{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,12]],"date-time":"2026-09-12T00:14:07Z","timestamp":1789172047843,"version":"build-2803163510"},"reference-count":51,"publisher":"Wiley","issue":"20","license":[{"start":{"date-parts":[[2026,7,22]],"date-time":"2026-07-22T00:00:00Z","timestamp":1784678400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"},{"start":{"date-parts":[[2026,7,22]],"date-time":"2026-07-22T00:00:00Z","timestamp":1784678400000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"funder":[{"DOI":"10.13039\/501100002701","name":"Ministry of Education","doi-asserted-by":"publisher","award":["RS\u20102018\u2010NR031048"],"award-info":[{"award-number":["RS\u20102018\u2010NR031048"]}],"id":[{"id":"10.13039\/501100002701","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["bpspubs.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["British J Pharmacology"],"published-print":{"date-parts":[[2026,10]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:sec>\n                    <jats:title>Background and Purpose<\/jats:title>\n                    <jats:p>\n                      Cilostazol, a phosphodiesterase 3 inhibitor, causes intolerable headaches in over one third of patients, frequently leading to treatment discontinuation. We investigated whether\n                      <jats:italic>ABCC5<\/jats:italic>\n                      variant rs7636910 (NM_005688.4:c.1146A\u2009&gt;\u2009G) protects against cilostazol\u2010induced headaches through altered cyclic nucleotide signalling.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Experimental Approach<\/jats:title>\n                    <jats:p>Analysis included 101 healthy Korean volunteers from Phase 1 clinical trials, with independent replication in a multi\u2010ethnic cohort (n\u2009=\u2009369) from the All of Us Research Program. Functional consequences of rs7636910 were evaluated through splicing analysis, expression studies, transport assays and cellular models examining cyclic nucleotide dynamics and vascular responses.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Key Results<\/jats:title>\n                    <jats:p>\n                      G allele carriers showed a reduced risk of moderate\u2010to\u2010severe headaches (OR\u2009=\u20090.29, 95% CI 0.12\u20130.73), replicated in the multi\u2010ethnic cohort (OR\u2009=\u20090.26, dominant model). The variant disrupted canonical splicing, causing a 38\u2010bp deletion, premature termination, and nonsense\u2010mediated decay, reducing\n                      <jats:italic>ABCC5<\/jats:italic>\n                      expression by more than 20% in blood and thyroid tissues. Cilostazol was not an MRP5 substrate, and pharmacokinetics were genotype\u2010independent. In\n                      <jats:italic>ABCC5<\/jats:italic>\n                      \u2010knockdown HCASMCs (Human Coronary Artery Smooth Muscle Cells), baseline cAMP was elevated tonically with paradoxical cGMP accumulation, whereas drug\u2010induced cAMP fold\u2010increases remained comparable to controls. Tonic cAMP elevation desensitised PKA, abolishing PDE3 inhibitor\u2010induced vascular relaxation despite elevated cAMP\u2014a loss recapitulated by PKA inhibition in MRP5\u2010normal cells.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion and Implications<\/jats:title>\n                    <jats:p>The rs7636910 variant reduces cilostazol\u2010induced headaches through a signalling\u2010based mechanism independent of drug pharmacokinetics, suggesting that transporter variants affecting endogenous substrate handling are as clinically important as drug\u2010metabolising enzyme polymorphisms. This variant represents a candidate pharmacogenetic biomarker for identifying cilostazol\u2010tolerant patients.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1111\/bph.70597","type":"journal-article","created":{"date-parts":[[2026,7,22]],"date-time":"2026-07-22T19:13:01Z","timestamp":1784747581000},"page":"6113-6131","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Pharmacogenetic mechanism of cilostazol\u2010induced headaches: Splicing\u2010mediated loss of\n                    <i>ABCC5<\/i>\n                    gene function"],"prefix":"10.1111","volume":"183","author":[{"given":"Sung Hee","family":"Lee","sequence":"first","affiliation":[{"name":"Department of Pharmacology Asan Medical Center, University of Ulsan College of Medicine  Seoul South Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"So Myoung","family":"Kim","sequence":"additional","affiliation":[{"name":"Department of Pharmacology Asan Medical Center, University of Ulsan College of Medicine  Seoul South Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dong\u2010Hwan","family":"Lee","sequence":"additional","affiliation":[{"name":"Department of Clinical Pharmacology Hallym University Chuncheon Sacred Heart Hospital  Chuncheon South Korea"},{"name":"Department of Pharmacology Hallym University College