{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,19]],"date-time":"2026-10-19T15:22:56Z","timestamp":1792423376730,"version":"4.5.0"},"reference-count":65,"publisher":"Wiley","issue":"12","license":[{"start":{"date-parts":[[2019,6,30]],"date-time":"2019-06-30T00:00:00Z","timestamp":1561852800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"funder":[{"DOI":"10.13039\/100006108","name":"National Center for Advancing Translational Sciences","doi-asserted-by":"publisher","award":["UL1TR002319,"],"award-info":[{"award-number":["UL1TR002319,"]}],"id":[{"id":"10.13039\/100006108","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000057","name":"National Institute of General Medical Sciences","doi-asserted-by":"publisher","award":["R01GM124264"],"award-info":[{"award-number":["R01GM124264"]}],"id":[{"id":"10.13039\/100000057","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100009633","name":"Eunice Kennedy Shriver National Institute of Child Health and Human Development","doi-asserted-by":"publisher","award":["U10HD047892"],"award-info":[{"award-number":["U10HD047892"]}],"id":[{"id":"10.13039\/100009633","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["accp1.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["The Journal of Clinical Pharma"],"published-print":{"date-parts":[[2019,12]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:p>Hydralazine, an antihypertensive agent used during pregnancy, undergoes <jats:italic>N<\/jats:italic>\u2010acetylation primarily via <jats:italic>N<\/jats:italic>\u2010acetyltransferase 2 (NAT2) to form 3\u2010methyl\u20101,2,4\u2010triazolo[3,4\u2010a]phthalazine (MTP). To characterize the steady\u2010state pharmacokinetics (PK) of hydralazine during pregnancy and evaluate the effects of NAT2 genotype on hydralazine and MTP PK during pregnancy, 12 pregnant subjects received oral hydralazine (5\u201025\u00a0mg every 6 hours) in mid\u2010 (n\u00a0=\u00a05) and\/or late pregnancy (n\u00a0=\u00a08). Serial blood samples were collected over 1 dosing interval, and steady\u2010state noncompartmental PK parameters were estimated. Subjects were classified as either (rapid acetylators, n\u00a0=\u00a06) or slow acetylators (SAs, n\u00a0=\u00a06) based on NAT2 genotype. During pregnancy, when compared with the SA group, the RA group had faster weight\u2010adjusted hydralazine apparent oral clearance (70.0\u00a0\u00b1\u00a013.6 vs 20.1\u00a0\u00b1\u00a06.9 L\/h, <jats:italic>P\u00a0&lt;\u00a0<\/jats:italic>.05), lower dose\u2010normalized area under the concentration\u2010time curve (AUC; 1.5\u00a0\u00b1\u00a00.8 vs 5.9\u00a0\u00b1\u00a03.7 ng\u00b7h\/mL, <jats:italic>P\u00a0&lt;\u00a0<\/jats:italic>.05), lower dose\u2010normalized peak concentrations (0.77\u00a0\u00b1\u00a00.51 vs 4.04\u00a0\u00b1\u00a03.18 ng\/mL, <jats:italic>P\u00a0&lt;\u00a0<\/jats:italic>.05), and larger weight\u2010adjusted apparent oral volume of distribution (302\u00a0\u00b1\u00a0112 vs 116\u00a0\u00b1\u00a045 L\/kg, <jats:italic>P\u00a0&lt;\u00a0<\/jats:italic>.05). Furthermore, the MTP\/hydralazine AUC ratio was \u223c10\u2010fold higher in the RA group (78\u00a0\u00b1\u00a030 vs 8\u00a0\u00b1\u00a03, <jats:italic>P\u00a0&lt;\u00a0<\/jats:italic>.05) than in the SA group. No gestational age or dose\u2010dependent effects were observed, possibly because of the small sample size. This study describes for the first time, the PK of oral hydralazine and its metabolite, MTP, during pregnancy, and confirmed that the PK of oral hydralazine is NAT2 genotype dependent during pregnancy.