{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,13]],"date-time":"2026-03-13T16:20:23Z","timestamp":1773418823831,"version":"3.50.1"},"reference-count":27,"publisher":"Oxford University Press (OUP)","issue":"3","license":[{"start":{"date-parts":[[2025,12,7]],"date-time":"2025-12-07T00:00:00Z","timestamp":1765065600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/academic.oup.com\/pages\/standard-publication-reuse-rights"}],"funder":[{"name":"Kyowa Kirin Co., Ltd"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2026,3,5]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:sec>\n                    <jats:title>Objectives<\/jats:title>\n                    <jats:p>To evaluate the impact of supraclinical doses of carbidopa on the pharmacokinetics and pharmacodynamics of levodopa in rat and monkey models of Parkinson\u2019s disease and to assess the causes for the insufficiency of dihydroxyphenylalanine (DOPA) decarboxylase inhibition at the clinical dose of carbidopa.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>The effects of supraclinical doses of carbidopa and entacapone, a catechol-O-methyltransferase inhibitor, were compared with those of equivalent clinical doses in Parkinson\u2019s disease models. Pharmacological assessments were conducted using 6-hydroxydopamine-lesioned rats and 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-treated common marmosets. DOPA decarboxylase levels in the human liver, human kidney, and rat liver were quantified.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Key findings<\/jats:title>\n                    <jats:p>Supraclinical doses of carbidopa extended the plasma half-life of levodopa in rats, whereas high-dose entacapone did not. Prolonged and sustained pharmacological effects of levodopa were observed in both Parkinson\u2019s disease models with supraclinical doses of carbidopa (80-fold and 200-fold greater than the clinical equivalent in rats and marmosets, respectively). DOPA decarboxylase levels in the human liver, human kidney, and rat liver were estimated to be in the submicromolar range, comparable to or exceeding plasma carbidopa concentrations at the clinical dose.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>High-dose carbidopa co-administration is a promising approach to achieve sustained clinical efficacy of levodopa while mitigating the risk of motor complications.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1093\/jpp\/rgaf118","type":"journal-article","created":{"date-parts":[[2025,11,12]],"date-time":"2025-11-12T13:10:08Z","timestamp":1762953008000},"source":"Crossref","is-referenced-by-count":0,"title":["High-dose carbidopa achieves sustained levodopa pharmacokinetics and efficacy in Parkinson\u2019s disease models"],"prefix":"10.1093","volume":"78","author":[{"ORCID":"https:\/\/orcid.org\/0009-0005-9972-3376","authenticated-orcid":false,"given":"Akane","family":"Hayashi","sequence":"first","affiliation":[{"name":"Research Division, Research Planning Department, Research Management Office, Kyowa Kirin , Tokyo 100-0004 ,","place":["Japan"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0009-0004-2323-6013","authenticated-orcid":false,"given":"Atsushi","family":"Hosomi","sequence":"additional","affiliation":[{"name":"Pharmacokinetics Research Laboratories, Research Unit, Research Division, Kyowa Kirin , Shizuoka 411-0943 ,","place":["Japan"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0009-0009-2704-0065","authenticated-orcid":false,"given":"Shinichi","family":"Uchida","sequence":"additional","affiliation":[{"name":"Biomedical Science Research Laboratories 1, Research Unit, Research Division, Kyowa Kirin , Shizuoka 411-0943 ,","place":["Japan"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0009-0006-8898-835X","authenticated-orcid":false,"given":"Junichi","family":"Enokizono","sequence":"additional","affiliation":[{"name":"Development Division, Medical Pharmacology Department, Kyowa Kirin , Tokyo 100-0004 ,","place":["Japan"]}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"286","published-online":{"date-parts":[[2025,12,7]]},"reference":[{"key":"2026031309515522400_ref1","doi-asserted-by":"publisher","first-page":"374","DOI":"10.1056\/NEJM196702162760703","article-title":"Aromatic amino acids and modification of parkinsonism","volume":"276","author":"Cotzias","year":"1967","journal-title":"N Engl J Med"},{"key":"2026031309515522400_ref2","doi-asserted-by":"publisher","first-page":"337","DOI":"10.1056\/NEJM196902132800701","article-title":"Modification of parkinsonism \u2013 Chronic treatment with L-dopa","volume":"280","author":"Cotzias","year":"1969","journal-title":"N Engl J Med"},{"key":"2026031309515522400_ref3","doi-asserted-by":"publisher","first-page":"4","DOI":"10.1006\/exnr.1996.6379","article-title":"Dopamine synthesis, uptake, metabolism, and receptors: Relevance to gene therapy of Parkinson\u2019s disease","volume":"144","author":"Elsworth","year":"1997","journal-title":"Exp Neurol"},{"key":"2026031309515522400_ref4","doi-asserted-by":"publisher","first-page":"271","DOI":"10.1248\/bpb1978.1.271","article-title":"Effect of carbidopa (MK-486) on the metabolic fate of L-3,4-dihydroxyphenylalanine (L-DOPA). 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