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Skin penetration from the inside to the outside: A review
Drug Discovery Today: Disease Mechanisms
Vol. 5, No. 2 2008
Editors-in-Chief Toren Finkel – National Heart, Lung and Blood Institute, National Institutes of Health, USA Charles Lowenstein – The John Hopkins School of Medicine, Baltimore, USA
DRUG DISCOVERY
TODAY
DISEASE Common skin conditions and disorders MECHANISMS
Skin penetration from the inside to the outside: A review Alexa Patzelt1,*, Christina Antoniou2, Wolfram Sterry1, Ju¨rgen Lademann1 1 2
Department of Dermatology, Charite´ – Universitaetsmedizin Berlin, 10117 Berlin, Germany Department of Dermatology & Venerology, A. Sygros Hospital, Athens, Greece
The penetration pathways of topically applied sub-
penetration. Theoretical inverse penetration routes
stances into the skin have been investigated extensively
include the intercellular, the follicular, and the intra-
over the past years. There is a general agreement that
cellular routes, as well as transport via the sebaceous
the intercellular penetration pathway is of highest
glands or via desquamation, as mentioned above.
importance, followed by the follicular penetration
By reviewing the available literature, it could be
pathway.
assessed that lipophilic substances tend to utilize the
The
intracellular
penetration
pathway
appears to be negligible.
flow of sebum to the skin surface as an inverse pene-
By contrast, the inverse penetration pathways of sys-
tration pathway, whereas hydrophilic substances
temically administered substances into the skin or onto
rather reach the skin via the sweat. The results further
the skin surface have not received much attention. As
indicate that the substances penetrate back into the
the epidermis does not contain blood vessels, systemi-
skin after they reach the skin surface, as if applied
cally administered substances must use other trans-
topically. This is evidenced by the fact that higher
port mechanisms for crossing the epidermis, but these
concentrations of test substances were found in the
are still largely unknown.
stratum corneum in comparison to lower skin layers.
For a long time, it was assumed that desquamation
While inverse intercellular penetration and the process
could provide an explanation for inverse penetration.
of desquamation must still be considered as possible
Substances were thought to reach the basal cell layer
inverse penetration pathways, they appear to be of
from the circulation system via diffusion, and then to be
lesser importance.
slowly transported towards the skin surface within the keratinizing and cornifying cells. This process of skin renewal is known to take approximately 3–4 weeks, which is in contrast to recent evidence suggesting that systemically administered substances are able to reach the skin within hours of application. This indicates that other explanations must exist for the process of inverse *Corresponding author: A. Patzelt ([email protected]) 1740-6765/$ ß 2008 Elsevier Ltd. All rights reserved.
DOI: 10.1016/j.ddmec.2008.05.002
Section Editor: Michael Roberts – School of Medicine, University of Queensland, Australia Protection shield skin Providing a protective barrier at the interface between the hostile external environment and the organism is a major function of the skin [1]. According to Elias et al. [2], most epidermal functions can be considered protective and most of e229
Drug Discovery Today: Disease Mechanisms | Common skin conditions and disorders
the protective functions are localized to the stratum corneum. The dermal protective barrier operates in two directions: on the one hand, the skin protects against external influences such as mechanical, physical and chemical damages including light [3]. On the other hand, the skin forms a permeability barrier that impedes transcutaneous water loss [4], and maintains the homeostasis of the body [3]. Therefore, also the inverse penetration of systemically administered substances to the skin surface is impeded by this natural barrier.
Penetration pathways from the outside to the inside Nevertheless, the skin does not represent a complete barrier, but allows the ingress of topical substances. Three possible penetration pathways of topically applied substances into the skin are well accepted: (1) the intercellular; (2) the follicular; and (3) the intracellular routes. The relevance of these routes for percutaneous absorption of compounds depends upon their frequency (area) and path length, as well as the diffusivity and solubility of the compound in each domain [5]. Concerning intercellular penetration, which is commonly assumed to represent the most important penetration pathway [6,7], Bos et al. [8] proposed the 500 Da rule for skin penetration of chemical compounds and drugs. They argued that only molecules smaller than 500 Da are able to penetrate the skin. The basis of their assumption was that virtually all common contact allergens as well as commonly used dermatopharmaceutics and topical drugs have a molecular weight smaller than 500 Da. Although, this may be only valid for intercellular penetration. By contrast, for the follicular penetration pathway, Lademann et al. [9,10] observed that nanoparticles with a size of 320 nm showed a highly efficient follicular penetration in comparison to non-particulate, molecular-sized substances. Moreover, the hair follicles were shown to serve as long-term reservoirs for drug delivery [10], and to enable faster penetration than the intercellular pathway [11]. The intracellular penetration pathway is a pathway of diffusion, which is important for the penetration of water [12], but obviously not for other topical substances.
Penetration pathways from the inside to the outside In contrast to the well-studied penetration pathways of topically applied substances into the skin, the penetration pathways of systemically administered substances to the skin have rarely been investigated. This is of interest in the dermatological field, as a multiplicity of pharmaceutics are administered systemically to address skin disorders, indicating that these substances must reach the skin or the skin surface via ‘inverse penetration’ pathways. If a substance is administered systemically, it then reaches the blood system and hereby all organs that are supplied by blood vessels. Although the skin is supplied by the blood e230
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system as well, the blood vessels only reach the papillae of the dermis and have no direct contact to the skin surface. While it is widely known that systemically administered substances are able to reach the skin surface, it is not clear which inverse penetration pathways are utilized for this purpose.
