Transdermal Uptake of Substances Banned in Sports and Its Relevance for Doping Controls

Abstract

Transdermal drug delivery has emerged as an area of significant interest in both pharmaceutical sciences and antidoping research. This narrative review explores the implications of transdermal uptake of substances banned in sports, emphasizing its relevance for doping control analysis. The human skin’s complex role as both a barrier and a site of drug absorption is examined, alongside studies investigating the transdermal administration of substances on the World Anti-Doping Agency Prohibited List, including approved transdermal formulations and drug candidates. Recent cases demonstrate that (unintentional) dermal exposure of athletes to substances banned in professional sports, e.g., clostebol, can lead to an adverse analytical finding in doping controls. Consequently, studies investigating the detectability and metabolism of transdermally administered doping substances, which might even support identifying the route of exposure, are becoming increasingly important. This review emphasizes the relevance of addressing the skin as a pathway for both intentional doping and unintentional contamination, outlining critical implications for global antidoping efforts and future research priorities.

Keywords

Sport - Doping - Exposure - Skin

Publikationsverlauf

Eingereicht: 16. Januar 2025

Angenommen nach Revision: 16. Juni 2025

Artikel online veröffentlicht:
17. Juli 2025

• References

• 1 Prausnitz MR, Langer R. Transdermal drug delivery. Nat Biotechnol 2008; 26: 1261-1268
• 2 Trommer H, Neubert RH. Overcoming the stratum corneum: the modulation of skin penetration. A review. Skin Pharmacol Physiol 2006; 19: 106-121
• 3 Wickett RR, Visscher MO. Structure and function of the epidermal barrier. Am J Infect Control 2006; 34: S98-S110
• 4 Pena-Juarez MC, Guadarrama-Escobar OR, Escobar-Chavez JJ. Transdermal Delivery Systems for Biomolecules. J Pharm Innov 2022; 17: 319-332
• 5 Ramadon D, McCrudden MTC, Courtenay AJ. et al. Enhancement strategies for transdermal drug delivery systems: current trends and applications. Drug Deliv Transl Res 2022; 12: 758-791
• 6 Hadgraft J, Lane ME. Transdermal delivery of testosterone. Eur J Pharm Biopharm 2015; 92: 42-48
• 7 Geyer H, Flenker U, Mareck U. et al. The detection of the misuse of testosterone gel. In: Schaenzer W, Geyer H, Gotzmann A et al., Hrsg Recent Advances In Doping Analysis. Köln: Sport und Buch Strauß; 2007
• 8 Kotronoulas A, Gomez-Gomez A, Fabregat A. et al. Evaluation of markers out of the steroid profile for the screening of testosterone misuse. Part I: Transdermal administration. Drug Test Anal 2018; 10: 821-831
• 9 Schonfelder M, Hofmann H, Schulz T. et al. Potential detection of low-dose transdermal testosterone administration in blood, urine, and saliva. Drug Test Anal 2016; 8: 1186-1196
• 10 de la Torre X, Colamonici C, Iannone M. et al. Detection of clostebol in sports: Accidental doping?. Drug Test Anal 2020; 12: 1561-1569
• 11 Kintz P, Gheddar L. Evidence of ostarine cross-contamination via sweat in 2 athletes sharing the same neoprene hamstring sleeves. An original situation of drug transfer where the anti-doping rule violation was suspended by the sport authorities. Clin Chim Acta 2024; 559: 119688
• 12 Lask S. Keine Sperre für Gewichtheberin Vicky Schlittig – ein vorläufiger Erfolg. ECOVIS Sportrechtsblog; 2023
• 13 Kintz P, Gheddar L, Pichini S. et al. Clostebol and sport: about controversies involving contamination vs. doping offence. Clin Chem Lab Med 2024; 63: 258-261
• 14 Gessner L, Thevis M, Rothschild MA. et al. Detectability of oxandrolone, metandienone, clostebol and dehydrochloromethyltestosterone in urine after transdermal application. Drug Test Anal 2022; 14: 1744-1761
• 15 Thevis M, Kuuranne T, Fedoruk M. et al. Sports drug testing and the athletes’ exposome. Drug Test Anal 2021; 13: 1814-1821
• 16 Eichner A, Lewis LA, Leonard B. et al. Generic Pharmaceuticals as a Source of Diuretic Contamination in Athletes Subject to Sport Drug Testing. Front Sports Act Living 2021; 3: 692244
• 17 Thevis M, Gorgens C, Guddat S. et al. Mass spectrometry in sports drug testing-Analytical approaches and the athletes’ exposome. Scand J Med Sci Sports 2024; 34: e14228
• 18 World Anti-Doping Agency. World Anti-Doping Code 2021 2021 https://www.wada-ama.org/sites/default/files/resources/files/2021_wada_code.pdf [status: 9 Aug 2024].
