Today, crossing the stratum corneum (SC) may be a challenge for cosmetic actives as well as non-actives, such as carriers or excipients used in cosmetics or pharmaceutical products, which also can act in the skin. For this, the chemical must penetrate the skin, making its pharmacological aspects essential. Knowing how an ingredient penetrates and its speed of penetration, formulators can control what penetrates and modulates the pharmacodynamic response by adapting the nature and quantity of the active administered. However, the current understanding of percutaneous penetration and parameters that can influence it remains a sub judice area. Ethnicity or pigmentation, for instance, can be implied in percutaneous absorption for which several studies, described here, have been conducted to clarify their roles.
Inter-ethnic Differences of Penetration
Percutaneous penetration in general has been evaluated using both invasive and noninvasive techniques. Thus, the assessment of the penetration of several compounds through the skin can be evaluated indirectly via several extrapolations, including from SC thickness or its hydration. Tape-stripping is a technique that evaluates skin penetration by measuring the compound quantity present in tapes after their removal. On the other hand, invasive techniques, described later, allow for a direct skin penetration evaluation. More, in vitro studies using Franz cells are also performed to directly assess skin penetration. However, it was not until the late 1980s that interethnic differences in penetration specifically were investigated. Penetration can be studied via pharmacokinetics, i.e., assessing the flux of actives in living organisms over time, or via pharmacodynamics, i.e., assessing a biologic effect induced by the compound depending on the compound amount applied on skin. These two perspectives and results associated are summarized here. Pharmacokinetic responses: Asoka1 used tritium-labeled diflorasone diacetate to investigate its percutaneous penetration in light Caucasian skin and dark black skin. Urinary, fecal and blood radioactivity excretions were analyzed, and no differences in urinary or fecal radioactivity were observed. However, fecal radioactivity excretion appeared to be more prolonged in black volunteers (results not shown in the study).
In another study,2 Wedig applied 2-6-14C dipyrithione using different vehicles, including methanol, a cream base and a shampoo base, to black and Caucasian skin. Based on the total mean, 34% less of the active was absorbed by black skin, in comparison with Caucasian skin, and seven of seven means calculated from different applications showed the same tendency (p < 0.02).
Later, absorption of the compounds benzoic acid, acetylsalicylic acid and caffeine was compared by Lotte on Asian, Caucasian and black skin.3 Radio-labeled compounds were applied, and at 30 min and 24 hr, the amount of substance present in the SC and in urinary excretions were analyzed, respectively. Researchers observed no significant differences in the percutaneous absorption of these compounds between the three groups when it is observed in SC as well as in urinary excretions.
Kompaore studied the vasomotor response of undamaged and tape-stripped skin to four nicotinates with different molecular weights and liposolubilities: methylnicotinate (MN), ethylnicotinate (EN), hexylnicotinate (HN) and vitamin E.4 Cutaneous blood flow parameters were measured by Laser Doppler Velocimetry (LDV). This study showed a significantly shorter lag time in penetrating Asian skin than Caucasian (p < 0.05) or black (p < 0.01) treated or untreated skin. The same was also true for Caucasian versus black skin (p < 0.05).
Among the described studies, two suggested less absorption in black skin and faster absorption in Asian skin, while others show no differences between black and Caucasian, or black, Caucasian and Asian skin. Thus, the results are inconclusive in terms of pharmacokinetic responses, which may result from the techniques used. For instance, the number of subjects can considerably modify the results due to inter-individual variability among the same ethnic group subjects.1 It is important to note that each of these studies was performed with a few number subjects—3 to 13 per group.
Besides this parameter, observing the urinary excretion of radiolabeled compounds is possible after several pharmacologic steps, including penetration, distribution, metabolism and excretion. Thus, differences in these various stages can involve differences in the final results, even if penetration is similar. In addition, for studies using measurements of cutaneous blood flux by LDV, it is necessary that both penetration and biological effects take place. Therefore, differences in the reactivity of vessels can also cause differences in the final result, even if the penetration is similar. Further, another researcher5 suggests that one cannot make a statement on differential permeabilities of different skin types unless one argues, for instance, that an increase in microvessel sensitivity can compensate for decreased penetration.