Theoretical penetration pathways Hypothetically, five possible ‘inverse’ penetration pathways exist. The same pathways which are utilized by topically applied substances into the skin can also be considered for ‘inverse penetration’, the (1) intercellular, the (2) follicular and the (3) intracellular routes. Moreover, the (4) sweat glands/sweat ducts may represent potential inverse penetration pathways, in addition to the process of (5) desquamation.
Systemically administered skin treatments High numbers of treatment options are associated with a multiplicity of skin disorders. A plurality of dermatological diseases can be treated with topical substances. The most commonly applied substances include topical steroids [13], topical antibiotics [14], antimycotics [15], vitamin D3 analogs [16], retinoids [17], tars [18], anthralin [19], keratolytics [20] and topical immunomodulators [21]. However, certain severe forms of skin diseases also require systemic treatment, which must penetrate to the skin from the circulatory system. In the following, an overview is given regarding those substances, for which postulations about their inverse penetration pathways exist. Available results for these substances are summarized in Table 1. Based on the results found, conclusions will be drawn regarding the mechanisms of inverse penetration.
Antimicrobial substances Local treatment is often insufficient for infectious diseases, and these are therefore often treated systemically. It is particularly crucial in these cases to ensure that drugs reach the target organs. Ivermectin
Investigations on the inverse penetration process of ivermectin have recently been conducted. Since 1991, ivermectin has been utilized in the therapy of scabies. Until now, it was assumed that the drug is delivered to the tunnelling mites via ingested intraepidermal fluids, and that the fertile mites die after a single oral dose, whereas the larvae require a second dose 10–14 days later [22]. As the immature mites are known to move over the body at night, it was assumed that they might take up the drug from the skin surface [22]. This was indicated by the fact that in 70–90% of cases, a single dose of ivermectin is sufficient to cure scabies [23]. Haas et al. [24] utilized ion mobility spectrometry to investigate the skin surface of five patients suffering from scabies after a single
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Drug Discovery Today: Disease Mechanisms | Common skin conditions and disorders
Table 1. Systemically administered substances and their recovery in the skin Substances
Characterization Serum/plasma level Sebum
Sweat
Skin
Ivermectin 200 mg/kg single dose after 8 h [24]
Lipophilic
52 ng/ml (after 5.2 h and 150 mg/kg) [51]
ND
ND
Skin surface: Seborrhoic area: 39.2 40.2 mg/kg Non-seborrhoic area: 25.9 11.2 mg/kg
Terbinafine 250 mg/day after 14 day [25]
Lipophilic
1.46 mg/ml
21.83 mg/g
0.0 (after 12 days) [28]
Epidermis–dermis (back): 2.0 mg/g Stratum corneum (back): 7.63 mg/g
Itraconazole 200 mg/day after 7 day [26]
Lipophilic
0.49 mg/ml
4.64 mg/ml
0.072 mg/ml
Stratum corneum: Palms: 0.053 mg/ml Beard: 0.444 mg/ml Back: 0.389 mg/ml
Griseofulvin [32]
Lipophilic
2 mg/ml
ND
0.2–0.3 mg/ml
Outermost level I: 20.8 1.5 ng/mg Level II: 10.0 1.5 ng/mg Innermost level III: 7.5 2.2 ng/mg
Ketoconazole 200 mg/day after 14 day [31]
Lipophilic
7.87 4.72 mg/ml
0.0 mg/ml
0.084 mg/ml
Stratum corneum (palmar): 5.18 6.0 mg/g
Fluconazole 50 mg/day after 12 day [34]
Hydrophilic
1.81 mg/ml
ND
4.89 mg/ml
Epidermis–dermis (back): 2.93 mg/g Stratum corneum (back): 66.4 mg/g
Ofloxacin 400 mg single dose [36]
Hydrophilic
9.26 mmol/l after 1.7 h ND
ND
Cutaneous microdialysate 4.16 mmol/l Theoretical peripheral compartment: 4.5 mmol/l
Doxorubicin 20 to 25 mg/m2 Hydrophilic every 2 weeks, 6 cycles [39]
ND
ND
Qualitative detection In sweat ducts
Detection of fluorescence in stratum corneum – qualtitative detection of doxorubicin
5-MOP 1.2 mg/kg single dose after 3 h [43]
Lipophilic
0.38 0.16 mg/ml
ND
ND
Percentage of administered 5-MOP in the skin assumed average body surface area of 1.8 m2: 59 15%
Ethanol 31.2 g ethanol [44]
Hydrophilic
0.74 g/l after 40 min
Indirectly determined by sealing the hair follicles No significant difference to unsealed follicles
Indirectly determined by sealing the sweat ducts – no significant differences to unsealed sweat ducts
Skin surface
ND
ND
Skin surface Amount of TCDD eliminated daily via the skin surface of the total body burden: 0.003–0.004%
TCDD 6 months after intoxication [45]
Lipophilic
Patient 1: 80.900 pg/g Patient 2: 16.100 pg/g
oral dose of ivermectin (200 mg/kg). Because of the lipophilicity of ivermectin, the authors distinguished between seborrhoic (high density of sebaceous glands) and non-seborrhoic (lower density of sebaceous glands) skin sites. They found significantly
Forehead: significantly higher concentration of ethanol than in the region of the forearm
higher concentrations of ivermectin in seborrhoic skin areas in comparison to non-seborrhoic areas, and therefore concluded a fast and preferential elimination via the sebum. An additional elimination process via the sweat was discussed. www.drugdiscoverytoday.com
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Antimycotics