• 19 Merlo ABM, Lobigs L, Piper T. et al. Unravelling the threat of contamination in elite sports: Exploring diverse sources impacting adverse analytical findings and the risk of inadvertent exposure to prohibited substances. Forensic Sci Int 2024; 365: 112240
• 20 Law RM, Ngo MA, Maibach HI. Twenty Clinically Pertinent Factors/Observations for Percutaneous Absorption in Humans. Am J Clin Dermatol 2020; 21: 85-95
• 21 Rodchenkov G. The Rodchenkov Affair: How I Brought Down Russia’s Secret Doping Empire. London: WH Allen; 2020
• 22 Kanitakis J. Anatomy, histology and immunohistochemistry of normal human skin. Eur J Dermatol 2022; 12: 12
• 23 Kolarsick PAJ, Kolarsick MA, Goodwin C. Anatomy and Physiology of the Skin. JDNA 2011; 3: 203-213
• 24 Wong R, Geyer S, Weninger W. et al. The dynamic anatomy and patterning of skin. Exp Dermatol 2016; 25: 92-98
• 25 Bohling A, Bielfeldt S, Himmelmann A. et al. Comparison of the stratum corneum thickness measured in vivo with confocal Raman spectroscopy and confocal reflectance microscopy. Skin Res Technol 2014; 20: 50-57
• 26 Matsui T, Amagai M. Dissecting the formation, structure and barrier function of the stratum corneum. Int Immunol 2015; 27: 269-280
• 27 Eckhart L, Lippens S, Tschachler E. et al. Cell death by cornification. Biochim Biophys Acta 2013; 1833: 3471-3480
• 28 Rice G, Rompolas P. Advances in resolving the heterogeneity and dynamics of keratinocyte differentiation. Curr Opin Cell Biol 2020; 67: 92-98
• 29 Wiechers JW. The barrier function of the skin in relation to percutaneous absorption of drugs. Pharm Weekbl 1989; 11: 185-198
• 30 Feingold KR. The outer frontier: the importance of lipid metabolism in the skin. J Lipid Res 2009; 50 Suppl: S417-S422
• 31 Souto EB, Fangueiro JF, Fernandes AR. et al. Physicochemical and biopharmaceutical aspects influencing skin permeation and role of SLN and NLC for skin drug delivery. Heliyon 2022; 8: e08938
• 32 Smith LT, Holbrook KA, Byers PH. Structure of the Dermal Matrix during Development and in the Adult. J Invest Dermatol 1982; 79: 93-104
• 33 Usach I, Martinez R, Festini T. et al. Subcutaneous Injection of Drugs: Literature Review of Factors Influencing Pain Sensation at the Injection Site. Adv Ther 2019; 36: 2986-2996
• 34 Good R, Powers MS, Campbell P. et al. A new transdermal delivery system for estradiol. JCR 1985; 2: 89-97
• 35 Leppert W, Malec-Milewska M, Zajaczkowska R. et al. Transdermal and Topical Drug Administration in the Treatment of Pain. Molecules 2018; 23: 681
• 36 Molinuevo JL, Arranz FJ. Impact of transdermal drug delivery on treatment adherence in patients with Alzheimer’s disease. Expert Rev Neurother 2012; 12: 31-37
• 37 Kovacik A, Kopecna M, Vavrova K. Permeation enhancers in transdermal drug delivery: benefits and limitations. Expert Opin Drug Deliv 2020; 17: 145-155
• 38 Blume-Peytavi U, Massoudy L, Patzelt A. et al. Follicular and percutaneous penetration pathways of topically applied minoxidil foam. Eur J Pharm Biopharm 2010; 76: 450-453
• 39 Otberg N, Richter H, Schaefer H. et al. Variations of hair follicle size and distribution in different body sites. J Invest Dermatol 2004; 122: 14-19
• 40 Vickers CFH. Existence of reservoir in the stratum corneum – Experimental proof. Arch Dermatol 1963; 88: 20-23
• 41 Darvin ME. Optical Methods for Non-Invasive Determination of Skin Penetration: Current Trends, Advances, Possibilities, Prospects, and Translation into In Vivo Human Studies. Pharmaceutics 2023; 15: 2272
• 42 US Food and Drug Administration, Hrsg. Approved Drug Products with Therapeutic Equivalence Evaluations | Orange Book. 44. Aufl. Beltsville, MD, USA: US Department of Health and Human Services 2024
• 43 Heads of Medicine Agencies HMA. MRI Product Index 2024 https://mri.cts-mrp.eu/portal/home?domain=h [status: 30 Sep 2024].
• 44 Davis SR, Evans AM, Humberstone A. Application site affects the pharmacokinetics of topical testosterone applied to the axilla compared with the inner arm. Clin Ther 2014; 36: 1395-1401
• 45 Ishida N, Oshima Y, Katsura A. et al. Application Site of Transdermal Scopolamine Influences Efficacy and Drug Concentration in Salivary Glands in Rats. Biol Pharm Bull 2023; 46: 1805-1809
• 46 Nalamachu S, Wieman M, Bednarek L. et al. Influence of anatomic location of lidocaine patch 5% on effectiveness and tolerability for postherpetic neuralgia. Patient Prefer Adherence 2013; 7: 551-557
• 47 Taggart W, Dandekar K, Ellman H. et al. The effect of site of application on the transcutaneous absorption of 17-beta estradiol from a transdermal delivery system (Climara). Menopause 2000; 7: 364-369
• 48 Bormann JL, Maibach HI. Effects of anatomical location on in vivo percutaneous penetration in man. Cutan Ocul Toxicol 2020; 39: 213-222
• 49 MacGregor TR, Matzek KM, Keirns JJ. et al. Pharmacokinetics of transdermally delivered clonidine. Clin Pharmacol Ther 1985; 38: 278-284
• 50 US Food and Drug Administration. FDA Summary Basis of Approval: Buprenorphine. FDA Study BP96-0501 2010 https://www.accessdata.fda.gov/drugsatfda_docs/nda/2010/021306Orig1s000ClinPharmR.pdf [status: 30 Sep 2024].
