Skin pigmentation may act as a “sponge” for some medications ranging from antibiotics to nicotine patches, potentially influencing the speed with which active drugs reach their intended targets, a pair of scientists report in a perspective article published in the journal Human Genomics.
There has been a growing awareness of genetic susceptibility or tolerance to medications. Redheads for example had been shown to need more inhalational anaesthetic than dark-haired individuals. The researchers argue that a sizable proportion of drugs and other compounds can bind to melanin pigments in the skin, leading to differences in how bioavailable and efficacious these drugs and other compounds are in people with varying skin tones.
“Our review paper concludes that melanin, the pigment responsible for skin colour, shows a surprising affinity for certain drug compounds,” said paper coauthor Simon Groen, an assistant professor of evolutionary systems biology at the University of California, Riverside. “Melanin’s implications for drug safety and dosing have been largely overlooked, raising alarming questions about the efficacy of standard dosing since people vary a lot in skin tones.”
According to Groen and coauthor Sophie Zaaijer, a consultant and researcher affiliated with UC Riverside who specialises in diversity, equity, and inclusion (DEI) in preclinical R&D and clinical trials, current FDA guidelines for toxicity testing fail to adequately address the impact of skin pigmentation on drug interactions.
“This oversight is particularly concerning given the push for more diverse clinical trials, as outlined in the agency’s Diversity Action Plan,” Zaaijer said. “But current early-stage drug development practices still primarily focus on drug testing in white populations of Northern European descent.”
In one example, the researchers found evidence of nicotine affinity for skin pigments, potentially affecting smoking habits across people with a variety of skin tones and raising questions about the efficacy of skin-adhered nicotine patches for smoking cessation.
“Are we inadvertently shortchanging smokers with darker skin tones if they turn to these patches in their attempts to quit?” Groen said.
Groen and Zaaijer propose utilising a new workflow involving human 3D skin models with varying pigmentation levels that could offer pharmaceutical companies an efficient method to assess drug binding properties across different skin types.
“Skin pigmentation should be considered as a factor in safety and dosing estimates,” Zaaijer said. “We stand on the brink of a transformative era in the biomedical industry, where embracing inclusivity is not just an option anymore but a necessity.”
According to the researchers, skin pigmentation is just one example. Genetic variations among minority groups can lead to starkly different drug responses across races and ethnicities, affecting up to 20% of all medications, they said.
“Yet, our molecular understanding of these differences remains very limited,” Zaaijer said.
For example, a study on acetaminophen – a drug that binds melanin – found no difference in total plasma levels of acetaminophen between individuals of African- and European-American ancestries. Oxidation clearance of acetaminophen did however show ancestry-based differences and was 37% lower in African–versus European-Americans, which could have been partially explained by polymorphisms in CYP2E1.
The researchers point out that a shift towards inclusive drug development is set to take place as instigated by a new law, the Food and Drug Omnibus Reform Act, enacted in 2022, which will mandate considering patient diversity in R&D and clinical trials.
The researchers hope to activate the pharmaceutical industry and academia to start doing systematic experimental evaluations in preclinical research in relation to skin pigmentation and drug kinetics. They also encourage patients and advocacy groups to start asking about ancestry-related testing and efficacy of drugs.