of Medicine  Chuncheon South\u00a0Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Md.","family":"Hasanuzzaman","sequence":"additional","affiliation":[{"name":"Department of Pharmacology Asan Medical Center, University of Ulsan College of Medicine  Seoul South Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Danbi","family":"Park","sequence":"additional","affiliation":[{"name":"Department of Pharmacology Asan Medical Center, University of Ulsan College of Medicine  Seoul South Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Md. Intazur","family":"Rahaman","sequence":"additional","affiliation":[{"name":"Department of Pharmacology Asan Medical Center, University of Ulsan College of Medicine  Seoul South Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Seokil","family":"Lee","sequence":"additional","affiliation":[{"name":"Department of Pharmacology Asan Medical Center, University of Ulsan College of Medicine  Seoul South Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yongchul","family":"Gu","sequence":"additional","affiliation":[{"name":"Department of Pharmacology Asan Medical Center, University of Ulsan College of Medicine  Seoul South Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hye Won","family":"Kim","sequence":"additional","affiliation":[{"name":"Department of Pharmacology Asan Medical Center, University of Ulsan College of Medicine  Seoul South Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wonhee","family":"Park","sequence":"additional","affiliation":[{"name":"Graduate Program of Industrial Pharmaceutical Science Yonsei University  Incheon South Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hyunho","family":"Kim","sequence":"additional","affiliation":[{"name":"Division of Medical Oncology, Department of Internal Medicine St. Vincent's Hospital, Catholic University of Korea  Suwon South Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Woo\u2010Dae","family":"Bang","sequence":"additional","affiliation":[{"name":"Division of Cardiology, Department of Internal Medicine University of Ulsan College of Medicine, Gangneung Asan Hospital  Gangneung South Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Joonhee","family":"Park","sequence":"additional","affiliation":[{"name":"Department of Dermatology Northwestern University Feinberg School of Medicine  Chicago Illinois USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yejin","family":"Park","sequence":"additional","affiliation":[{"name":"Department of Biotechnology Duksung Women's University  Seoul South Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hyun June","family":"Park","sequence":"additional","affiliation":[{"name":"Department of Biotechnology Duksung Women's University  Seoul South Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jinu","family":"Lee","sequence":"additional","affiliation":[{"name":"Graduate Program of Industrial Pharmaceutical Science Yonsei University  Incheon South Korea"},{"name":"College of Pharmacy and Yonsei Institute of Pharmaceutical Sciences Yonsei University  Incheon South Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sung Kweon","family":"Cho","sequence":"additional","affiliation":[{"name":"Department of Pharmacology Ajou University School of Medicine  Suwon South Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6972-1143","authenticated-orcid":false,"given":"Kyungsoo","family":"Park","sequence":"additional","affiliation":[{"name":"Department of Pharmacology Yonsei University College of Medicine  Seoul South Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Min Goo","family":"Lee","sequence":"additional","affiliation":[{"name":"Department of Pharmacology Yonsei University College of Medicine  Seoul South Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ji Hyun","family":"Lee","sequence":"additional","affiliation":[{"name":"Department of Clinical Pharmacology and Therapeutics, College of Medicine Kyung Hee University  Seoul South Korea"},{"name":"Department of Biomedical Science and Technology Kyung Hee University  Seoul South Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eun\u2010Jae","family":"Lee","sequence":"additional","affiliation":[{"name":"Department of Neurology Asan Medical Center, University of Ulsan College of Medicine  Seoul South Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"So Won","family":"Kim","sequence":"additional","affiliation":[{"name":"Department of Pharmacology Asan Medical Center, University of Ulsan College of Medicine  Seoul South Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2026,7,22]]},"reference":[{"key":"e_1_2_12_2_1","doi-asserted-by":"publisher","DOI":"10.1186\/2193-1801-3-732"},{"key":"e_1_2_12_3_1","doi-asserted-by":"publisher","DOI":"10.1177\/03331024111430856"},{"issue":"2","key":"e_1_2_12_4_1","first-page":"S374","article-title":"The concise guide to PHARMACOLOGY 2023\/24: Transporters","volume":"180","author":"Alexander S. 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