• 51 Roskos KV, Maibach HI, Guy RH. The effect of aging on percutaneous absorption in man. J Pharmacokinet Biopharm 1989; 17: 617-630
• 52 Giacomoni PU, Mammone T, Teri M. Gender-linked differences in human skin. J Dermatol Sci 2009; 55: 144-149
• 53 Dias VC, Tendler B, Oparil S. et al. Clinical Experience With Transdermal Clonidine in African-American and Hispanic-American Patients With Hypertension. Am J Ther 1999; 6: 19-24
• 54 Prather RD, Tu TG, Rolf CN. et al. Nicotine pharmacokinetics of Nicoderm (nicotine transdermal system) in women and obese men compared with normal-sized men. J Clin Pharmacol 1993; 33: 644-649
• 55 Singh I, Morris AP. Performance of transdermal therapeutic systems: Effects of biological factors. Int J Pharm Investig 2011; 1: 4-9
• 56 Taylor SC. Skin of color: biology, structure, function, and implications for dermatologic disease. J Am Acad Dermatol 2002; 46: S41-S62
• 57 Langton AK, Sherratt MJ, Sellers WI. et al. Geographical ancestry is a key determinant of epidermal morphology and dermal composition. Br J Dermatol 2014; 171: 274-282
• 58 Weigand DA, Haygood C, Gaylor JR. Cell layers and density of Negro and Caucasian stratum corneum. J Invest Dermatol 1974; 62: 563-568
• 59 Guy RH, Tur E, Bjerke S. et al. Are there age and racial differences to methyl nicotinate-induced vasodilatation in human skin?. J Am ACaD Dermatol 1985; 12: 1001-1006
• 60 Leopold C, Maibach HI. Effect of lipophilic vehicles on in vivo skin penetration of methyl nicotinate in different races. Int J Pharm 1996; 139: 161-167
• 61 Harding CR, Watkinson A, Rawlings AV. et al. Dry skin, moisturization and corneodesmolysis. Int J Cosmet Sci 2000; 22: 21-52
• 62 Tagami H, Kobayashi H, Zhen XS. et al. Environmental effects on the functions of the stratum corneum. J Investig Dermatol Symp Proc 2001; 6: 87-94
• 63 Warner RR, Stone KJ, Boissy YL. Hydration disrupts human stratum corneum ultrastructure. J Invest Dermatol 2003; 120: 275-284
• 64 Drustrup J, Fullteron A, Christrup L. et al. Utilization of prodrugs to enhance the transdermal absorption of morphine. Int J Pharm 1991; 71: 105-116
• 65 Valiveti S, Hammell DC, Paudel KS. et al. In vivo evaluation of 3-O-alkyl ester transdermal prodrugs of naltrexone in hairless guinea pigs. J Control Release 2005; 102: 509-520
• 66 Wang W, Song T, Wan X. et al. Investigate the control release effect of ion-pair in the development of escitalopram transdermal patch using FT-IR spectroscopy, molecular modeling and thermal analysis. Int J Pharm 2017; 529: 391-400
• 67 Zhao H, Liu C, Quan P. et al. Mechanism study on ion-pair complexes controlling skin permeability: Effect of ion-pair dissociation in the viable epidermis on transdermal permeation of bisoprolol. Int J Pharm 2017; 532: 29-36
• 68 Bauer K, Frömming K-H, Führer C. et al. Pharmazeutische Technologie. Stuttgart: Wissenschaftliche Verlagsgesellschaft Stuttgart; 2017
• 69 Sacha M, Faucon L, Hamon E. et al. Ex vivo transdermal absorption of a liposome formulation of diclofenac. Biomed Pharmacother 2019; 111: 785-790
• 70 Rai CI, Kuo TH, Chen YC. Novel Administration Routes, Delivery Vectors, and Application of Vaccines Based on Biotechnologies: A Review. Vaccines (Basel) 2024; 12: 1002
• 71 World Anti Doping Agency. Prohibited List 2024 2024 https://www.wada-ama.org/en/prohibited-list [status: 8 Aug 2024].
• 72 Liang S, Li Z, Bao C. et al. Non-Cardiotoxic Tetradecanoic Acid-2,4-Dinitrophenol Ester Nanomicelles in Microneedles Exert Potent Anti-Obesity Effect by Regulating Adipocyte Browning and Lipogenesis. Small 2023; 19: e2301751
• 73 Foreman MI, Clanachan I. The percutaneous penetration of nandrolone decanoate. Br J Dermatol 1975; 93: 47-52
• 74 Setty BS, Kar AB. Interruption of spermatogenesis by percutaneous application of steroids. Steroids 1967; 10: 687-698
• 75 Polonini H, de Oliveira Ferreira A, Raposo NRB. et al. Transdermal Oxandrolone: Ex Vivo Percutaneous Absorption Study. Curr Drug Deliv 2017; 14: 696-700
• 76 Behre HM, von Eckardstein S, Kliesch S. et al. Long-term substitution therapy of hypogonadal men with transscrotal testosterone over 7-10 years. Clin Endocrinol (Oxf) 1999; 50: 629-635
• 77 Meikle AW, Mazer NA, Moellmer JF. et al. Enhanced transdermal delivery of testosterone across nonscrotal skin produces physiological concentrations of testosterone and its metabolites in hypogonadal men. J Clin Endocrinol Metab 1992; 74: 623-628
• 78 Wang C, Berman N, Longstreth JA. et al. Pharmacokinetics of transdermal testosterone gel in hypogonadal men: application of gel at one site versus four sites: a General Clinical Research Center Study. J Clin Endocrinol Metab 2000; 85: 964-969
• 79 Saeed A, Vaught GM, Gavardinas K. et al. 2-Chloro-4-[[(1R,2R)-2-hydroxy-2-methyl-cyclopentyl]amino]-3-methyl-benzonitrile: A Transdermal Selective Androgen Receptor Modulator (SARM) for Muscle Atrophy. J Med Chem 2016; 59: 750-755
• 80 Krishnan V, Patel NJ, Mackrell JG. et al. Development of a selective androgen receptor modulator for transdermal use in hypogonadal patients. Andrology 2018; 6: 455-464
