On the pharmacokinetics of topically applied 5-aminolevulinic acid and two of its esters

Moan, Johan Emelian; Wei, Li; Iani, Vladimir

doi:10.1002/1097-0215(200102)9999:9999<::aid-ijc1154>3.0.co;2-k

Cited by 78 publications

(76 citation statements)

References 8 publications

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“…ALA-esters, which are more lipophilic than ALA, 2 were introduced to get a deeper penetration and thus facilitate the treatment of larger tumors. [3][4][5] Porphyrins in biological samples, such as cells and skin, are often quantified by direct fluorescence readings. It is well known, however, that these dyes, notably lipophilic ones like PpIX, have a strong tendency to aggregate in aqueous solutions.…”

supporting

confidence: 93%

“…In mice, which have a thin stratum corneum and a thin epidermis, the present work indicates that significant amounts of topically applied ALA passes into the circulation to produce PpIX in organs remote from the area on which ALA was applied. We have earlier, by direct fluorescence readings, found that ALA goes systemically in mice and produces PpIX in remote skin spots, 3 in agreement with the present data (Figs. 1-4).…”

Section: Discussionmentioning

confidence: 56%

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Pharmacology of protoporphyrin IX in nude mice after application of ALA and ALA esters

Moan¹,

Wei²,

Juzeniene³

et al. 2002

Intl Journal of Cancer

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Aminolevulinic acid (ALA), ALA methylester (ALA-Me) and ALA hexylester (ALA-Hex) were topically applied for 5 and 20 hr, respectively, on normal skin of mice. The distribution of protoporphyrin IX (PpIX) induced in 7 different tissues by these drugs was determined either by spectrofluorometric measurements with an optical fibre probe or by chemical extraction of PpIX from the tissues. The results from these 2 types of measurements were compared. Both methods showed that ALA and the esters induced similar amounts of PpIX at the skin spot where they were applied and that the esters produced much less PpIX at remote skin spots (i.e., spots outside the location where the drugs were applied) than ALA did, notably after 20 hr application. After 20 hr of drug application ALA produced much more PpIX in liver, intestine and lungs than the esters did. In contrast with the direct fluorescence measurements, the extraction method showed detectable amounts of PpIX in liver, intestine and lung after application of the esters, notably of ALAMe. The discrepancy is probably related to the fact that the pigmented tissues absorb light and, therefore, the direct fluorescence readings are misleading. Notably in the liver, which contains high concentration of light-absorbing pigments, very weak direct fluorescence was seen. In no case there was any accumulation of PpIX in muscle tissue nor in brain. The esters seem to penetrate less into the circulation than ALA, and PpIX formed by them in the skin is faster cleared than PpIX formed from ALA. This is also true after oral and i.p. administration of the drugs. © 2002 Wiley-Liss, Inc. Key words: ALA; ALA-esters; pharmacology; PDT; protoporphyrin IXThe use of 5-aminolevulinic acid (ALA) for fluorescence detection (FD) and photodynamic therapy (PDT) of tumors has several advantages over traditional PDT, where photosensitizing dyes are injected intravenously or given orally. First, ALA can be applied topically because ALA molecules are small enough to penetrate the stratum corneum. 1 Second, ALA-induced protoporphyrin IX (PpIX) is cleared from the body more rapidly than other sensitizers, and, therefore, gives less and shorter lasting cutaneous photosensitization.A limitation of ALA-PDT is the shallow penetration of ALA into tissues. ALA-esters, which are more lipophilic than ALA, 2 were introduced to get a deeper penetration and thus facilitate the treatment of larger tumors. [3][4][5] Porphyrins in biological samples, such as cells and skin, are often quantified by direct fluorescence readings. It is well known, however, that these dyes, notably lipophilic ones like PpIX, have a strong tendency to aggregate in aqueous solutions. 6,7 Furthermore, the aggregates have much lower fluorescence quantum yields and photosensitizing efficiencies than monomers. 6 -8 Different degrees of aggregation may take place in different organs. This, in addition to different degrees of pigmentation, makes direct fluorescence measurements of limited value in pharmacological studies where concentration levels i...