Sebum is considered to be a highly important inverse penetration pathway for terbinafine [25] and itraconazol [26]. When given orally, terbinafine, a lipophilic substance [15], is absorbed and rapidly distributed to the skin and sebum in concentrations that exceed the minimum inhibitory concentrations [27]. In the study by Faergemann et al. [25], levels of terbinafine were studied in the plasma, stratum corneum, dermis–epidermis, sebum and hair during and after the daily systemic application of 250 mg terbinafine for one and two weeks. For both study designs, the authors found the highest concentrations of terbinafine in the sebum, and the second highest concentration in the stratum corneum. Levels of terbinafine in the plasma and the epidermis–dermis were significantly lower. These results are in concordance with earlier studies of Faergemann et al. [28,29], where the highest concentrations of terbinafine were also found in sebum and in the stratum corneum. No terbinafine was found in the sweat. Similar results were obtained for itraconazole (lipophilic [30]) [26]. Highest concentrations of itraconazole were found in the sebum, followed by the stratum corneum. The authors also investigated different skin sites, and detected higher concentrations in the beard region and on the back, in comparison to the palmar stratum corneum, although itraconazol was detectable in this region for a longer time period. Only very low amounts of itraconazole were found in the sweat. Therefore, the authors assumed at least three routes of delivery of itraconazol to the skin: (1) desquamation because of the long-time presence of itraconazole in the palmar stratum corneum, (2) a less significant excretion through the sweat glands and (3) a massive excretion through the sebaceous glands. Ketoconazole [31] and griseofulvin [32] also represent lipophilic antimycotic substances. Both substances could not be detected in the sebum except for ketoconazole, which could be collected from patients on prolonged ketoconazole therapy. Both substances emerged with the sweat. Based on their results, Harris et al. [31] discussed four possible routes with which ketoconazole can reach the stratum corneum, and divided these into slow and rapid routes. As slow inverse penetration processes, desquamation as well as sebum excretion were proposed. The authors indicated that the production and transport of the sebum to the skin surface takes about 3–4 weeks. As rapid inverse penetration pathways, the intercellular pathway and delivery with the sweat were suggested. The authors concluded that similar to the findings for griseofulvin [32], ketoconazol is delivered to the skin surface mostly via the sweat, after which it is readily partitioned from the fluid phase of the sweat to the keratinocytes, hairs, nails, and sebum. Fluconazole, on the contrary, is a hydrophilic azole [30]. At least two articles are available that address the bioavailabilty e232
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of fluconazole in the skin subsequent to oral application. Wildfeuer et al. [33] found the highest concentration of fluconazole in the stratum corneum, the second highest concentration in the sweat, followed by the dermis–epidermis and the serum. Results of the same nature were found by Faergemann et al. [34]. The authors discussed the diffusion routes through the epidermis–dermis, the desquamation process and the sebum and sweat secretion as possible inverse penetration pathways. They concluded that the intercellular pathway as well as the pathway via the sweat may be of highest relevance. Antibiotics
Ofloxacin represents, according to its log P of 0.1, a hydrophilic antibiotic drug [35]. Bielecka-Grzela et al. [36] evaluated the ofloxacin penetration into the skin. They found significantly lower concentrations of ofloxacin in the skin in comparison to the plasma. Apart from antimicrobial substances, few other systemically administered substances provided information about their pathway to the skin.
Chemotherapeutics Doxorubicin is a hydrophilic cytostatic drug with fluorescent properties, frequently utilized against solid and angiomatous tumours [37]. It is not primarily a dermatological drug. Nevertheless, doxorubicin often induces severe and doselimiting side effects affecting the skin, which are known as palmar–plantar erythrodysaesthesia (PPE) [38]. The pathogenesis of this disease indicates that doxorubicin reaches the skin. Jacobi et al. [39] used laser scanning microscopy to measure the skin surface of patients receiving doxorubicin via infusions. Using kinetic laser scanning microscopy measurements, the authors demonstrated that the sweat functioned as a carrier of doxorubicin to the skin surface, and that subsequently, the sweat containing the drug penetrated into the stratum corneum and into deeper skin layers. The preference of PPE occurring in the region of the palms and plants may be explained by the increased stratum corneum reservoir in these body regions [40].
5-Methoxypsoralon (5-MOP) Photochemotherapy with 5-methoxypsoralon plus ultraviolet A light irradiation is an effective treatment for several skin diseases. In earlier studies, the skin blister fluid technique was utilized to measure the interstitial fluid concentration of 5MOP. Depending on the time of blister formation, the 5-MOP concentration in skin blister fluid was 25–50% that of the plasma concentration [41,42]. On the contrary, Zucchi et al. [43] studied the 5-MOP skin distribution by measuring its content in 20 mm thick skin slices, and observed that the drug content was higher in external slices and decreased exponentially from the stratum
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corneum towards the dermis. They concluded that this result was owing to the reported high affinity of 5-MOP for the skin. The authors calculated that after 3 h, 59 15% of the administered dose were present in the skin and therefore higher concentrations of 5-MOP were present in the skin than in plasma.
Ethanol Ethanol intake is also associated with a variety of skin diseases [44]. Jacobi et al. conducted a study to identify the release pathways of orally administered ethanol through the skin. For ethanol, they found that the pathways via the sweat channels and follicles were of minor importance, and assumed that the main pathway of ethanol emission was most likely via the lipid layers. They suggested that ethanol interacted with the skin lipids, as indicated in penetration studies where ethanol was applied topically.