• 81 Ito Y, Hasegawa R, Fukushima K. et al. Self-dissolving micropile array chip as percutaneous delivery system of protein drug. Biol Pharm Bull 2010; 33: 683-690
• 82 Peters EE, Ameri M, Wang X. et al. Erythropoietin-coated ZP-microneedle transdermal system: preclinical formulation, stability, and delivery. Pharm Res 2012; 29: 1618-1626
• 83 Noh G, Keum T, Seo JE. et al. Iontophoretic Transdermal Delivery of Human Growth Hormone (hGH) and the Combination Effect of a New Type Microneedle, Tappy Tok Tok((R)). Pharmaceutics 2018; 10: 153
• 84 Yang JA, Kim ES, Kwon JH. et al. Transdermal delivery of hyaluronic acid – human growth hormone conjugate. Biomaterials 2012; 33: 5947-5954
• 85 Song Y, Hemmady K, Puri A. et al. Transdermal delivery of human growth hormone via laser-generated micropores. Drug Deliv Transl Res 2018; 8: 450-460
• 86 Chen MY, Chen YY, Tsai HT. et al. Transdermal Delivery of Luteinizing Hormone-releasing Hormone with Chitosan Microneedles: A Promising Tool for Androgen Deprivation Therapy. Anticancer Res 2017; 37: 6791-6797
• 87 Malinovskaja K, Laaksonen T, Hirvonen J. Controlled transdermal delivery of leuprorelin by pulsed iontophoresis and ion-exchange fiber. Eur J Pharm Biopharm 2014; 88: 594-601
• 88 Kochhar C, Imanidis G. In vitro transdermal iontophoretic delivery of leuprolide under constant current application. J Control Release 2004; 98: 25-35
• 89 Lu X, Sun Y, Han M. et al. Triptorelin nanoparticle-loaded microneedles for use in assisted reproductive technology. Drug Deliv 2023; 30: 2226367
• 90 Nicoli S, Rimondi S, Colombo P. et al. Physical and chemical enhancement of transdermal delivery of triptorelin. Pharm Res 2001; 18: 1634-1637
• 91 Raiman J, Koljonen M, Huikko K. et al. Delivery and stability of LHRH and Nafarelin in human skin: the effect of constant/pulsed iontophoresis. Eur J Pharm Sci 2004; 21: 371-377
• 92 Shin HJ, Bak SU, La HN. et al. Efficient transdermal delivery of functional protein cargoes by a hydrophobic peptide MTD 1067. Sci Rep 2022; 12: 10853
• 93 Russell-Jones G, Himes R. Water-in-oil microemulsions for effective transdermal delivery of proteins. Expert Opin Drug Deliv 2011; 8: 537-546
• 94 Sobolevsky T, Walpurgis K, Goergens C. et al. Detection of capromorelin in urine following oral and dermal routes of administration. Drug Test Anal 2023; 15: 1449-1453
• 95 Uematsu T, Nakano M, Kosuge K. et al. The pharmacokinetics of the β2-adrenoceptor agonist, tulobuterol, given transdermally and by inhalation. Eur J Clin Pharmacol 1993; 44: 361-364
• 96 Kakubari I, Nakamura N, Takayasu T. et al. Effects of solvents on skin permeation of formoterol fumarate. Biol Pharm Bull 2006; 29: 146-149
• 97 El-Gendy NA, Sabry NA, El-Attar M. et al. Transdermal delivery of salbutamol sulphate: formulation and evaluation. Pharm Dev Technol 2009; 14: 216-225
• 98 El Menshawe SF, Aboud HM, Elkomy MH. et al. A novel nanogel loaded with chitosan decorated bilosomes for transdermal delivery of terbutaline sulfate: artificial neural network optimization, in vitro characterization and in vivo evaluation. Drug Deliv Transl Res 2020; 10: 471-485
• 99 Baumann F, Paul T, Ossmann S. et al. Mesoporous Silica-Based Membranes in Transdermal Drug Delivery: The Role of Drug Loss in the Skin. Pharmaceutics 2024; 16: 995
• 100 Regenthal R, Voskanian M, Baumann F. et al. Pharmacokinetic evaluation of a transdermal anastrozole-in-adhesive formulation. Drug Des Devel Ther 2018; 12: 3653-3664
• 101 Gao L, Gao L, Huang S. et al. Nanoemulsion-based transdermal delivery of third-generation steroidal and non-steroidal aromatase inhibitors in preclinical models. Cell Prolif 2024; 58: e13753
• 102 Jukanti R, Sheela S, Bandari S. et al. Enhanced Bioavailability of Exemestane Via Proliposomes based Transdermal Delivery. J Pharm Sci 2011; 100: 3208-3222
• 103 Gao L, Zhu L, Shen C. et al. The transdermal cream of Formestane anti-breast cancer by controlling PI3K-Akt pathway and the tumor immune microenvironment. Front Immunol 2023; 14: 1041525
• 104 de la Torre X, Martinez Brito D, Colamonici C. et al. Metabolism of formestane in humans: Identification of urinary biomarkers for antidoping analysis. Steroids 2019; 146: 34-42
• 105 Alves GL, Teixeira FV, da Rocha PBR. et al. Preformulation and characterization of raloxifene-loaded lipid nanoparticles for transdermal administration. Drug Deliv Transl Res 2022; 12: 526-537
• 106 Mahmood S, Taher M, Mandal UK. Experimental design and optimization of raloxifene hydrochloride loaded nanotransfersomes for transdermal application. Int J Nanomedicine 2014; 9: 4331-4346
• 107 Lin YL, Chen CH, Wu HY. et al. Inhibition of breast cancer with transdermal tamoxifen-encapsulated lipoplex. J Nanobiotechnology 2016; 14: 11
• 108 Zhao K, Singh J. Mechanisms of percutaneous absorption of tamoxifen by terpenes: eugenol, D-limonene and menthone. J Control Release 1998; 55: 253-260