<\/jats:p>","DOI":"10.1002\/jcph.1477","type":"journal-article","created":{"date-parts":[[2019,7,1]],"date-time":"2019-07-01T05:33:46Z","timestamp":1561959226000},"page":"1678-1689","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":26,"title":["Effect of <i>N<\/i>\u2010Acetyltransferase 2 Genotype on the Pharmacokinetics of Hydralazine During Pregnancy"],"prefix":"10.1002","volume":"59","author":[{"given":"Lyrialle W.","family":"Han","sequence":"first","affiliation":[{"name":"Department of Pharmaceutics University of Washington  Seattle WA USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rachel J.","family":"Ryu","sequence":"additional","affiliation":[{"name":"Department of Pharmacy University of Washington  Seattle WA USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael","family":"Cusumano","sequence":"additional","affiliation":[{"name":"Hospital Sisters Health System St. John's Hospital  Springfield IL USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Thomas R.","family":"Easterling","sequence":"additional","affiliation":[{"name":"Department of Obstetrics &amp; Gynecology University of Washington  Seattle WA USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Brian R.","family":"Phillips","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutics University of Washington  Seattle WA USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Linda J.","family":"Risler","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutics University of Washington  Seattle WA USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Danny D.","family":"Shen","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutics University of Washington  Seattle WA USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mary F.","family":"Hebert","sequence":"additional","affiliation":[{"name":"Department of Pharmacy University of Washington  Seattle WA USA"},{"name":"Department of Obstetrics &amp; Gynecology University of Washington  Seattle WA USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2019,6,30]]},"reference":[{"key":"e_1_2_10_2_1","doi-asserted-by":"publisher","DOI":"10.1111\/jmwh.12725"},{"key":"e_1_2_10_3_1","doi-asserted-by":"publisher","DOI":"10.1097\/GCO.0b013e32835e0ef5"},{"key":"e_1_2_10_4_1","doi-asserted-by":"publisher","DOI":"10.1097\/AOG.0000000000000590"},{"key":"e_1_2_10_5_1","doi-asserted-by":"publisher","DOI":"10.1097\/01.AOG.0000437382.03963.88"},{"key":"e_1_2_10_6_1","doi-asserted-by":"publisher","DOI":"10.1136\/heartjnl-2011-300949"},{"key":"e_1_2_10_7_1","unstructured":"Hypertension in pregnancy: diagnosis and management clinical guideline. National Institute for Health and Care Excellence.https:\/\/www.nice.org.uk\/guidance\/cg107. Accessed June 24 2019."},{"key":"e_1_2_10_8_1","doi-asserted-by":"publisher","DOI":"10.1053\/j.semperi.2014.08.016"},{"key":"e_1_2_10_9_1","doi-asserted-by":"publisher","DOI":"10.1055\/s-2007-999553"},{"key":"e_1_2_10_10_1","doi-asserted-by":"publisher","DOI":"10.2165\/00003088-197702050-00001"},{"issue":"4","key":"e_1_2_10_11_1","first-page":"351","article-title":"Metabolism and disposition of hydralazine\u201014C in man and dog","volume":"2","author":"Lesser JM","year":"1974","journal-title":"Drug Metab Dispos"},{"issue":"2","key":"e_1_2_10_12_1","first-page":"116","article-title":"Plasma levels of real and \u201capparent\u201d hydralazine in man and rat","volume":"5","author":"Zak SB","journal-title":"Drug Metab Dispos"},{"key":"e_1_2_10_13_1","doi-asserted-by":"publisher","DOI":"10.1002\/jps.2600670833"},{"issue":"1","key":"e_1_2_10_14_1","first-page":"129","article-title":"Pharmacokinetics of hydralazine, apparent hydralazine and hydralazine pyruvic acid hydrazone in humans","volume":"26","author":"Shepherd AM","year":"1979","journal-title":"Res Commun Chem Pathol Pharmacol"},{"issue":"12","key":"e_1_2_10_15_1","first-page":"2388","article-title":"Metabolism of hydralazine in man","volume":"27","author":"Wagner