{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,3]],"date-time":"2026-09-03T06:13:22Z","timestamp":1788416002876,"version":"build-2803163510"},"reference-count":28,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,9,3]],"date-time":"2026-09-03T00:00:00Z","timestamp":1788393600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100002460","name":"Chung-Ang University","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100002460","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100003725","name":"National Research Foundation of Korea","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100003725","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Pharmacol."],"abstract":"<jats:p>\n                    L-Arginine (ARG) is the primary substrate for nitric oxide (NO) synthesis via nitric oxide synthase (NOS), and L-citrulline (CIT) is its endogenous precursor. Although oral CIT has been reported to increase systemic ARG levels, the quantitative basis for its\n                    <jats:italic>in vivo<\/jats:italic>\n                    conversion to ARG and contribution to NO-mediated effects remains unclear. Therefore, this study aimed to quantitatively characterize the pharmacokinetic relationship between ARG and CIT\n                    <jats:italic>in vivo<\/jats:italic>\n                    and to determine whether CIT-derived ARG exposure could explain the pharmacodynamic effects observed after oral supplementation. Sprague-Dawley rats received oral ARG (500\u00a0mg\/kg, n = 6), CIT (500\u00a0mg\/kg, n = 6), or an equidose L-alanine control (n = 6) daily for 30 days. After 30 days of supplementation, both ARG and CIT groups exhibited significantly elevated plasma NOx levels, approximately 1.6-fold higher eNOS protein expression in the aortic arch compared with controls (p &amp;lt; 0.05), and reduced blood glucose concentrations. Plasma concentration\u2013time profiles of both analytes following intravenous and oral administration of each compound were simultaneously analyzed within a single population pharmacokinetic model. The model estimated higher oral bioavailability for CIT than for ARG (F\n                    <jats:sub>CIT<\/jats:sub>\n                    , 82.2% vs. F\n                    <jats:sub>ARG<\/jats:sub>\n                    , 52.6%). It also indicated that CIT elimination was predominantly mediated by conversion to ARG (F\n                    <jats:sub>met<\/jats:sub>\n                    = 0.999), resulting in greater systemic ARG exposure following oral CIT than following direct oral ARG administration. These findings provide a quantitative pharmacokinetic basis for the NO-mediated pharmacodynamic effects observed with both compounds and support the role of CIT as an effective oral precursor of ARG.\n                  <\/jats:p>","DOI":"10.3389\/fphar.2026.1889835","type":"journal-article","created":{"date-parts":[[2026,9,3]],"date-time":"2026-09-03T05:22:07Z","timestamp":1788412927000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["Quantitative characterization of L-citrulline as a precursor of L-arginine in rats: pharmacokinetic basis for nitric oxide-mediated effects"],"prefix":"10.3389","volume":"17","author":[{"given":"Sungmin","family":"Song","sequence":"first","affiliation":[{"name":"School of Pharmacy, Sungkyunkwan University","place":["Suwon, Gyeonggi, Republic of Korea"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Subindra Kazi","family":"Thapa","sequence":"additional","affiliation":[{"name":"Monash Institute of Pharmaceutical Sciences, Monash University","place":["Melbourne, VIC, Australia"]},{"name":"Department of Pharmacy, College of Pharmacy, Wonkwang University","place":["Iksan, Jeonbuk, Republic of Korea"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mahesh","family":"Upadhyay","sequence":"additional","affiliation":[{"name":"Department of Pharmacy, College of Pharmacy, Wonkwang University","place":["Iksan, Jeonbuk, Republic of Korea"]},{"name":"Australian Institute of Tropical Health and Medicine (AITHM), James Cook University","place":["Cairns, QLD, Australia"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Seonwoo","family":"Yang","sequence":"additional","affiliation":[{"name":"College of Pharmacy, Chung-Ang University","place":["Seoul, Republic of Korea"]},{"name":"Department of Global Innovative Drugs, The Graduate School of Chung-Ang University","place":["Seoul, Republic of Korea"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Taesun","family":"Kim","sequence":"additional","affiliation":[{"name":"College of Pharmacy, Chung-Ang University","place":["Seoul, Republic of Korea"]},{"name":"Department of Global Innovative Drugs, The Graduate School of Chung-Ang University","place":["Seoul, Republic of Korea"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Seung-Dong","family":"Yoo","sequence":"additional","affiliation":[{"name":"School of Pharmacy, Sungkyunkwan University","place":["Suwon, Gyeonggi, Republic of Korea"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Beom Soo","family":"Shin","sequence":"additional","affiliation":[{"name":"School of Pharmacy, Sungkyunkwan University","place":["Suwon, Gyeonggi, Republic of Korea"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Soyoung","family":"Shin","sequence":"additional","affiliation":[{"name":"College of Pharmacy, Chung-Ang University","place":["Seoul, Republic of Korea"]},{"name":"Department of Global Innovative Drugs, The Graduate School of Chung-Ang University","place":["Seoul, Republic of Korea"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2026,9,3]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"596","DOI":"10.3945\/jn.116.240382","article-title":"Supplemental citrulline is more efficient than arginine in increasing systemic arginine availability in mice","volume":"147","author":"Agarwal","year":"2017","journal-title":"J. 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