• 109 Norman JJ, Brown MR, Raviele NA. et al. Faster pharmacokinetics and increased patient acceptance of intradermal insulin delivery using a single hollow microneedle in children and adolescents with type 1 diabetes. Pediatr Diabetes 2013; 14: 459-465
• 110 Engwerda EEC, Tack CJ, de Galan BE. Pharmacokinetic and Pharmacodynamic Variability of Insulin When Administered by Jet Injection. J Diabetes Sci Technol 2017; 11: 947-952
• 111 Smith A. Novel transdermal delivery systems for treatment of diabetes. OnDrug Delivery 2014; 28-31
• 112 Agrawal SS, Aggarwal A. Randomised, cross-over, comparative bioavailability trial of matrix type transdermal drug delivery system (TDDS) of carvedilol and hydrochlorothiazide combination in healthy human volunteers: a pilot study. Contemp Clin Trials 2010; 31: 272-278
• 113 Kim D-K, Park J-C, Chang I-H. et al. Enhanced Controlled Transdermal Delivery of Hydrochlorothiazide from an Ethylene-vinyl Acetate Matrix. J Pharm Investig 2010; 40: 167-173
• 114 Song W, Cun D, Quan P. et al. Dual-directional regulation of drug permeating amount by combining the technique of ion-pair complexation with chemical enhancers for the synchronous permeation of indapamide and bisoprolol in their compound patch through rabbit skin. Eur J Pharm Biopharm 2015; 91: 59-65
• 115 Sleeper MM, O’Donnell P, Fitzgerald C. et al. Pharmacokinetics of furosemide after intravenous, oral and transdermal administration to cats. J Feline Med Surg 2019; 21: 882-886
• 116 Cutler AJ, Suzuki K, Starling B. et al. d-Amphetamine Transdermal System in Treatment of Children and Adolescents with Attention-Deficit/Hyperactivity Disorder: Secondary Endpoint Results and Post Hoc Effect Size Analyses from a Pivotal Trial. J Child Adolesc Psychopharmacol 2023; 33: 176-182
• 117 Pierce D, Dixon CM, Wigal SB. et al. Pharmacokinetics of methylphenidate transdermal system (MTS): results from a laboratory classroom study. J Child Adolesc Psychopharmacol 2008; 18: 355-364
• 118 Marchant BK, Reimherr FW, Robison RJ. et al. Methylphenidate transdermal system in adult ADHD and impact on emotional and oppositional symptoms. J Atten Disord 2011; 15: 295-304
• 119 DelBello MP, Hochadel TJ, Portland KB. et al. A double-blind, placebo-controlled study of selegiline transdermal system in depressed adolescents. J Child Adolesc Psychopharmacol 2014; 24: 311-317
• 120 Al-Tawil N, Odar-Cederlof I, Berggren AC. et al. Pharmacokinetics of transdermal buprenorphine patch in the elderly. Eur J Clin Pharmacol 2013; 69: 143-149
• 121 Portenoy RK, Southam MA, Gupta SK. et al. Transdermal Fentanyl for Cancer Patients – Repeated Dose Pharmacokinetics. Anesthesiology 1993; 78: 36-43
• 122 Zecca E, Manzoni A, Centurioni F. et al. Pharmacokinetic study between a bilayer matrix fentalyl patch and a monolayer matrix fentanyl patch: single dose administration in healthy volunteers. Br J Clin Pharmacol 2015; 80: 110-115
• 123 Gavin PD, Tremper L, Smith A. et al. Transdermal oxycodone patch for the treatment of postherpetic neuralgia: a randomized, double-blind, controlled trial. Pain Manag 2017; 7: 255-267
• 124 Shah J, Nair AB, Shah H. et al. Enhancement in antinociceptive and anti-inflammatory effects of tramadol by transdermal proniosome gel. Asian J Pharm Sci 2020; 15: 786-796
• 125 Aldrich L, Roush J, KuKanich B. Plasma concentrations of tramadol after transdermal application of a single metered dose of a compounded tramadol gel to cats. Am J Vet Res 2021; 82: 840-845
• 126 Park C, Zuo J, Somayaji V. et al. Development of a novel cannabinoid-loaded microemulsion towards an improved stability and transdermal delivery. Int J Pharm 2021; 604: 120766
• 127 Valiveti S, Hammell DC, Earles DC. et al. In vitro/in vivo correlation studies for transdermal delta 8-THC development. J Pharm Sci 2004; 93: 1154-1164
• 128 Matsuoka H, Kuwajima I, Shimada K. et al. Comparison of efficacy and safety between bisoprolol transdermal patch (TY-0201) and bisoprolol fumarate oral formulation in Japanese patients with grade I or II essential hypertension: randomized, double-blind, placebo-controlled study. J Clin Hypertens (Greenwich) 2013; 15: 806-814
• 129 Iwano T, Toda H, Nakamura K. et al. Preventative effects of bisoprolol transdermal patches on postoperative atrial fibrillation in high-risk patients undergoing non-cardiac surgery: A subanalysis of the MAMACARI study. J Cardiol 2021; 78: 349-354
• 130 Calatayud-Pascual MA, Sebastian-Morello M, Balaguer-Fernandez C. et al. Influence of Chemical Enhancers and Iontophoresis on the In Vitro Transdermal Permeation of Propranolol: Evaluation by Dermatopharmacokinetics. Pharmaceutics 2018; 10: 265
• 131 Amarachinta PR, Sharma G, Samed N. et al. Central composite design for the development of carvedilol-loaded transdermal ethosomal hydrogel for extended and enhanced anti-hypertensive effect. J Nanobiotechnology 2021; 19: 100
• 132 Tanwar YS, Chauhan CS, Sharma A. Development and evaluation of carvedilol transdermal patches. Acta Pharm 2007; 57: 151-159