2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) TCDD is the most toxic of the polychlorinated aromatic compounds, and is a by-product of certain industrial processes and combustion [45]. Owing to its high lipophilicity, TCDD accumulates in adipose tissue and is slowly metabolized [46]. There are no established treatment strategies for TCDD detoxification. Faecal excretion seems to be an important pathway; elimination via breast milk and via skin lipids has also been discussed. Indications for a continuous elimination of TCDD via the skin were found with 0.003–0.004% of the total body burden. This could be increased to 0.006% when petrolatum was applied. As the skin lipids are derived largely from sebaceous glands and to a lesser extent from desquamating corneocytes in intact skin, the authors [46] assumed that both processes could contribute to the elimination of TCDD from the organism.
Mechanism of inverse penetration The evidence provided by the results and postulations of the reviewed articles clearly indicates that lipophilic substances reach the skin surface via the sebum, while hydrophilic substances utilize the sweat for delivery to the skin surface. This was shown for the lipophilic ivermectin, which was found in significantly higher concentrations in seborrhoic skin areas [24], as well as for the lipophilic antimycotics terbinafine [25] and itraconazole [26]. For these substances, the highest concentrations were found in the sebum, followed by the stratum corneum, while lower concentrations were found in deeper skin layers. These results suggest that terbinafine and itraconazole are delivered to the skin surface via the sebum, and then penetrate back into the stratum corneum as if applied topically. The substances ivermectin, terbinafine and itraconazole are lipophilic, leading to inverse penetration via the sebum.
Drug Discovery Today: Disease Mechanisms | Common skin conditions and disorders
For lipophilic 5-methoxypsoralon, higher concentrations were present in the skin in comparison to the plasma, which again disagrees with the assumption that the substance mainly uses the intercellular penetration pathway for inverse penetration, as higher concentrations were found in external skin sites. Although no data was available, inverse penetration via the sebum may play a role, as 5-MOP is also a lipophilic substance [48]. Ketoconazole [31] and griseofulvin [32] are also lipophilic antimycotic substances. Therefore, at least for ketoconazole, drug delivery via the sebum has been suggested [31]. Astonishingly, both substances could not be detected in the sebum. Both substances emerged in the sweat. This effect can be explained by considering the metabolism of both substances. Ketoconazole is readily absorbed after conversion to the water-soluble salt by gastric acid [31]. In griseofulvin, a methyl group is replaced by hydrogen at one of the methyl groups [49]. In this way, the major metabolite 6-demethylgriseofulvin originates, which is mainly eliminated by the urine, indicating an increased hydrophilicity. Therefore, both substances are hydrophilic after metabolism, which provides an explanation for the increased detection in the sweat in comparison to the sebum. The highest concentrations of the hydrophilic fluconazole were likewise detected in the stratum corneum und the sweat [34]. For doxorubicin, the emerging of fluorescence out of the sweat duct could be visualized by laser scanning microscopy [39]. On the contrary, significantly lower concentrations were detected for ofloxacin in the skin in comparison to the plasma [36]. This is contradictory to the preceding results of the other hydrophilic substances, which showed increased concentrations in the skin in comparison to the plasma. This deviation could be explained by the ineptitude of the method of microdialysis for this type of investigation. Assuming that ofloxacin also prefers the inverse penetration via the sweat as in the other cases of hydrophilic substances higher concentrations should be found in the stratum corneum und decreasing concentrations in the lower layers of the skin. Unfortunately, microdialysis only measures intradermal concentrations, and no information is therefore available about concentrations in the upper skin layers. The results obtained by microdialysis may thus not reflect the concentrations present in the skin. Some results suggest that additional inverse penetration pathways, such as the intercellular inverse penetration pathway and the process of desquamation, also exist. Ethanol obviously prefers inverse penetration via the intercellular pathway, in spite of its hydrophilicity. This may be owing to the interactions between ethanol and the skin lipids. Another explanation could be the low molecular size of ethanol, which may facilitate intercellular penetration for this substance. Moreover, the results could also be www.drugdiscoverytoday.com
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time-dependent. For topically applied caffeine, for example, it was shown that the hair follicles represent fast penetration pathways, while the intercellular pathway became effective only after about 20 min [11,50]. Previously, the process of desquamation was frequently assumed to be an important pathway for inverse penetration. It was supposed that after systemic application and distribution via the blood, the substances are incorporated into the cells of the basal cell layer, which move towards the surface, keratinize, cornify and reach the skin surface over a period of 3– 4 weeks [31]. Since it is now known that the substances reach the skin surface within hours, this route must be reconsidered. By reviewing the available literature, desquamation may be a possible detoxification pathway of 2,3,7,8-tetrachlordibenzop-dioxin, in addition to the sebum excretion pathway.
Conclusion It can conclusively be assumed that four of the described theoretical inverse penetration pathways are of relevance for the penetration of systemically administered substances to the skin or skin surface. 1. Inverse penetration via the sebum represents an important and efficient route mainly for lipophilic substances. 2. On the contrary, inverse penetration via the sweat appears to be of high relevance for hydrophilic substances as well as for the hydrophilic metabolites of lipophilic substances. The sweat and the sebum are physiological substances with which systemically administered substances are delivered to the skin and distributed onto the skin surface. Subsequently, they penetrate back into the skin, as if applied topically. 3. Inverse intercellular penetration is probably of lesser relevance as higher concentrations of the systemically administered substances were found in the superior layers. Nevertheless, for some substances such as ethanol, this penetration pathway seems to be important. Possible explanations might be the low molecular size of ethanol and the good solvent properties of ethanol. 4. Desquamation also seems to be of lesser importance than was previously believed. It is important to note, however, that this process may contribute to the inverse penetration of certain systemically administered substances. 5. For inverse intracellular penetration, no indications could be found in the literature.