J","year":"1977","journal-title":"Arzneimittelforschung"},{"key":"e_1_2_10_16_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1476-5381.1977.tb08426.x"},{"issue":"1","key":"e_1_2_10_17_1","first-page":"19","article-title":"Study of in vitro effects of hydralazine metabolites\u2013comparative evaluation of products of hydroxylation, hydrolysis and conjugation","volume":"235","author":"McLean AJ","year":"1978","journal-title":"Arch Int Pharmacodyn Ther"},{"key":"e_1_2_10_18_1","doi-asserted-by":"publisher","DOI":"10.1002\/jps.2600770320"},{"key":"e_1_2_10_19_1","doi-asserted-by":"publisher","DOI":"10.1002\/med.2610010105"},{"key":"e_1_2_10_20_1","doi-asserted-by":"publisher","DOI":"10.1021\/jm00244a018"},{"issue":"2","key":"e_1_2_10_21_1","first-page":"189","article-title":"Metabolism of hydralazine in man. Part II: investigation of features relevant to drug safety","volume":"37","author":"Dubois JP","year":"1987","journal-title":"Arzneimittelforschung"},{"key":"e_1_2_10_22_1","doi-asserted-by":"publisher","DOI":"10.1161\/01.HYP.3.5.580"},{"key":"e_1_2_10_23_1","doi-asserted-by":"publisher","DOI":"10.2217\/pgs.13.202"},{"issue":"5","key":"e_1_2_10_24_1","first-page":"559","article-title":"Acetylation and its role in the mutagenicity of the antihypertensive agent hydralazine","volume":"23","author":"Lemke LE","year":"1995","journal-title":"Drug Metab Dispos"},{"key":"e_1_2_10_25_1","doi-asserted-by":"publisher","DOI":"10.1038\/clpt.1980.173"},{"key":"e_1_2_10_26_1","doi-asserted-by":"publisher","DOI":"10.1124\/dmd.117.078543"},{"key":"e_1_2_10_27_1","volume-title":"Goodman and Gilman's The Pharmacological Basis of Therapeutics","author":"Hardman J","year":"2001"},{"key":"e_1_2_10_28_1","doi-asserted-by":"publisher","DOI":"10.1164\/arrd.1960.81.1P1.1"},{"key":"e_1_2_10_29_1","first-page":"394","article-title":"Human acetylation polymorphism","volume":"63","author":"Evans DA","year":"1964","journal-title":"J Lab Clin Med"},{"key":"e_1_2_10_30_1","doi-asserted-by":"publisher","DOI":"10.1093\/toxsci\/54.1.19"},{"key":"e_1_2_10_31_1","doi-asserted-by":"publisher","DOI":"10.1007\/BF01059448"},{"key":"e_1_2_10_32_1","doi-asserted-by":"publisher","DOI":"10.1038\/clpt.1983.144"},{"key":"e_1_2_10_33_1","doi-asserted-by":"publisher","DOI":"10.1007\/BF00542329"},{"key":"e_1_2_10_34_1","doi-asserted-by":"publisher","DOI":"10.1080\/01443615.1986.11978611"},{"key":"e_1_2_10_35_1","doi-asserted-by":"publisher","DOI":"10.1177\/0091270004269704"},{"key":"e_1_2_10_36_1","doi-asserted-by":"publisher","DOI":"10.1038\/clpt.1984.131"},{"issue":"4","key":"e_1_2_10_37_1","first-page":"293","article-title":"Influence of food on the bioavailability of \u201creal\u201d and \u201capparent\u201d hydralazine from conventional and slow\u2010release preparations","volume":"1","author":"Liedholm H","year":"1982","journal-title":"Drug Nutr Interact"},{"key":"e_1_2_10_38_1","doi-asserted-by":"publisher","DOI":"10.1002\/cpt1977221104"},{"key":"e_1_2_10_39_1","doi-asserted-by":"publisher","DOI":"10.1038\/clpt.1985.207"},{"key":"e_1_2_10_40_1","doi-asserted-by":"publisher","DOI":"10.1007\/BF00554667"},{"key":"e_1_2_10_41_1","doi-asserted-by":"publisher","DOI":"10.1023\/A:1015915812987"},{"key":"e_1_2_10_42_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0378-4347(00)81145-7"},{"key":"e_1_2_10_43_1","doi-asserted-by":"publisher","DOI":"10.2217\/pgs.11.122"},{"key":"e_1_2_10_44_1","volume-title":"R: A Language and Environment for Statistical Computing","author":"R Development Core Team","year":"2008"},{"key":"e_1_2_10_45_1","doi-asserted-by":"publisher","DOI":"10.1038\/clpt.1980.238"},{"key":"e_1_2_10_46_1","doi-asserted-by":"publisher","DOI":"10.1002\/cpt1977216715"},{"key":"e_1_2_10_47_1","doi-asserted-by":"publisher","DOI":"10.1067\/mcp.2001.116495"},{"issue":"7","key":"e_1_2_10_48_1","first-page":"406","article-title":"Acetylation status using hydralazine in African