• 133 Kintz P, Ameline A. Testing for 2,4-dinitrophenol in human hair by LC-MS/MS and interpretation issues. J Pharm Biomed Anal 2024; 237: 115795
• 134 Huang T, Zhang K, Sun L. et al. Body protective compound-157 enhances alkali-burn wound healing in vivo and promotes proliferation, migration, and angiogenesis in vitro. Drug Des Devel Ther 2015; 9: 2485-2499
• 135 Klicek R, Sever M, Radic B. et al. Pentadecapeptide BPC 157, in clinical trials as a therapy for inflammatory bowel disease (PL14736), is effective in the healing of colocutaneous fistulas in rats: role of the nitric oxide-system. J Pharmacol Sci 2008; 108: 7-17
• 136 Krivic A, Anic T, Seiwerth S. et al. Achilles detachment in rat and stable gastric pentadecapeptide BPC 157: Promoted tendon-to-bone healing and opposed corticosteroid aggravation. J Orthop Res 2006; 24: 982-989
• 137 Seiwerth S, Milavic M, Vukojevic J. et al. Stable Gastric Pentadecapeptide BPC 157 and Wound Healing. Front Pharmacol 2021; 12: 627533
• 138 Gooren LJ, Bunck MC. Transdermal testosterone delivery: testosterone patch and gel. World J Urol 2003; 21: 316-319
• 139 Badoud F, Boccard J, Schweizer C. et al. Profiling of steroid metabolites after transdermal and oral administration of testosterone by ultra-high pressure liquid chromatography coupled to quadrupole time-of-flight mass spectrometry. J Steroid Biochem Mol Biol 2013; 138: 222-235
• 140 Azova S, Wolfsdorf J. Precocious sexual development in a male toddler caused by unrecognized transdermal exposure to testosterone: case report and review of the literature. J Pediatr Endocrinol Metab 2021; 34: 675-678
• 141 Patel A, Rivkees SA. Prenatal Virilization Associated with Paternal Testosterone Gel Therapy. Int J Pediatr Endocrinol 2010; 2010: 1-4
• 142 Stephen MD, Jehaimi CT, Brosnan PG. et al. Sexual precocity in a 2-year-old boy caused by indirect exposure to testosterone cream. Endocr Pract 2008; 14: 1027-1030
• 143 Anielski P, Thieme D, Schlupp A. et al. Detection of testosterone, nandrolone and precursors in horse hair. Anal Bioanal Chem 2005; 383: 903-908
• 144 Thieme D, Anielski P, Grosse J. et al. Identification of anabolic steroids in serum, urine, sweat and hair. Analytica Chimica Acta 2003; 483: 299-306
• 145 Negro-Vilar A. Selective androgen receptor modulators (SARMs): a novel approach to androgen therapy for the new millennium. J Clin Endocrinol Metab 1999; 84: 3459-3462
• 146 Ullrich T, Sasmal S, Boorgu V. et al. 3-alkoxy-pyrrolo[1,2-b]pyrazolines as selective androgen receptor modulators with ideal physicochemical properties for transdermal administration. J Med Chem 2014; 57: 7396-7411
• 147 World Anti-Doping Agency. 2022 Anti-Doping Testing Figures 2024 https://www.wada-ama.org/sites/default/files/2024-04/2022_anti-doping_testing_figures_en.pdf [status: 8 Oct 2024].
• 148 Esposito CL, Ac AG, Laszlo E. et al. A quantitative UHPLC-MS/MS method for the growth hormone-releasing peptide-6 determination in complex biological matrices and transdermal formulations. Talanta 2021; 233: 122555
• 149 Teutonico D, Montanari S, Ponchel G. Leuprolide acetate: pharmaceutical use and delivery potentials. Expert Opin Drug Deliv 2012; 9: 343-354
• 150 Delcourt V, Garcia P, Chabot B. et al. TB500/TB1000 and SGF1000: A scientific approach for a better understanding of misbranded and adulterated drugs. Drug Test Anal 2023; 15: 458-464
• 151 Esposito S, Deventer K, Goeman J. et al. Synthesis and characterization of the N-terminal acetylated 17-23 fragment of thymosin beta 4 identified in TB-500, a product suspected to possess doping potential. Drug Test Anal 2012; 4: 733-738
• 152 Nathan RA. Beta2 Agonist Therapy: Oral Versus Inhaled Delivery. J Asthma 1992; 29: 49-54
• 153 Horiguchi T, Kondo R, Miyazaki J. et al. Clinical Evaluation of a Transdermal Therapeutic System of the β2-Agonist Tulobuterol in Patients with Mild or Moderate Persistent Bronchial Asthma. Arzneim-Forsch/Drug Res 2004; 54: 280-285
• 154 Kakubari I, Shinkai N, Kawakami J. et al. Formulation and evaluation of ethylene-vinyl acetate copolymer matrix patches containing formoterol fumarate. Biol Pharm Bull 2006; 29: 513-516
• 155 Riiser A, Stensrud T, Stang J. et al. Can beta2-agonists have an ergogenic effect on strength, sprint or power performance? Systematic review and meta-analysis of RCTs. Br J Sports Med 2020; 54: 1351-1359
• 156 Hostrup M, Jessen S, Backer V. et al. Beta(2) -adrenergic agonists can enhance intense performance and muscle strength in healthy individuals. Allergy 2021; 76: 2318-2319
• 157 Hostrup M, Jessen S. Beyond bronchodilation: Illuminating the performance benefits of inhaled beta(2) -agonists in sports. Scand J Med Sci Sports 2024; 34: e14567
• 158 Bougault V, Turmel J, St-Laurent J. et al. Asthma, airway inflammation and epithelial damage in swimmers and cold-air athletes. Eur Respir J 2009; 33: 740-746
• 159 Stole Melsom H, Randa A, Hisdal J. et al. Prevalence of Asthma among Norwegian Elite Athletes. Transl Sports Med 2022; 2022: 3887471
