{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,1,13]],"date-time":"2026-01-13T21:03:19Z","timestamp":1768338199587,"version":"3.49.0"},"reference-count":78,"publisher":"Wiley","issue":"11","license":[{"start":{"date-parts":[[2020,6,21]],"date-time":"2020-06-21T00:00:00Z","timestamp":1592697600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Brit J Clinical Pharma"],"published-print":{"date-parts":[[2020,11]]},"abstract":"<jats:sec><jats:label\/><jats:p>Following its introduction as an antituberculosis agent close to 75 years ago, the use of para\u2010aminosalicylic acid (PAS) has been limited by gastrointestinal intolerance and multiple formulations were produced in attempts to reduce its occurrence. More recently, an enteric\u2010coated, granular, slow\u2010release PAS formulation (PASER) was introduced and is now in wide\u2010spread use for the treatment of drug\u2010resistant tuberculosis. The current PASER dosing regimen is based on recommendations derived from older studies using a variety of different PAS formulations and relegate PAS to a role as an exclusively bacteriostatic agent. However, there is ample evidence that if sufficiently high serum concentrations are reached, PAS can be bactericidal and that intolerance following once daily dosing, that aids the achievement of such concentrations, is no worse than that following intermittent daily dosing. In particular, prevention of resistance to companion drugs appears to be dependent on the size of the single dose, and hence the peak concentrations, and not on maintaining serum levels consistently above minimum inhibitory concentration. We present a narrative review of the development of PAS formulations, dosing practices, and published data regarding pharmacokinetics and pharmacodynamics and the relationship of PAS dosage to intolerance and efficacy. Our conclusions suggests that we are at present not using PAS to its maximum ability to contribute to regimen efficacy and protect companion drugs.<\/jats:p><\/jats:sec>","DOI":"10.1111\/bcp.14395","type":"journal-article","created":{"date-parts":[[2020,5,29]],"date-time":"2020-05-29T19:50:53Z","timestamp":1590781853000},"page":"2123-2132","source":"Crossref","is-referenced-by-count":21,"title":["The pharmacokinetics of para\u2010aminosalicylic acid and its relationship to efficacy and intolerance"],"prefix":"10.1111","volume":"86","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-2089-3614","authenticated-orcid":false,"given":"Ahmed A.","family":"Abulfathi","sequence":"first","affiliation":[{"name":"Division of Clinical Pharmacology, Department of Medicine, Faculty of Medicine and Health Sciences Stellenbosch University  Cape Town South Africa"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Peter R.","family":"Donald","sequence":"additional","affiliation":[{"name":"Desmond Tutu TB Centre, Department of Paediatrics and Child Health, Faculty of Medicine and Health Sciences Stellenbosch University  Cape Town South Africa"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kim","family":"Adams","sequence":"additional","affiliation":[{"name":"Division of Clinical Pharmacology, Department of Medicine, Faculty of Medicine and Health Sciences Stellenbosch University  Cape Town South Africa"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0093-6445","authenticated-orcid":false,"given":"Elin M.","family":"Svensson","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutical Biosciences Uppsala University  Uppsala Sweden"},{"name":"Department of Pharmacy, Radboud Institute for Health Sciences Radboud University Medical Center  Nijmegen the Netherlands"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Andreas H.","family":"Diacon","sequence":"additional","affiliation":[{"name":"Task Applied Science  Bellville South Africa"},{"name":"Department of Medicine, Faculty of Medicine and Health Sciences Stellenbosch University  Cape Town South Africa"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Helmuth","family":"Reuter","sequence":"additional","affiliation":[{"name":"Division of Clinical Pharmacology, Department of Medicine, Faculty of Medicine and Health Sciences Stellenbosch University  Cape Town South Africa"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"311","published-online":{"date-parts":[[2020,6,21]]},"reference":[{"key":"e_1_2_7_2_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0041-3879(50)80073-9"},{"key":"e_1_2_7_3_1","unstructured":"BruntonLL KnollmannBC Hilal\u2010DandanR.Goodman & Gilman's the Pharmacological Basis of Therapeutics 13th Ed.McGraw Hill Medical;2018."