Chemical formula: C₅H₉NO₃ Molecular mass: 131.13 g/mol PubChem compound: 137
5-aminolevulinic acid (5-ALA) is a natural biochemical precursor of heme that is metabolised in a series of enzymatic reactions to fluorescent porphyrins, particularly PPIX. 5-ALA synthesis is regulated by an intracellular pool of free heme via a negative feedback mechanism. Administration of excess exogenous 5-ALA avoids the negative feedback control, and accumulation of PPIX occurs in target tissue. In the presence of visible light, fluorescence of PPIX (photodynamic effect) in certain target tissues can be used for photodynamic diagnosis.
Systemic administration of 5-aminolevulinic acid (5-ALA) results in an overload of the cellular porphyrin metabolism and accumulation of PPIX in various epithelia and cancer tissues. Malignant glioma tissue (WHO-grade III and IV, e.g. glioblastoma, gliosarcoma or anaplastic astrocytoma) has also been demonstrated to synthesise and accumulate porphyrins in response to 5-ALA administration. The concentration of PPIX is significantly lower in white matter than in cortex and tumour. Tissue surrounding the tumour and normal brain may also be affected. However, 5-ALA induced PPIX formation is significantly higher in malignant tissue than in normal brain.
In contrast, in low-grade tumours (WHO-grade I and II, e.g. oligodendroglioma) no fluorescence could be observed after application of the active substance. Medulloblastomas or brain metastases revealed inconsistent results or no fluorescence.
The phenomenon of PPIX accumulation in WHO grade III and IV malignant gliomas may be explained by higher 5-ALA uptake into the tumour tissue or an altered pattern of expression or activity of enzymes (e.g. ferrochelatase) involved in haemoglobin biosynthesis in tumour cells. Explanations for higher 5-ALA uptake include a disrupted blood-brain barrier, increased neo-vascularisation, and the overexpression of membrane transporters in glioma tissue.
After excitation with blue light (λ=400-410 nm), PPIX is strongly fluorescent (peak at λ=635 nm) and can be visualised after appropriate modifications to a standard neurosurgical microscope.
Fluorescence emission can be classified as intense (solid) red fluorescence (corresponds to vital, solid tumour tissue) and vague pink fluorescence (corresponds to infiltrating tumour cells), whereas normal brain tissue lacking enhanced PPIX levels reflects the violet-blue light and appears blue.
Following topical application of 5-aminolaevulinic acid (ALA), the substance is metabolized to protoporphyrin IX (PpIX), a photoactive compound which accumulates intracellularly in the treated lesions. PpIX is activated by illumination with light of a suitable wavelength and energy. In the presence of oxygen, reactive oxygen species are formed. The latter causes damage of cellular components and eventually destroys the target cells.
When ALA is used with the red-light PDT protocol, PpIX accumulates intracellularly in the target cells during incubation under light-tight dressing. The subsequent illumination activates the accumulated porphyrins and thus leads to phototoxicity for the light-exposed target cells.
When ALA is used with natural or artificial daylight PDT protocols, PpIX is continuously produced and activated within the target cells during light exposure, resulting in a constant micro-phototoxic effect. No occlusive dressing is necessary, but it can be used optionally during incubation for artificial daylight PDT.
PDT with artificial daylight devices showed comparable results to PDT with natural daylight. Artificial daylight PDT devices may vary in terms of specific light spectrum, irradiance and illumination time. The analysis of exemplary artificial daylight devices (i.e. MultiLite, Medisun PDT 9000, and indoorLux) indicated sufficient PpIX activation by all tested devices.
This medicinal product shows good solubility in aqueous solutions. After ingestion, 5-aminolevulinic acid (5-ALA) itself is not fluorescent but is taken up by tumour tissue and is intracellularly metabolised to fluorescent porphyrins, predominantly PPIX.
5-ALA as drinking solution is rapidly and completely absorbed and peak plasma levels of 5-ALA are reached 0.5–2 hours after oral administration of 20 mg/kg body weight. Plasma levels return to baseline values 24 hours after administration of an oral dose of 20 mg/kg body weight. The influence of food has not been investigated because this medicinal product is generally given on empty stomach prior to induction of anaesthesia.
5-ALA is preferentially taken up by the liver, kidney, endothelials and skin as well as by malignant gliomas (WHO grade III and IV) and metabolised to fluorescent PPIX. Four hours after oral administration of 20 mg/kg body weight 5-ALA HCl, the maximum PPIX plasma level is reached. PPIX plasma levels rapidly decline during the subsequent 20 hours and are not detectable anymore 48 hours after administration. At the recommended oral dose of 20 mg/kg body weight, tumour to normal brain fluorescence ratios are usually high and offer lucid contrast for visual perception of tumour tissue under violet-blue light for at least 9 hours.