• 160 Limenh LW, Worku NK, Melese M. et al. Effectiveness, safety, and preference of transdermal insulin compared to subcutaneous insulin in the treatment of diabetes patients: a systematic review of clinical trials. Diabetol Metab Syndr 2024; 16: 197
• 161 Zhang Y, Yu J, Kahkoska AR. et al. Advances in transdermal insulin delivery. Adv Drug Deliv Rev 2019; 139: 51-70
• 162 Zhao J, Xu G, Yao X. et al. Microneedle-based insulin transdermal delivery system: current status and translation challenges. Drug Deliv Transl Res 2022; 12: 2403-2427
• 163 Cadwallader AB, De La Torre X, Tieri A. et al. The abuse of diuretics as performance-enhancing drugs and masking agents in sport doping: pharmacology, toxicology and analysis. Br J Pharmacol 2010; 161: 1-16
• 164 Abbas K, Barnhardt EW, Nash PL. et al. A review of amphetamine extended release once-daily options for the management of attention-deficit hyperactivity disorder. Expert Rev Neurother 2024; 24: 421-432
• 165 Steingard R, Taskiran S, Connor DF. et al. New Formulations of Stimulants: An Update for Clinicians. J Child Adolesc Psychopharmacol 2019; 29: 324-339
• 166 Heal DJ, Pierce DM. Methylphenidate and its isomers: their role in the treatment of attention-deficit hyperactivity disorder using a transdermal delivery system. CNS Drugs 2006; 20: 713-738
• 167 Hubbard JW, Srinivas NR, Quinn D. et al. Enantioselective aspects of the disposition of dl-threo-methylphenidate after the administration of a sustained-release formulation to children with attention deficit-hyperactivity disorder. J Pharm Sci 1989; 78: 944-947
• 168 Rossano F, Caiazza C, Sobrino A. et al. Efficacy and safety of selegiline across different psychiatric disorders: A systematic review and meta-analysis of oral and transdermal formulations. Eur Neuropsychopharmacol 2023; 72: 60-78
• 169 Ahn JS, Lin J, Ogawa S. et al. Transdermal buprenorphine and fentanyl patches in cancer pain: a network systematic review. J Pain Res 2017; 10: 1963-1972
• 170 Davis MP, Pasternak G, Behm B. Treating Chronic Pain: An Overview of Clinical Studies Centered on the Buprenorphine Option. Drugs 2018; 78: 1211-1228
• 171 Nelson L, Schwaner R. Transdermal fentanyl: pharmacology and toxicology. J Med Toxicol 2009; 5: 230-241
• 172 Muijsers RB, Wagstaff AJ. Transdermal fentanyl: an updated review of its pharmacological properties and therapeutic efficacy in chronic cancer pain control. Drugs 2001; 61: 2289-2307
• 173 Grotenhermen F. Pharmacokinetics and pharmacodynamics of cannabinoids. Clin Pharmacokinet 2003; 42: 327-360
• 174 Mahmoudinoodezh H, Telukutla SR, Bhangu SK. et al. The Transdermal Delivery of Therapeutic Cannabinoids. Pharmaceutics 2022; 14: 438
• 175 Chu PC, Liao MH, Liu MG. et al. Key Transdermal Patch Using Cannabidiol-Loaded Nanocarriers with Better Pharmacokinetics in vivo. Int J Nanomedicine 2024; 19: 4321-4337
• 176 Aqil M, Sultana Y, Ali A. Transdermal delivery of beta-blockers. Expert Opin Drug Deliv 2006; 3: 405-418
• 177 Astellas Pharma Inc. TOA EIYO Ltd. Bisono^® Tape 2 mg, a Transdermal Patch of β1 Blocker, Launched in Japan 2019 https://www.astellas.com/en/system/files/news/2019-06/Fin_Eg_BTP2mg_Launch.pdf [status: 18 Oct 2024].
• 178 Daughton CG. Illicit drugs: contaminants in the environment and utility in forensic epidemiology. Rev Environ Contam Toxicol 2011; 210: 59-110
• 179 Breuer J, Garzinsky AM, Thomas A. et al. Complementary information concerning the suspected interindividual transmission of GW1516, a substance prohibited in sport, through intimate contact: a case report. Forensic Toxicol 2024; 42: 248-254
• 180 Thevis M, Fussholler G, Schanzer W. Zeranol: doping offence or mycotoxin? A case-related study. Drug Test Anal 2011; 3: 777-783
• 181 Walpurgis K, Thomas A, Geyer H. et al. Dietary Supplement and Food Contaminations and Their Implications for Doping Controls. Foods 2020; 9: 1012
• 182 Walpurgis K, Rubio A, Wagener F. et al. Elimination profiles of microdosed ostarine mimicking contaminated products ingestion. Drug Test Anal 2020; 12: 1570-1580
• 183 Rhodes L, Zollers B, Wofford JA. et al. Capromorelin: a ghrelin receptor agonist and novel therapy for stimulation of appetite in dogs. Vet Med Sci 2018; 4: 3-16
• 184 Wofford JA, Zollers B, Rhodes L. et al. Evaluation of the safety of daily administration of capromorelin in cats. J Vet Pharmacol Ther 2018; 41: 324-333
• 185 Thevis M, Kuuranne T, Geyer H. Annual banned-substance review 16(th) edition-Analytical approaches in human sports drug testing 2022/2023. Drug Test Anal 2024; 16: 5-29
• 186 Piper T, Thevis M. Do urinary concentrations of dimethyl sulfoxide and its metabolite dimethyl sulfone indicate topical administration of doping agents? In: Thevis M, Geyer H, Mareck U, editors. The 37th Cologne Workshop on Dope Analysis. 27 edn. Köln: Sport und Buch Strauß; 2019
• 187 World Anti-Doping Agency. WADA Technical Document – TD2022MRPL 2022 https://www.wada-ama.org/sites/default/files/resources/files/td2022mrpl_v1.0_final_eng.pdf [status: 6 Dec 2024].
