Chemical formula: C₅H₉NO₃ Molecular mass: 131.13 g/mol PubChem compound: 137
Aminolevulinic acid is a natural biochemical precursor of heme that is metabolised in a series of enzymatic reactions to fluorescent porphyrins, particularly PPIX. Aminolevulinic acid synthesis is regulated by an intracellular pool of free heme via a negative feedback mechanism. Administration of excess exogenous aminolevulinic acid 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 aminolevulinic acid 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 multiforme, gliosarcoma or anaplastic astrocytoma) has also been demonstrated to synthesise and accumulate porphyrins in response to aminolevulinic acid 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, aminolevulinic acid 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. medulloblastoma, oligodendroglioma) no fluorescence could be observed after application of the active substance. Brain metastases revealed inconsistent or no fluorescence.
The phenomenon of PPIX accumulation in WHO grade III and IV malignant gliomas may be explained by higher aminolevulinic acid 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 aminolevulinic acid 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.
This medicinal product shows good solubility in aqueous solutions. After ingestion, aminolevulinic acid itself is not fluorescent but is taken up by tumour tissue and is intracellularily metabolised to fluorescent porphyrins, predominantly PPIX.
Aminolevulinic acid as drinking solution is rapidly and completely absorbed and peak plasma levels of aminolevulinic acid 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.
Aminolevulinic acid 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 aminolevulinic acid 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. Aminolevulinic acid is also taken up and metabolised to PPIX by other tissues, e.g. liver, kidneys or skin. Plasma protein binding of aminolevulinic acid is unknown.
Aminolevulinic acid 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 aminolevulinic acid values and different oral doses of this medicinal product.
Pharmacokinetics of aminolevulinic acid in patients with renal or liver impairment has not been investigated.
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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