hypertensives at Kenyatta National Hospital","volume":"69","author":"Rashid JR","year":"1992","journal-title":"East Afr Med J"},{"key":"e_1_2_10_49_1","doi-asserted-by":"publisher","DOI":"10.1002\/jps.2600740218"},{"issue":"2","key":"e_1_2_10_50_1","first-page":"357","article-title":"Determination of hydralazine pyruvic acid hydrazone and its correlation with \u2018apparent\u2019 hydralazine","volume":"31","author":"Haegele KD","year":"1981","journal-title":"Arzneimittelforschung"},{"key":"e_1_2_10_51_1","doi-asserted-by":"publisher","DOI":"10.1111\/jcpt.12155"},{"key":"e_1_2_10_52_1","first-page":"133","article-title":"Factors affecting the acetylation in\u2010vivo of para\u2010aminobenzoic acid by human subjects","volume":"27","author":"Drucker MM","year":"1964","journal-title":"Clin Sci"},{"key":"e_1_2_10_53_1","doi-asserted-by":"publisher","DOI":"10.1007\/BF00561785"},{"key":"e_1_2_10_54_1","doi-asserted-by":"publisher","DOI":"10.1007\/BF01066016"},{"key":"e_1_2_10_55_1","doi-asserted-by":"publisher","DOI":"10.1136\/bmj.289.6442.410"},{"key":"e_1_2_10_56_1","doi-asserted-by":"publisher","DOI":"10.3109\/03602539408998315"},{"key":"e_1_2_10_57_1","first-page":"5245904","article-title":"Hydralazine induced lupus syndrome presenting with recurrent pericardial effusion and a negative antinuclear antibody","volume":"2017","author":"Iyer P","year":"2017","journal-title":"Case Rep Rheumatol"},{"key":"e_1_2_10_58_1","doi-asserted-by":"publisher","DOI":"10.1136\/bmj.327.7421.955"},{"key":"e_1_2_10_59_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1600-0773.1998.tb01461.x"},{"key":"e_1_2_10_60_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ebiom.2016.07.031"},{"key":"e_1_2_10_61_1","doi-asserted-by":"publisher","DOI":"10.1097\/01.ede.0000112214.33432.cc"},{"key":"e_1_2_10_62_1","doi-asserted-by":"publisher","DOI":"10.1086\/510518"},{"key":"e_1_2_10_63_1","doi-asserted-by":"publisher","DOI":"10.1002\/jps.2600681123"},{"key":"e_1_2_10_64_1","doi-asserted-by":"publisher","DOI":"10.1038\/clpt.1980.229"},{"key":"e_1_2_10_65_1","doi-asserted-by":"publisher","DOI":"10.1002\/art.1780240802"},{"key":"e_1_2_10_66_1","doi-asserted-by":"publisher","DOI":"10.1002\/jps.2600771208"}],"updated-by":[{"DOI":"10.1002\/jcph.1596","type":"correction","label":"Correction","source":"publisher","updated":{"date-parts":[[2020,2,16]],"date-time":"2020-02-16T00:00:00Z","timestamp":1581811200000}}],"container-title":["The Journal of Clinical Pharmacology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/api.wiley.com\/onlinelibrary\/tdm\/v1\/articles\/10.1002%2Fjcph.1477","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/jcph.1477","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/full-xml\/10.1002\/jcph.1477","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/accp1.onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/jcph.1477","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,9,8]],"date-time":"2023-09-08T20:05:56Z","timestamp":1694203556000},"score":1,"resource":{"primary":{"URL":"https:\/\/accp1.onlinelibrary.wiley.com\/doi\/10.1002\/jcph.1477"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2019,6,30]]},"references-count":65,"journal-issue":{"issue":"12","published-print":{"date-parts":[[2019,12]]}},"alternative-id":["10.1002\/jcph.1477"],"URL":"https:\/\/doi.org\/10.1002\/jcph.1477","archive":["Portico"],"relation":{},"ISSN":["0091-2700","1552-4604"],"issn-type":[{"value":"0091-2700","type":"print"},{"value":"1552-4604","type":"electronic"}],"subject":[],"published":{"date-parts":[[2019,6,30]]},"assertion":[{"value":"2019-03-22","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2019-06-11","order":1,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2019-06-30","order":2,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}]}}