Pharmacodynamic responses: Guy investigated whether differences in penetration exist between different skin types exposed topically to the vasodilatator MN.6 MN was applied on black and Caucasian skin and the pharmacological responses was analyzed by LDV and photoplethysmography (PGG). Guy found no significant differences between the two groups, except that the magnitude of the PPG maximum response was greater for the Caucasian group than that for the black group. No statistical differences were found between black and white skin in terms of time to reach the peak response.
Berardesca et al. studied the transcutaneous penetration of the two nicotinates MN and HN in Caucasian and in Latino subjects.7 No differences in penetration between Caucasian and Latino skin were observed. Subsequently, the same authors studied reactive hyperaemia on black and Caucasian skin.8 Hyperaemia was measured after a vasoconstrictive stimulus induced by the topical application of 0.05% clobetasol proprionate. A decreased reactivity of blood vessels in black skin was noted but no differences were observed between both groups in terms of area under the curve response. However, the area under the curve decreased in both groups after the vasoconstrictive stimulus—but only in the black skin group was the decrease significant (p < 0.04). No differences in peak response were found but the values were statistically lower after the treatment in only black skin (p < 0.01). For the slope of blood flow rise, no differences were recorded between the two groups.
Nevertheless, the values of the slope of blood flow decay after peak response were similar between groups before treatment, but differed significantly only in black skin post-treatment (p < 0.04). This data reveals a higher reaction in black skin, which may be due to higher penetration or simply to different reactivity of the blood vessels. Studies by the same authors continued with tests evaluating the penetration of nicotinates MN and HN on untreated skin, occluded skin and delipidized skin.9 Lower LDV levels were recorded in black skin throughout the study. Significant racial differences were also recorded for the area under the curve response in the untreated skin and pre-occluded sites (p = 0.04 and p = 0.004, respectively), and for the initial response and peak response in the pre-occluded sites (p = 0.01 and p = 0.006, respectively). This data suggests a decreased susceptibility of black skin to nicotinate.
The response to the topically applied nicotinate MN also was evaluated on black, Asian and Caucasian subjects.5 MN induced-vasodilatation was assessed by LDV. The data showed no correlation between basal values and skin pigmentation. However, it is important to note that Emax, i.e., the diameter of the maximum visually perceptible erythematous area; AUE, or the area under the erythematous diameter versus time curve; and Lmax, i.e., the maximum LDV response, are statistically similar. So even if Emax and AUE appear to be the most sensitive in Caucasian skin, the Lmax is lowest for this group.
Differential responses of AUL, or the area under the LDV response versus time curve, also were recorded. At lower concentrations of MN, the response of black skin is higher than that of the Caucasian skin. At higher concentrations, AUL is significantly higher in black and Asian skin than Caucasian skin.
In 2009, another biologic effect was investigated.10 Jourdain examined the stinging or pain sensation threshold after application of several concentrations of capsaicin to Caucasian, Asian and black skin. He noted that the detection threshold was lower in Caucasian skin and higher in black skin (p = 0.027). However, despite ethnic-specific data, no statistically significant difference in the distribution of capsaicin detection threshold was found between the three groups (p = 0.072). Later, the effect of capsaicin was evaluated by Wang11 on skin types I–III (Caucasian), II–III (Asian), III–V (Latino) and VI (black). Five minutes post-application, self-ratings of burning or pain sensations were recorded as well as measurements taken of warmth sensations, heat pain thresholds, skin blood flow and axon flare reaction. Most black-skinned individuals did not feel sensation or pain, in contrast with Caucasian subjects who reported burning or pain starting approximately 3–5 min post application. Latino subjects also reported sensations after 3–5 min. In general, Asian subjects reported burning or pain more quickly, i.e., at 1–2 min. Quantitative testing of burning or pain shows the same results: Asian > Latino > Caucasian > black. However, no statistically significant differences in skin blood flow among the groups were recorded.