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Editors-in-Chief Toren Finkel – National Heart, Lung and Blood Institute, National Institutes of Health, USA Charles Lowenstein – The John Hopkins School of Medicine, Baltimore, USA
DRUG DISCOVERY
TODAY
DISEASE Common skin conditions and disorders MECHANISMS
Skin penetration from the inside to the outside: A review Alexa Patzelt1,*, Christina Antoniou2, Wolfram Sterry1, Ju¨rgen Lademann1 1 2
Department of Dermatology, Charite´ – Universitaetsmedizin Berlin, 10117 Berlin, Germany Department of Dermatology & Venerology, A. Sygros Hospital, Athens, Greece
The penetration pathways of topically applied sub-
penetration. Theoretical inverse penetration routes
stances into the skin have been investigated extensively
include the intercellular, the follicular, and the intra-
over the past years. There is a general agreement that
cellular routes, as well as transport via the sebaceous
the intercellular penetration pathway is of highest
glands or via desquamation, as mentioned above.
importance, followed by the follicular penetration
By reviewing the available literature, it could be
pathway.
assessed that lipophilic substances tend to utilize the
The
intracellular
penetration
pathway
appears to be negligible.
flow of sebum to the skin surface as an inverse pene-
By contrast, the inverse penetration pathways of sys-
tration pathway, whereas hydrophilic substances
temically administered substances into the skin or onto
rather reach the skin via the sweat. The results further
the skin surface have not received much attention. As
indicate that the substances penetrate back into the
the epidermis does not contain blood vessels, systemi-
skin after they reach the skin surface, as if applied
cally administered substances must use other trans-
topically. This is evidenced by the fact that higher
port mechanisms for crossing the epidermis, but these
concentrations of test substances were found in the
are still largely unknown.
stratum corneum in comparison to lower skin layers.
For a long time, it was assumed that desquamation
While inverse intercellular penetration and the process
could provide an explanation for inverse penetration.
of desquamation must still be considered as possible
Substances were thought to reach the basal cell layer
inverse penetration pathways, they appear to be of
from the circulation system via diffusion, and then to be
lesser importance.
slowly transported towards the skin surface within the keratinizing and cornifying cells. This process of skin renewal is known to take approximately 3–4 weeks, which is in contrast to recent evidence suggesting that systemically administered substances are able to reach the skin within hours of application. This indicates that other explanations must exist for the process of inverse *Corresponding author: A. Patzelt ([email protected]) 1740-6765/$ ß 2008 Elsevier Ltd. All rights reserved.
DOI: 10.1016/j.ddmec.2008.05.002
Section Editor: Michael Roberts – School of Medicine, University of Queensland, Australia Protection shield skin Providing a protective barrier at the interface between the hostile external environment and the organism is a major function of the skin [1]. According to Elias et al. [2], most epidermal functions can be considered protective and most of e229
Drug Discovery Today: Disease Mechanisms | Common skin conditions and disorders
the protective functions are localized to the stratum corneum. The dermal protective barrier operates in two directions: on the one hand, the skin protects against external influences such as mechanical, physical and chemical damages including light [3]. On the other hand, the skin forms a permeability barrier that impedes transcutaneous water loss [4], and maintains the homeostasis of the body [3]. Therefore, also the inverse penetration of systemically administered substances to the skin surface is impeded by this natural barrier.
Penetration pathways from the outside to the inside Nevertheless, the skin does not represent a complete barrier, but allows the ingress of topical substances. Three possible penetration pathways of topically applied substances into the skin are well accepted: (1) the intercellular; (2) the follicular; and (3) the intracellular routes. The relevance of these routes for percutaneous absorption of compounds depends upon their frequency (area) and path length, as well as the diffusivity and solubility of the compound in each domain [5]. Concerning intercellular penetration, which is commonly assumed to represent the most important penetration pathway [6,7], Bos et al. [8] proposed the 500 Da rule for skin penetration of chemical compounds and drugs. They argued that only molecules smaller than 500 Da are able to penetrate the skin. The basis of their assumption was that virtually all common contact allergens as well as commonly used dermatopharmaceutics and topical drugs have a molecular weight smaller than 500 Da. Although, this may be only valid for intercellular penetration. By contrast, for the follicular penetration pathway, Lademann et al. [9,10] observed that nanoparticles with a size of 320 nm showed a highly efficient follicular penetration in comparison to non-particulate, molecular-sized substances. Moreover, the hair follicles were shown to serve as long-term reservoirs for drug delivery [10], and to enable faster penetration than the intercellular pathway [11]. The intracellular penetration pathway is a pathway of diffusion, which is important for the penetration of water [12], but obviously not for other topical substances.
Penetration pathways from the inside to the outside In contrast to the well-studied penetration pathways of topically applied substances into the skin, the penetration pathways of systemically administered substances to the skin have rarely been investigated. This is of interest in the dermatological field, as a multiplicity of pharmaceutics are administered systemically to address skin disorders, indicating that these substances must reach the skin or the skin surface via ‘inverse penetration’ pathways. If a substance is administered systemically, it then reaches the blood system and hereby all organs that are supplied by blood vessels. Although the skin is supplied by the blood e230
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system as well, the blood vessels only reach the papillae of the dermis and have no direct contact to the skin surface. While it is widely known that systemically administered substances are able to reach the skin surface, it is not clear which inverse penetration pathways are utilized for this purpose.
