemia-reperfusion injury

“…Sections were scored with a semiquantitative scale designed to evaluate changes in the kidney 24 h after IRI. Histological changes were mainly evaluated by quantitative measurement of the tubular injury by assessing specific variables in 10 individual high-power fields (magnification: (10,30, or 100 mg/kg) or DW after clamping of the renal pedicles for 45 min. The survival of mice was observed for Ͼ7 days.…”

Tunable phosphatase-sensitive stable prodrugs of 5-aminolevulinic acid for tumor fluorescence photodetection

“…The resulting polarity, thus, limits 5-ALA's ability to pass biological barriers. This, along with its short half-life, small volume of distribution and accumulation in the liver and kidneys [16], makes 5-ALA non suitable for systemic administration [17]. To overcome these shortcomings, different strategies aimed at improving the drug-likeness and the pharmacokinetic profile have been employed.…”

Next Generation intraoperative Lymph node staging for Stratified colon cancer surgery (GLiSten): a multicentre, multinational feasibility study of fluorescence in predicting lymph node-positive disease

“…Plasma 5-ALA concentrations declined with a terminal half-life of approximately 45 minutes. 43 In neurosurgery, a randomised controlled Phase III multicentre trial 36 was performed to investigate the safety and efficacy of fluorescence-guided resection in malignant gliomas. The study involved oral administration of 5-ALA (20 mg/kg) 3 hours (range 2-4 hours) before induction of anaesthesia.…”