},{"key":"e_1_2_7_4_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0366-0869(54)80128-6"},{"issue":"1","key":"e_1_2_7_5_1","first-page":"48","article-title":"Correspondence with a pioneer, J\u00fcrgen Lehmann (1898\u20101989), producer of the first effective antituberculosis specific","volume":"79","author":"Dubovsky H","year":"1991","journal-title":"S Afr Med J"},{"key":"e_1_2_7_6_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(46)91185-3"},{"key":"e_1_2_7_7_1","first-page":"269","article-title":"Streptomycin in experimental tuberculosis","volume":"52","author":"Feldman W","year":"1945","journal-title":"Am Rev Tuberc"},{"key":"e_1_2_7_8_1","doi-asserted-by":"publisher","DOI":"10.3181\/00379727-55-14461"},{"key":"e_1_2_7_9_1","doi-asserted-by":"publisher","DOI":"10.1001\/jama.1946.02870480024007"},{"key":"e_1_2_7_10_1","doi-asserted-by":"publisher","DOI":"10.1136\/bmj.2.4688.1073"},{"key":"e_1_2_7_11_1","doi-asserted-by":"publisher","DOI":"10.1136\/bmj.2.4688.1102"},{"key":"e_1_2_7_12_1","doi-asserted-by":"publisher","DOI":"10.1136\/bmj.1.4769.1157"},{"key":"e_1_2_7_13_1","doi-asserted-by":"publisher","DOI":"10.1136\/bmj.1.4911.435"},{"key":"e_1_2_7_14_1","doi-asserted-by":"publisher","DOI":"10.1136\/bmj.2.4582.769"},{"key":"e_1_2_7_15_1","doi-asserted-by":"publisher","DOI":"10.1136\/bmj.2.4844.1005"},{"issue":"10","key":"e_1_2_7_16_1","first-page":"S231","article-title":"Studies on the treatment of tuberculosis undertaken by the British Medical Research Council tuberculosis units, 1946\u20101986, with relevant subsequent publications","volume":"3","author":"Fox W","year":"1999","journal-title":"Int J Tuberc Lung Dis"},{"key":"e_1_2_7_17_1","doi-asserted-by":"publisher","DOI":"10.1513\/AnnalsATS.201509-632PS"},{"key":"e_1_2_7_18_1","doi-asserted-by":"publisher","DOI":"10.1183\/09031936.02.00309102"},{"key":"e_1_2_7_19_1","doi-asserted-by":"publisher","DOI":"10.1002\/j.1875-9114.1994.tb02787.x"},{"key":"e_1_2_7_20_1","first-page":"13","volume-title":"Drug Susceptibility in the Chemotherapy of Mycobacterial Infections","author":"Heifets LB","year":"1991"},{"key":"e_1_2_7_21_1","doi-asserted-by":"publisher","DOI":"10.1007\/s40261-014-0172-7"},{"key":"e_1_2_7_22_1","doi-asserted-by":"publisher","DOI":"10.1128\/AAC.03073-14"},{"key":"e_1_2_7_23_1","doi-asserted-by":"publisher","DOI":"10.1016\/S1473-3099(15)00263-7"},{"key":"e_1_2_7_24_1","doi-asserted-by":"publisher","DOI":"10.1128\/AAC.04049-14"},{"key":"e_1_2_7_25_1","unstructured":"Paser (Jacobus Pharmaceutical Company Inc.).https:\/\/medlibrary.org\/lib\/rx\/meds\/paser\/.2010."},{"key":"e_1_2_7_26_1","first-page":"1","volume-title":"Companion Handb to WHO Guidel Program Manag Drug\u2010Resistant Tuberc","author":"WHO","year":"2014"},{"key":"e_1_2_7_27_1","doi-asserted-by":"publisher","DOI":"10.1164\/rccm.201407-1264OC"},{"key":"e_1_2_7_28_1","doi-asserted-by":"publisher","DOI":"10.1128\/AAC.01474-06"},{"key":"e_1_2_7_29_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(18)31644-1"},{"key":"e_1_2_7_30_1","volume-title":"WHO consolidated guidelines on drug\u2010resistant tuberculosis treatment","author":"WHO","year":"2019"},{"key":"e_1_2_7_31_1","volume-title":"WHO consolidated guidelines on drug\u2010resistant tuberculosis treatment","author":"WHO","year":"2019"},{"key":"e_1_2_7_32_1","doi-asserted-by":"publisher","DOI":"10.4103\/lungindia.lungindia_141_18"},{"key":"e_1_2_7_33_1","unstructured":"R: The R project for statistical computing.https:\/\/www.r-project.org\/"},{"key":"e_1_2_7_34_1","unstructured":"RohatgiA.WebPlotDigitizer version 4.2.https:\/\/apps.automeris.io\/wpd\/.2019."