These results must be interpreted with caution because biological effects appear when compounds applied to the epidermis are transported in the dermis and are supported by microvasculature. Thus, a different biological effect can be observed due to different percutaneous penetration, or it can be the result of a different carrier into the dermis or a different microvessel reactivity, which is totally unrelated to penetration. As previously noted, all these steps may be influenced by racial differences, not just percutaneous penetration. Vessel reactivity can depend on other parameters like stiffness and compliance of the ground substance—i.e., the amorphous and noncellular component of the extracellular matrix where fibers, cells and connective tissues are embedded—and of the tissues surrounding the vessels.8
Factors that influence erythema range from difficulty in visualizing erythema on dark skin, to metabolism, mediators of inflammation, the ability to microcirculate and eliminate the drug, and once again, blood vessel microreactivity.7, 9 This shows that the sensitivity of the technique used is an important limit.
Finally, when pain is measured as the final result, a difference in neurosensitivity can be implied. It may also be also due to a difference in dermal or epidermal nervous innervation density.10 Thus, differences in visualization of erythema or in detection of pain can only depend on genetic factors and not on pigmentation.
Inter-ethnic Differences of Barrier Function
Results regarding differences in percutaneous absorption between ethnicities are inconclusive. However, studies have been performed on other parameters that can be implied on the resulting total percutaneous penetration. For instance, barrier function can be assessed by measuring trans-epidermal water loss (TEWL).12 Skin hydration may also be involved and can be evaluated by skin water content (WC). However, measurements of skin moisture can be altered by possible interference with hair, sweat or cutaneous product residues.13
Sugino assessed the physiological differences between the skin of different ethnicities by comparing TEWL and water content in four races: Caucasians, African-Americans, Hispano-Americans and Asians.14 TEWL measurements exhibited water content in a decreasing order of: African-American > Caucasian > Latino > Asian. Interestingly, Asian skin had the highest WC.
Reed investigated TEWL and SC cohesion on subjects with skin types II–III and V–VI (mixed ethnicity).15 No statistically significant differences in basal TEWL were reported, with a trend for higher basal TEWL in darker skin. The assessment of barrier integrity was also carried out on the different groups as a function of race, gender and skin type. The only group that demonstrated differences in barrier integrity were subjects with skin types V–VI, compared with those of types II–III (p < 0.001); subjects with types V–VI recovered more rapidly than those with types II-III at all times after tape-stripping. This was the only group demonstrating a difference. Further, the data showed that the only difference observed in barrier function were between skin types and not between races. This implies that the difference is related only to the skin color and not to the race of the subject.
Barrier function, recovery rate and skin blood flow were assessed by Yosipovitch, on four ethnic groups of the three skin types I–II, III–IV and V–VI.16 This study found no differences between the four groups in skin blood flow or in TEWL basal state, post-stripping, and 3 hr recovery measurements. At the level of barrier integrity, there were no differences between the four groups or between the three skin types. Grimes assessed moisture content and barrier function on African-American and Caucasian subjects.13 WC and TEWL baseline values were similar in both groups. After tape-stripping, an immediate increase in TEWL was noted in Caucasian skin but after 24 hr, this initial increase was not evident. The TEWL and WC were similar to that seen in black skin. Diridollou investigated skin dryness on the dorsal and ventral forearm as a function of ethnicity and age among four groups: African-Americans, Asians, Caucasians and Latinos.17 For the older group, on the ventral forearm, the dryness was significantly higher for African-Americans than Hispanics and Asians (p < 0.001), and on the dorsal forearm, higher in African-Americans (p < 0.05) and Caucasians (p < 0.05) than Asians. No differences were observed between Caucasians and African-Americans, or between Latinos and the other groups. Thus, dryness did not change as function of ethnicity for younger subjects, but was higher in older African-American and Caucasian subjects than Asian and Latino subjects.
TEWL, skin hydration, dryness and desquamation indicies were evaluated on black skin, i.e., sub-Saharienne African or Caribbean; mixed-race skin, i.e., African or Caribbean black and Caucasian skin; and Caucasian skin.18 No differences were observed between the three groups in terms of TEWL, skin hydration and dryness indices.
Muizzuddin examined the barrier function of three ethnic groups: African-American, Caucasian and East-Asian, by assessing TEWL and barrier strength.19 TEWL was the lowest in African-American skin, and so, Asian and Caucasian skin showed higher values (p < 0.001). Baseline TEWL of Asian skin was slightly lower than Caucasian skin (p < 0.001). In terms of barrier strength, African-American skin required more stripping (p < 0.001) to disrupt its barrier than Asian and Caucasian skin; Caucasian skin had an intermediate value whereas Asian skin had the lowest (p < 0.001). Cohesion in the uppermost layer of the SC was analyzed and African-American skin showed stronger cohesion, compared with the East-Asian (p < 0.001).