• 188 Kintz P. The forensic response after an adverse analytical finding (doping) involving a selective androgen receptor modulator (SARM) in human athlete. J Pharm Biomed Anal 2022; 207: 114433
• 189 Kintz P, Gheddar L, Ameline A. et al. Identification of S22 (ostarine) in human nails and hair using LC-HRMS. Application to two authentic cases. Drug Test Anal 2020; 12: 1508-1513
• 190 Geyer H, Schanzer W, Thevis M. Anabolic agents: recent strategies for their detection and protection from inadvertent doping. Br J Sports Med 2014; 48: 820-826
• 191 Schanzer W, Geyer H, Fussholler G. et al. Mass spectrometric identification and characterization of a new long-term metabolite of metandienone in human urine. Rapid Commun Mass Spectrom 2006; 20: 2252-2258
• 192 Sobolevsky T, Rodchenkov G.. Long-term detection of dehydrochloromethyltestosterone: one-year experience. In: Schaenzer W, Thevis M, Geyer H et al., Hrsg. Manfred Donike Workshop – Proceedings of the 30th Cologne Workshop on Dope Analysis 2012 in Recent Advances In Doping Analysis. Köln: Sport und Buch Strauß 2012
• 193 Thevis M, Piper T, Thomas A. Recent advances in identifying and utilizing metabolites of selected doping agents in human sports drug testing. J Pharm Biomed Anal 2021; 205: 114312
• 194 Mareck U, Geyer H, Opfermann G. et al. Factors influencing the steroid profile in doping control analysis. J Mass Spectrom 2008; 43: 877-891
• 195 Kotronoulas A, Gomez-Gomez A, Fabregat A. et al. Evaluation of markers out of the steroid profile for the screening of testosterone misuse. Part II: Intramuscular administration. Drug Test Anal 2018; 10: 849-859
• 196 Nair VS, Doman CE, Morrison MS. et al. Evaluation of epiandrosterone as a long-term marker of testosterone use. Drug Test Anal 2020; 12: 1554-1560
• 197 Equey T, Salamin O, Ponzetto F. et al. Longitudinal Profiling of Endogenous Steroids in Blood Using the Athlete Biological Passport Approach. J Clin Endocrinol Metab 2023; 108: 1937-1946
• 198 Piper T, Thevis M. Improving the Determination of Carbon Isotope Ratios of Endogenous Steroids Found in Human Serum. Drug Test Anal 2024;
• 199 Liu L, Karim Z, Schlorer N. et al. Biotransformation of anabolic androgenic steroids in human skin cells. J Steroid Biochem Mol Biol 2024; 237: 106444
• 200 McLaren R. The Independent Person Report – WADA Investigation of Sochi Allegations 2016
• 201 Indorf P, Patzak A, Lichtenberger FB. Drug metabolism in animal models and humans: Translational aspects and chances for individual therapy. Acta Physiol (Oxf) 2021; 233: e13734
• 202 Sato K, Sugibayashi K, Morimoto Y. Species differences in percutaneous absorption of nicorandil. J Pharm Sci 1991; 80: 104-107
• 203 van Ravenzwaay B, Leibold E. A comparison between in vitro rat and human and in vivo rat skin absorption studies. Hum Exp Toxicol 2004; 23: 421-430
• 204 Michaels AS, Chandrasekaran SK, Shaw JE. Drug permeation through human skin: Theory and invitro experimental measurement. AIChE J 2004; 21: 985-996
• 205 Zhang Q, Grice JE, Li P. et al. Skin solubility determines maximum transepidermal flux for similar size molecules. Pharm Res 2009; 26: 1974-1985
• 206 Anissimov YG, Jepps OG, Dancik Y. et al. Mathematical and pharmacokinetic modelling of epidermal and dermal transport processes. Adv Drug Deliv Rev 2013; 65: 169-190
• 207 Abd E, Yousef SA, Pastore MN. et al. Skin models for the testing of transdermal drugs. Clin Pharmacol 2016; 8: 163-176
• 208 Wester RC, Christoffel J, Hartway T. et al. Human cadaver skin viability for in vitro percutaneous absorption: storage and detrimental effects of heat-separation and freezing. Pharm Res 1998; 15: 82-84
• 209 Jacobi U, Kaiser M, Toll R. et al. Porcine ear skin: an in vitro model for human skin. Skin Res Technol 2007; 13: 19-24
• 210 Wester RC, Melendres J, Sedik L. et al. Percutaneous absorption of salicylic acid, theophylline, 2, 4-dimethylamine, diethyl hexyl phthalic acid, and p-aminobenzoic acid in the isolated perfused porcine skin flap compared to man in vivo. Toxicol Appl Pharmacol 1998; 151: 159-165
• 211 Savill R, Baues H, Voigt E. et al. Cell culture as a toolbox to generate phase I metabolites for antidoping screening. Drug Test Anal 2021; 13: 1169-1177
• 212 Brandmair K, Tao TP, Gerlach S. et al. Suitability of different reconstructed human skin models in the skin and liver Chip2 microphysiological model to investigate the kinetics and first-pass skin metabolism of the hair dye, 4-amino-2-hydroxytoluene. J Appl Toxicol 2024; 44: 333-343
• 213 Tao TP, Brandmair K, Gerlach S. et al. Application of a skin and liver Chip2 microphysiological model to investigate the route-dependent toxicokinetics and toxicodynamics of consumer-relevant doses of genistein. J Appl Toxicol 2024; 44: 287-300