Theoretical penetration pathways Hypothetically, five possible ‘inverse’ penetration pathways exist. The same pathways which are utilized by topically applied substances into the skin can also be considered for ‘inverse penetration’, the (1) intercellular, the (2) follicular and the (3) intracellular routes. Moreover, the (4) sweat glands/sweat ducts may represent potential inverse penetration pathways, in addition to the process of (5) desquamation.
Systemically administered skin treatments High numbers of treatment options are associated with a multiplicity of skin disorders. A plurality of dermatological diseases can be treated with topical substances. The most commonly applied substances include topical steroids [13], topical antibiotics [14], antimycotics [15], vitamin D3 analogs [16], retinoids [17], tars [18], anthralin [19], keratolytics [20] and topical immunomodulators [21]. However, certain severe forms of skin diseases also require systemic treatment, which must penetrate to the skin from the circulatory system. In the following, an overview is given regarding those substances, for which postulations about their inverse penetration pathways exist. Available results for these substances are summarized in Table 1. Based on the results found, conclusions will be drawn regarding the mechanisms of inverse penetration.
Antimicrobial substances Local treatment is often insufficient for infectious diseases, and these are therefore often treated systemically. It is particularly crucial in these cases to ensure that drugs reach the target organs. Ivermectin
Investigations on the inverse penetration process of ivermectin have recently been conducted. Since 1991, ivermectin has been utilized in the therapy of scabies. Until now, it was assumed that the drug is delivered to the tunnelling mites via ingested intraepidermal fluids, and that the fertile mites die after a single oral dose, whereas the larvae require a second dose 10–14 days later [22]. As the immature mites are known to move over the body at night, it was assumed that they might take up the drug from the skin surface [22]. This was indicated by the fact that in 70–90% of cases, a single dose of ivermectin is sufficient to cure scabies [23]. Haas et al. [24] utilized ion mobility spectrometry to investigate the skin surface of five patients suffering from scabies after a single
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Drug Discovery Today: Disease Mechanisms | Common skin conditions and disorders
Table 1. Systemically administered substances and their recovery in the skin Substances
Characterization Serum/plasma level Sebum
Sweat
Skin
Ivermectin 200 mg/kg single dose after 8 h [24]
Lipophilic
52 ng/ml (after 5.2 h and 150 mg/kg) [51]
ND
ND
Skin surface: Seborrhoic area: 39.2 40.2 mg/kg Non-seborrhoic area: 25.9 11.2 mg/kg
Terbinafine 250 mg/day after 14 day [25]
Lipophilic
1.46 mg/ml
21.83 mg/g
0.0 (after 12 days) [28]
Epidermis–dermis (back): 2.0 mg/g Stratum corneum (back): 7.63 mg/g
Itraconazole 200 mg/day after 7 day [26]
Lipophilic
0.49 mg/ml
4.64 mg/ml
0.072 mg/ml
Stratum corneum: Palms: 0.053 mg/ml Beard: 0.444 mg/ml Back: 0.389 mg/ml
Griseofulvin [32]
Lipophilic
2 mg/ml
ND
0.2–0.3 mg/ml
Outermost level I: 20.8 1.5 ng/mg Level II: 10.0 1.5 ng/mg Innermost level III: 7.5 2.2 ng/mg
Ketoconazole 200 mg/day after 14 day [31]
Lipophilic
7.87 4.72 mg/ml
0.0 mg/ml
0.084 mg/ml
Stratum corneum (palmar): 5.18 6.0 mg/g
Fluconazole 50 mg/day after 12 day [34]
Hydrophilic
1.81 mg/ml
ND
4.89 mg/ml
Epidermis–dermis (back): 2.93 mg/g Stratum corneum (back): 66.4 mg/g
Ofloxacin 400 mg single dose [36]
Hydrophilic
9.26 mmol/l after 1.7 h ND
ND
Cutaneous microdialysate 4.16 mmol/l Theoretical peripheral compartment: 4.5 mmol/l
Doxorubicin 20 to 25 mg/m2 Hydrophilic every 2 weeks, 6 cycles [39]
ND
ND
Qualitative detection In sweat ducts
Detection of fluorescence in stratum corneum – qualtitative detection of doxorubicin
5-MOP 1.2 mg/kg single dose after 3 h [43]
Lipophilic
0.38 0.16 mg/ml
ND
ND
Percentage of administered 5-MOP in the skin assumed average body surface area of 1.8 m2: 59 15%
Ethanol 31.2 g ethanol [44]
Hydrophilic
0.74 g/l after 40 min
Indirectly determined by sealing the hair follicles No significant difference to unsealed follicles
Indirectly determined by sealing the sweat ducts – no significant differences to unsealed sweat ducts
Skin surface
ND
ND
Skin surface Amount of TCDD eliminated daily via the skin surface of the total body burden: 0.003–0.004%
TCDD 6 months after intoxication [45]
Lipophilic
Patient 1: 80.900 pg/g Patient 2: 16.100 pg/g
oral dose of ivermectin (200 mg/kg). Because of the lipophilicity of ivermectin, the authors distinguished between seborrhoic (high density of sebaceous glands) and non-seborrhoic (lower density of sebaceous glands) skin sites. They found significantly
Forehead: significantly higher concentration of ethanol than in the region of the forearm
higher concentrations of ivermectin in seborrhoic skin areas in comparison to non-seborrhoic areas, and therefore concluded a fast and preferential elimination via the sebum. An additional elimination process via the sweat was discussed. www.drugdiscoverytoday.com
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Antimycotics