Even if many of these studies show no significant differences between black and Caucasian skin, there is a slight trend for higher TEWL in black skin. This observation is confirmed by the tendency of black skin to present dryness.17 Dryness is the result of impaired barrier function and subsequent increased water loss, and seems dependent on others parameters such as external temperature and weather; for instance, sun exposure or humidity. One researcher20 provides an eloquent description of the scientific and clinical issues in this therapeutic arena. But the present paper provides for skin-related data to extend her observation to dermopharmacology. Besides, even if pigmentation and genotype/phenotype are related, one can question whether penetration itself is involved, whether this is the genotype/phenotype that can be implied, or both. Most of these studies were performed with subjects of different races. However, Reed noticed a difference only between subjects with different skin types.15 This leads to the question of whether the same person, with Caucasian or black skin, would present the same pharmacological response when exposed to parameters such as temperature or UV exposure.
Thus, several parameters must be considered before stating a conclusion about the relationship between pigmentation or ethnicity and percutaneous penetration. Results are still unclear and need further investigation. SC physiology, like thickness or lipid content, can be implied in penetration differences. It is easy to miss or to find differences due to many limitations, such as on device measurement capabilities or again, human variability.
The term ethnicity represents one group. It is defined by the genome and is different for each individual, independent of pigmentation. Imprecision of ethnicity measurements in some subjects are sometimes made and again, the number of subjects in a study is a limiting parameter. Several studies are performed with a small number of volunteers and results cannot be extended to a whole population. In addition, the biological effects of elements such as temperature, humidity and diet on percutaneous penetration are difficult to assess. Precision of techniques used, or measurements themselves that do not have an international normalization standard, can also be different across several studies. Taken together, however, differences exist. The next step will be to determine the clinical significance of these differences for skin care and pharmacology. The challenge facing dermatophysiology resides in developing formulations appropriated for a given ethnicity.
A genetic point of view was investigated by Rosemary21 and indeed, some genes, which are responsible for drug metabolism, are over-expressed or under-expressed in some ethnic groups. For instance, enzymes belonging to the families CYP1, CYP2 and CYP3 catalyze the oxidative transformation of exogenous compounds. The other CYP 450 enzymes are involved in the metabolism of endogenous compounds. The altered activity of these enzymes causes inter-individual variability in the oxidative metabolism of drugs. The human CYP2C subfamily of enzymes consists of four members and of the four, CYP2CP and CYP2C19 are primarily concerned with xenobiotic metabolism. Mutations of these genes can involve different phenotypes. The more known are CYP2C9*2 and CYP2C9*3, and CYP2C19*2 and CYP2C19*3. These mutations are responsible for the poor metabolism with a decreased enzyme activity for CYP2C9 mutations, and a total absence of activity for the CYP2C19 mutations.
In terms of phenotype distribution, Caucasian populations show a trend in the higher distribution of CYP2C*2 and *3 than Asian populations. African-Americans had a lower frequency of CYP2C9*2 compared with Caucasians, but higher than Asians. These enzymes are active in the bowel but may also be efficient in the skin and thus regulate penetration. As previously stated, skin enzymes responsible for drug metabolism can be implied in percutaneous penetration and enzyme activity is regulated by genetic factors. Thus, as Chen discussed in her study,20 a dosage regimen may need to be adapted depending on ethnicity for oral absorption. By the same token, one can imagine that enzyme activity or quantities present in skin can differ depending on skin type or ethnicity. Therefore, the penetration or metabolism of drugs or actives applied to skin may be different in black or Caucasian skin. Consequently, the industry may adapt dosage regimens in topical drug application as well as for the penetration and metabolism related to skin color or ethnicity.