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supporting

confidence: 93%

Section: Discussionmentioning

confidence: 56%

Pharmacology of protoporphyrin IX in nude mice after application of ALA and ALA esters

Moan¹,

Wei²,

Juzeniene³

et al. 2002

Intl Journal of Cancer

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“…It has also been observed that topical use of He-ALA restricts porphyrin accumulation to the site of application (Casas et al, 2001b;Moan et al, 2001), but the same intensity of PpIX fluorescence using lower concentrations of ALA esters compared to ALA was obtained in the tissue layers of normal rat colon (Endlicher et al, 2001). On the other hand, employing cell lines of different origins such as lung, bladder, glia, breast, lymphoma, leukemia, pancreas and colon among others (Luksiene et al, 2001;Casas and Batlle, 2002) porphyrin formation from He-ALA was not impaired, on the contrary it was highly increased by esterification of the ALA molecule.…”

Section: Discussionmentioning

confidence: 99%

ALA and ALA hexyl ester induction of porphyrins after their systemic administration to tumour bearing mice

et al. 2002

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The use of synthetic lipophilic molecules derived from 5-aminolevulinic acid (ALA) is currently under investigation to enhance cellular ALA penetration. In this work we studied the effect of systemic administration to mice of the hexyl ester of ALA (He-ALA) on porphyrin tissue synthesis as compared to ALA. In most normal tissues as well as in tumour, He-ALA induced less porphyrin synthesis than ALA after its systemic administration either intravenous or intraperitoneal, although explant organ cultures exposed to either ALA or He-ALA revealed equally active esterases. The only tissue that accumulated higher porphyrin levels from He-ALA (seven times more than ALA) was the brain, and this correlated well with a rapid increase in ALA/He-ALA content in brain after administration of He-ALA. This may be ascribed to a differential permeability to lipophilic substances controlled by the blood -brain barrier, a feature which could be further exploited to treat brain tumours.

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“…Moan et al (2001) studied the PpIX formation after topical application of ALA, ALA methyl ester and He-ALA on normal skin and on skin overlying a subcutaneous human colon adenocarcinoma. By means of an in vivo fluorescence signal from SOT measurements, they found that ALA induced the same levels of PpIX as compared to He-ALA applied in a 20% cream formulation, but in remote skin sites no fluorescence was detected.…”

Section: Discussionmentioning

confidence: 99%

“…On the other hand, topical use of ALA esters was not found to be better than ALA at increasing PpIX production, yet a surprisingly high photosensitiser selectivity was achieved (Peng et al, 1996;Casas et al, 2001b;Moan et al, 2001).…”

mentioning

confidence: 91%

Topical application of ALA and ALA hexyl ester on a subcutaneous murine mammary adenocarcinoma: tissue distribution

et al. 2003

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Although 5-aminolevulinic acid (ALA)-based photodynamic therapy (PDT) has proven to be clinically beneficial for the treatment of certain cancers, including a variety of skin cancers, optimal tissue localisation still remains a problem. An approach to improve the bioavailability of protoporphyrin IX (PpIX) is the use of ALA derivatives instead of ALA. In this work, we employed a subcutaneous murine mammary adenocarcinoma to study the tissue distribution pattern of the ALA hexyl ester (He-ALA) in comparison with ALA after their topical application in different vehicles. He-ALA induced porphyrin synthesis in the skin overlying the tumour (SOT), but it did not reach the tumour tissue as efficiently. Only 5 h after He-ALA lotion application, tumour porphyrin levels surpassed control values. He-ALA delivered in cream induced a substantially lower porphyrin synthesis in SOT, reinforcing the importance of the vehicle in the use of topical PDT. Porphyrin levels in internal organs remained almost within control values when He-ALA was employed. The addition of DMSO to ALA formulation slightly increased tumour and SOT porphyrin biosynthesis, but it did not when added to He-ALA lotion.

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On the pharmacokinetics of topically applied 5-aminolevulinic acid and two of its esters

Cited by 78 publications

References 8 publications

Pharmacology of protoporphyrin IX in nude mice after application of ALA and ALA esters

Pharmacology of protoporphyrin IX in nude mice after application of ALA and ALA esters

ALA and ALA hexyl ester induction of porphyrins after their systemic administration to tumour bearing mice

Topical application of ALA and ALA hexyl ester on a subcutaneous murine mammary adenocarcinoma: tissue distribution

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