Besides tumour tissue, faint fluorescence of the choroid plexus was reported. 5-ALA is also taken up and metabolised to PPIX by other tissues, e.g. liver, kidneys or skin. Plasma protein binding of 5-ALA is unknown.
5-ALA is eliminated quickly with a terminal half-life of 1-3 hours. Approximately 30% of an orally administered dose of 20 mg/kg body weight is excreted unchanged in urine within 12 hours.
There is dose proportionality between AUC0-inf of 5-ALA values and different oral doses of this medicinal product.
Pharmacokinetics of 5-ALA in patients with renal or liver impairment has not been investigated.
In vitro dermal absorption into human skin was studied using gel containing radiolabelled 5-aminolaevulinic acid (ALA). After 24 hours, the mean cumulative absorption (including accumulation in the dermis) through human skin was 0.2% of the administered dose. Corresponding studies in human skin with actinic keratosis lesions and/or roughened surface were not performed.
In a phase II clinical trial, 5-aminolaevulinic acid and protoporphyrin IX serum levels and ALA urine levels were measured before, 3 and 24 hours after administration of ALA for photodynamic treatment. None of the post-dose levels were increased in comparison to the naturally occurring pre-dose levels, showing absence of a relevant systemic absorption after topical administration.
A maximal use PK study was conducted in 12 patients bearing at least 10 mild to moderate AKs on the face or forehead. An entire tube of placebo and ALA followed by PDT was applied in a fixed sequence design with a washout period of 7 days to evaluate baseline and ALA dependent plasma concentrations of ALA and PpIX. In most patients an up to 2.5-fold increase of basic ALA plasma concentrations was observed during the first 3 hours after ALA application, which is still within the normal range of previously reported and published endogenous ALA concentrations. The plasma concentrations of metabolite PpIX were generally low in all patients and in none of the patients, an obvious increase of PpIX plasma concentrations was observed after ALA application.
Standard safety pharmacology experiments were performed under light protection in the mouse, rat and dog. Aminolevulinic acid administration does not influence the function of the gastrointestinal and central nervous system. A slight increase in saluresis cannot be excluded.
Single administration of high doses of aminolevulinic acid to mice or rats leads to unspecific findings of intolerance without macroscopic abnormalities or signs of delayed toxicity. Repeat-dose toxicity studies performed in rats and dogs demonstrate dose-dependent adverse reactions affecting changes in bile duct histology (non-reversible within a 14 day recovery period), transient increase in transaminases, LDH, total bilirubin, total cholesterol, creatinine, urea and vomiting (only in dogs). Signs of systemic toxicity (cardiovascular and respiratory parameters) occurred at higher doses in the anaesthetised dog: at 45 mg/kg body weight intravenously a slight decrease in peripheral arterial blood pressure and systolic left ventricular pressure was recorded. Five minutes after administration, the baseline values had been reached again. The cardiovascular effects seen are considered to be related to the intravenous route of administration.
Phototoxicity observed after aminolevulinic acid treatment in vitro and in vivo is obviously closely related to doseand time-dependent induction of PPIX synthesis in the irradiated cells or tissues. Destruction of sebaceous cells, focal epidermal necrosis with a transient acute inflammation and diffuse reactive changes in the keratinocytes as well as transient secondary oedema and inflammation of dermis are observed. Light exposed skin recovered completely except for a persistent reduction in the number of hair follicles. Accordingly, general light protective measures of eyes and skin are recommended for at least 24 hours after administration of this medicinal product.
Although pivotal studies on the reproductive and developmental behaviour of aminolevulinic acid have not been performed, it can be concluded that aminolevulinic acid induced porphyrin synthesis may lead to embryotoxic activity in mouse, rat and chick embryos only under the condition of direct concomitant light exposure. This medicinal product should, therefore, not be administered to pregnant women. Excessive single dose treatment of rats with aminolevulinic acid reversibly impaired male fertility for two weeks after dosing.
The majority of genotoxicity studies performed in the dark do not reveal a genotoxic potential of aminolevulinic acid. The compound potentially induces photogenotoxicity after subsequent irradiation or light exposure which is obviously related to the induction of porphyrin synthesis. Long-term in vivo carcinogenicity studies have not been conducted. However, considering the therapeutic indication, a single oral treatment with aminolevulinic acid might not be related to any serious potential carcinogenic risk.
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