Sebum is considered to be a highly important inverse penetration pathway for terbinafine [25] and itraconazol [26]. When given orally, terbinafine, a lipophilic substance [15], is absorbed and rapidly distributed to the skin and sebum in concentrations that exceed the minimum inhibitory concentrations [27]. In the study by Faergemann et al. [25], levels of terbinafine were studied in the plasma, stratum corneum, dermis–epidermis, sebum and hair during and after the daily systemic application of 250 mg terbinafine for one and two weeks. For both study designs, the authors found the highest concentrations of terbinafine in the sebum, and the second highest concentration in the stratum corneum. Levels of terbinafine in the plasma and the epidermis–dermis were significantly lower. These results are in concordance with earlier studies of Faergemann et al. [28,29], where the highest concentrations of terbinafine were also found in sebum and in the stratum corneum. No terbinafine was found in the sweat. Similar results were obtained for itraconazole (lipophilic [30]) [26]. Highest concentrations of itraconazole were found in the sebum, followed by the stratum corneum. The authors also investigated different skin sites, and detected higher concentrations in the beard region and on the back, in comparison to the palmar stratum corneum, although itraconazol was detectable in this region for a longer time period. Only very low amounts of itraconazole were found in the sweat. Therefore, the authors assumed at least three routes of delivery of itraconazol to the skin: (1) desquamation because of the long-time presence of itraconazole in the palmar stratum corneum, (2) a less significant excretion through the sweat glands and (3) a massive excretion through the sebaceous glands. Ketoconazole [31] and griseofulvin [32] also represent lipophilic antimycotic substances. Both substances could not be detected in the sebum except for ketoconazole, which could be collected from patients on prolonged ketoconazole therapy. Both substances emerged with the sweat. Based on their results, Harris et al. [31] discussed four possible routes with which ketoconazole can reach the stratum corneum, and divided these into slow and rapid routes. As slow inverse penetration processes, desquamation as well as sebum excretion were proposed. The authors indicated that the production and transport of the sebum to the skin surface takes about 3–4 weeks. As rapid inverse penetration pathways, the intercellular pathway and delivery with the sweat were suggested. The authors concluded that similar to the findings for griseofulvin [32], ketoconazol is delivered to the skin surface mostly via the sweat, after which it is readily partitioned from the fluid phase of the sweat to the keratinocytes, hairs, nails, and sebum. Fluconazole, on the contrary, is a hydrophilic azole [30]. At least two articles are available that address the bioavailabilty e232
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of fluconazole in the skin subsequent to oral application. Wildfeuer et al. [33] found the highest concentration of fluconazole in the stratum corneum, the second highest concentration in the sweat, followed by the dermis–epidermis and the serum. Results of the same nature were found by Faergemann et al. [34]. The authors discussed the diffusion routes through the epidermis–dermis, the desquamation process and the sebum and sweat secretion as possible inverse penetration pathways. They concluded that the intercellular pathway as well as the pathway via the sweat may be of highest relevance. Antibiotics
Ofloxacin represents, according to its log P of 0.1, a hydrophilic antibiotic drug [35]. Bielecka-Grzela et al. [36] evaluated the ofloxacin penetration into the skin. They found significantly lower concentrations of ofloxacin in the skin in comparison to the plasma. Apart from antimicrobial substances, few other systemically administered substances provided information about their pathway to the skin.
Chemotherapeutics Doxorubicin is a hydrophilic cytostatic drug with fluorescent properties, frequently utilized against solid and angiomatous tumours [37]. It is not primarily a dermatological drug. Nevertheless, doxorubicin often induces severe and doselimiting side effects affecting the skin, which are known as palmar–plantar erythrodysaesthesia (PPE) [38]. The pathogenesis of this disease indicates that doxorubicin reaches the skin. Jacobi et al. [39] used laser scanning microscopy to measure the skin surface of patients receiving doxorubicin via infusions. Using kinetic laser scanning microscopy measurements, the authors demonstrated that the sweat functioned as a carrier of doxorubicin to the skin surface, and that subsequently, the sweat containing the drug penetrated into the stratum corneum and into deeper skin layers. The preference of PPE occurring in the region of the palms and plants may be explained by the increased stratum corneum reservoir in these body regions [40].
5-Methoxypsoralon (5-MOP) Photochemotherapy with 5-methoxypsoralon plus ultraviolet A light irradiation is an effective treatment for several skin diseases. In earlier studies, the skin blister fluid technique was utilized to measure the interstitial fluid concentration of 5MOP. Depending on the time of blister formation, the 5-MOP concentration in skin blister fluid was 25–50% that of the plasma concentration [41,42]. On the contrary, Zucchi et al. [43] studied the 5-MOP skin distribution by measuring its content in 20 mm thick skin slices, and observed that the drug content was higher in external slices and decreased exponentially from the stratum
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corneum towards the dermis. They concluded that this result was owing to the reported high affinity of 5-MOP for the skin. The authors calculated that after 3 h, 59 15% of the administered dose were present in the skin and therefore higher concentrations of 5-MOP were present in the skin than in plasma.
Ethanol Ethanol intake is also associated with a variety of skin diseases [44]. Jacobi et al. conducted a study to identify the release pathways of orally administered ethanol through the skin. For ethanol, they found that the pathways via the sweat channels and follicles were of minor importance, and assumed that the main pathway of ethanol emission was most likely via the lipid layers. They suggested that ethanol interacted with the skin lipids, as indicated in penetration studies where ethanol was applied topically.