- J Asoka et al, Percutaneous absorption and excretion of tritium-labeled diflorasone diacetate, A new topical corticosteroid in the rat, monkey and man, J Invest Derm 71 372–377 (1978)
- JH Wedig and HI Maibach, Percutaneous penetration of dipyrithione in man: Effect of skin color (race), J Amer Acad Derm 5 433–438 (1981)
- C Lotte, RC Wester, A Rougier and HI Maibach, Racial differences in the in vivo percutaneous absorption of some organic compounds: a comparison between black, Caucasian and asian subjects; Archives of dermatological research, 284:456–459 (1993)
- F Kompaore and H Truruta, In vivo differences between Asian, black and white in the stratum corneum barrier function, Intl Arch Occupational Envt Health 65 223–225 (1993)
- CJ Gean, E Tur, HI Maibach and RH Guy, Cutaneous responses to topical methyl nicotinate in blacks, Oriental and Caucasian subjects, Arch Derm 281 95–98 (1989)
- G Richard, E Tur, S Bjerke and H Maibach, Are there age and racial differences to methyl nicotinate-induced vasodilatation in human skin? J Amer Acad Derm 12 1001–1006 (1985)
- E Berardesca and HI Maibach, Effect of race on percutaneous penetration of nicotinates in human skin: A comparison of whites and Hispano-Americans, Bioengineering and the Skin 4(1) 31–38 (1988)
- E Berardesca and HI Maibach, Cutaneous reactive hyperaemia: Racial differences induced by corticoid application, Brit J Derm 120 787–794 (1989)
- E Berardesca and HI Maibach, Racial differences in pharmacodynamic response to nicotinates in vivo in human skin: Blacks and white, Acta Dermato Venereologic 70 63–66 (1990)
- R Jourdain, HI Maibach, P Bastien, O De Lacharrière and L Breton, Ethnic variations in facial skin neurosensitivity assessed by capsaicin detection thresholds, Contact Derm 61 325–331 (2009)
- H Wang, ADP Papoui, RC Coghill, T Patel, N Wang and G Yosipovitch, Ethnic differences in pain, itch and thermal detection in response to topical capsaicin; African-Americans display a notably limited hyperalgesia and neurogenic inflammation, Brit J Derm 162 1023–1029 (2010)
- C Lotte, A Rougier, DR Wilson and HI Maibach, In vivo relationship between transepidermal water loss and percutaneous penetration of some organic compounds in man: Effect of anatomic site, Arch Derm 279 351–356 (1987)
- P Grimes, BL Edison, BA Green and RH Wildnauer, Evaluation of inherent differences between African-American and white skin surface properties using subjective and objective measures, Cutis 73 392–396 (2004)
- K Sugino, G Imokawa and HI Maibach, Ethnic difference of stratum corneum lipid in relation to stratum corneum function, J Invest Derm abstract only no. 594 100(4) (1993)
- JT Reed, R Ghadially and PM Elias, Skin type, but neither race nor gender, influence epidermal permeability barrier function, Arch Derm 131 1134–1138 (1995)
- G Yosipovitch, ATJ Goon, YH Chan and CL Goh, Are there any differences in skin barrier function, integrity and skin blood flow between different subpopulations of Asians and Caucasians? Exogenous Derm 1 302–306 (2002)
- S Diridollou, J De Rigal, B Querleux, F Leroy and VH Barbosa, Comparative study of the hydratation of the stratum corneum between four ethnic groups: Influence of age, Intl J Derm 46(suppl 1) 11–14 (2007)
- C Fotoh, A Elkhyat, S Mac, JM Sainthillier and P Humbert, Cutaneous differences between black, African or Caribbean mixed-race and Caucasian women: Biometrological approach of the hydrophilic film, Skin Res and Tech 14 327–335 (2008)
- N Muizzuddin, L Hellemans, L Van Overloop, H Corstjens, Declercq and D Maes, Structural and functional differences in barrier properties of African-American, Caucasian and East Asian skin, J Derm Sci, 59 123–128 (2010)
- ML Chen, Ethnic or racial differences revisited: Impact of dosage regimen and dosage form on pharmacokinetics and pharmacodynamics, Clinical Pharmacokinetics 45(10) 957–964 (2006)
- J Rosemary and A Chandrasekaran, The pharmacogenetics of CYP2C9 and CYP2C19: Ethnic variation and clinical significance, Current Clinical Pharmacology 2 93–109 (2007)