2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) TCDD is the most toxic of the polychlorinated aromatic compounds, and is a by-product of certain industrial processes and combustion [45]. Owing to its high lipophilicity, TCDD accumulates in adipose tissue and is slowly metabolized [46]. There are no established treatment strategies for TCDD detoxification. Faecal excretion seems to be an important pathway; elimination via breast milk and via skin lipids has also been discussed. Indications for a continuous elimination of TCDD via the skin were found with 0.003–0.004% of the total body burden. This could be increased to 0.006% when petrolatum was applied. As the skin lipids are derived largely from sebaceous glands and to a lesser extent from desquamating corneocytes in intact skin, the authors [46] assumed that both processes could contribute to the elimination of TCDD from the organism.
Mechanism of inverse penetration The evidence provided by the results and postulations of the reviewed articles clearly indicates that lipophilic substances reach the skin surface via the sebum, while hydrophilic substances utilize the sweat for delivery to the skin surface. This was shown for the lipophilic ivermectin, which was found in significantly higher concentrations in seborrhoic skin areas [24], as well as for the lipophilic antimycotics terbinafine [25] and itraconazole [26]. For these substances, the highest concentrations were found in the sebum, followed by the stratum corneum, while lower concentrations were found in deeper skin layers. These results suggest that terbinafine and itraconazole are delivered to the skin surface via the sebum, and then penetrate back into the stratum corneum as if applied topically. The substances ivermectin, terbinafine and itraconazole are lipophilic, leading to inverse penetration via the sebum.
Drug Discovery Today: Disease Mechanisms | Common skin conditions and disorders
For lipophilic 5-methoxypsoralon, higher concentrations were present in the skin in comparison to the plasma, which again disagrees with the assumption that the substance mainly uses the intercellular penetration pathway for inverse penetration, as higher concentrations were found in external skin sites. Although no data was available, inverse penetration via the sebum may play a role, as 5-MOP is also a lipophilic substance [48]. Ketoconazole [31] and griseofulvin [32] are also lipophilic antimycotic substances. Therefore, at least for ketoconazole, drug delivery via the sebum has been suggested [31]. Astonishingly, both substances could not be detected in the sebum. Both substances emerged in the sweat. This effect can be explained by considering the metabolism of both substances. Ketoconazole is readily absorbed after conversion to the water-soluble salt by gastric acid [31]. In griseofulvin, a methyl group is replaced by hydrogen at one of the methyl groups [49]. In this way, the major metabolite 6-demethylgriseofulvin originates, which is mainly eliminated by the urine, indicating an increased hydrophilicity. Therefore, both substances are hydrophilic after metabolism, which provides an explanation for the increased detection in the sweat in comparison to the sebum. The highest concentrations of the hydrophilic fluconazole were likewise detected in the stratum corneum und the sweat [34]. For doxorubicin, the emerging of fluorescence out of the sweat duct could be visualized by laser scanning microscopy [39]. On the contrary, significantly lower concentrations were detected for ofloxacin in the skin in comparison to the plasma [36]. This is contradictory to the preceding results of the other hydrophilic substances, which showed increased concentrations in the skin in comparison to the plasma. This deviation could be explained by the ineptitude of the method of microdialysis for this type of investigation. Assuming that ofloxacin also prefers the inverse penetration via the sweat as in the other cases of hydrophilic substances higher concentrations should be found in the stratum corneum und decreasing concentrations in the lower layers of the skin. Unfortunately, microdialysis only measures intradermal concentrations, and no information is therefore available about concentrations in the upper skin layers. The results obtained by microdialysis may thus not reflect the concentrations present in the skin. Some results suggest that additional inverse penetration pathways, such as the intercellular inverse penetration pathway and the process of desquamation, also exist. Ethanol obviously prefers inverse penetration via the intercellular pathway, in spite of its hydrophilicity. This may be owing to the interactions between ethanol and the skin lipids. Another explanation could be the low molecular size of ethanol, which may facilitate intercellular penetration for this substance. Moreover, the results could also be www.drugdiscoverytoday.com
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time-dependent. For topically applied caffeine, for example, it was shown that the hair follicles represent fast penetration pathways, while the intercellular pathway became effective only after about 20 min [11,50]. Previously, the process of desquamation was frequently assumed to be an important pathway for inverse penetration. It was supposed that after systemic application and distribution via the blood, the substances are incorporated into the cells of the basal cell layer, which move towards the surface, keratinize, cornify and reach the skin surface over a period of 3– 4 weeks [31]. Since it is now known that the substances reach the skin surface within hours, this route must be reconsidered. By reviewing the available literature, desquamation may be a possible detoxification pathway of 2,3,7,8-tetrachlordibenzop-dioxin, in addition to the sebum excretion pathway.
Conclusion It can conclusively be assumed that four of the described theoretical inverse penetration pathways are of relevance for the penetration of systemically administered substances to the skin or skin surface. 1. Inverse penetration via the sebum represents an important and efficient route mainly for lipophilic substances. 2. On the contrary, inverse penetration via the sweat appears to be of high relevance for hydrophilic substances as well as for the hydrophilic metabolites of lipophilic substances. The sweat and the sebum are physiological substances with which systemically administered substances are delivered to the skin and distributed onto the skin surface. Subsequently, they penetrate back into the skin, as if applied topically. 3. Inverse intercellular penetration is probably of lesser relevance as higher concentrations of the systemically administered substances were found in the superior layers. Nevertheless, for some substances such as ethanol, this penetration pathway seems to be important. Possible explanations might be the low molecular size of ethanol and the good solvent properties of ethanol. 4. Desquamation also seems to be of lesser importance than was previously believed. It is important to note, however, that this process may contribute to the inverse penetration of certain systemically administered substances. 5. For inverse intracellular penetration, no indications could be found in the literature.
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