},{"issue":"5","key":"e_1_2_7_35_1","first-page":"597","article-title":"Para\u2010aminosalicylic acid treatment in pulmonary tuberculosis","volume":"61","year":"1950","journal-title":"Am Rev Tuberc"},{"issue":"2","key":"e_1_2_7_36_1","first-page":"115","article-title":"Cooperative controlled trial of thiocarlide (DATC), PAS and bedrest alone in short\u2010term single\u2010drug treatment in retreated cavitary pulmonary tuberculosis","volume":"139","year":"1969","journal-title":"Beitr Klin Erforsch Tuberk Lungenkr"},{"issue":"2","key":"e_1_2_7_37_1","first-page":"226","article-title":"Para\u2010aminosalicylic acid treatment of tuberculosis; a review","volume":"61","author":"Bogen E","year":"1950","journal-title":"Am Rev Tuberc"},{"key":"e_1_2_7_38_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0041-3879(59)80099-4"},{"key":"e_1_2_7_39_1","first-page":"237","article-title":"Metabolism of isoniazid and Para\u2010amino salicylic acid (PAS) in the organism and its therapeutic significance","volume":"41","author":"Bang HO","year":"1962","journal-title":"Acta Tuberc Pneumol Scand"},{"key":"e_1_2_7_40_1","first-page":"68","article-title":"Continued studies in concentrations of Para\u2010amino\u2010salicylic acid (PAS) in the blood","volume":"41","author":"Frostad S","year":"1961","journal-title":"Acta Tuberc Pneumol Scand"},{"key":"e_1_2_7_41_1","doi-asserted-by":"publisher","DOI":"10.1093\/tropej\/fms053"},{"key":"e_1_2_7_42_1","doi-asserted-by":"publisher","DOI":"10.1345\/aph.1A088"},{"issue":"1","key":"e_1_2_7_43_1","first-page":"144","article-title":"Variations in the PAS concentration in the blood and their influence on treatment of tuberculosis","volume":"30","author":"Riska N","year":"1954","journal-title":"Acta Tuberc Scand"},{"key":"e_1_2_7_44_1","first-page":"430","article-title":"Optimal PAS dosage","volume":"86","author":"Riska N","year":"1962","journal-title":"Am Rev Respir Dis"},{"key":"e_1_2_7_45_1","doi-asserted-by":"publisher","DOI":"10.1002\/jps.2600630512"},{"key":"e_1_2_7_46_1","doi-asserted-by":"publisher","DOI":"10.1002\/jps.2600630921"},{"issue":"4","key":"e_1_2_7_47_1","first-page":"548","article-title":"Para\u2010aminosalicylic acid\u2010resin complex: studies in absorption, serum electrolytes, and tolerance","volume":"72","author":"Hollander AG","year":"1955","journal-title":"Am Rev Tuberc"},{"key":"e_1_2_7_48_1","doi-asserted-by":"publisher","DOI":"10.1378\/chest.49.2.165"},{"issue":"3","key":"e_1_2_7_49_1","first-page":"351","article-title":"The tolerability of calcium benzoyl\u2010PAS and calcium PAS; a double blind study","volume":"79","author":"Jeker K","year":"1959","journal-title":"Am Rev Tuberc"},{"key":"e_1_2_7_50_1","doi-asserted-by":"publisher","DOI":"10.1378\/chest.19.2.138"},{"key":"e_1_2_7_51_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0041-3879(58)80077-X"},{"issue":"3","key":"e_1_2_7_52_1","first-page":"169","article-title":"The role of the metabolism of p\u2010aminosalicylic acid (PAS) in the treatment of tuberculosis. Interaction with the metabolism of isonicotinic acid hydrazide (INH) and the synthesis of cholesterol","volume":"50","author":"Lehmann J","year":"1969","journal-title":"Scand J Respir Dis"},{"key":"e_1_2_7_53_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0041-3879(55)80078-5"},{"key":"e_1_2_7_54_1","doi-asserted-by":"publisher","DOI":"10.1136\/bmj.1.4769.1162"},{"key":"e_1_2_7_55_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ijantimicag.2017.01.024"},{"issue":"6","key":"e_1_2_7_56_1","first-page":"939","article-title":"The early bactericidal activity of drugs in patients with pulmonary tuberculosis","volume":"121","author":"Jindani A","year":"1980","journal-title":"Am Rev Respir Dis"},{"key":"e_1_2_7_57_1","doi-asserted-by":"publisher","DOI":"10.1164\/rccm.201909-1874ST"},{"issue":"3","key":"e_1_2_7_58_1","first-page":"368","article-title":"The absorption, distribution, excretion and fate of Para\u2010aminosalicylic acid","volume":"93","author":"Way EL","year":"1948","journal-title":"J Pharmacol Exp Ther"},{"key":"e_1_2_7_59_1","doi-asserted-by":"publisher","DOI":"10.1056\/NEJM195711282572202"},{"key":"e_1_2_7_60_1","doi-asserted-by":"publisher","DOI":"10.1006\/abbi.1993.1116"},{"key":"e_1_2_7_61_1","doi-asserted-by":"publisher","DOI":"10.1080\/10937400903158383"},{"key":"e_1_2_7_62_1","first-page":"104","article-title":"PAS therapy with a daily unfractionated dose","volume":"37","author":"Riska N","year":"1959","journal-title":"Acta Tuberc Scand"},{"key":"e_1_2_7_63_1","doi-asserted-by":"publisher","DOI":"10.1590\/S1806-37132010000500017"},{"key":"e_1_2_7_64_1","doi-asserted-by":"publisher","DOI":"10.2165\/00003088-198815040-00003"},{"key":"e_1_2_7_65_1","doi-asserted-by":"publisher","DOI":"10.1128\/AAC.02392-16"},{"key":"e_1_2_7_66_1","unstructured":"Guidelines for the programmatic management of drug\u2010resistant tuberculosis 2011 update."},{"key":"e_1_2_7_67_1","doi-asserted-by":"publisher","DOI":"10.1099\/00221287-13-1-176"},{"key":"e_1_2_7_68_1","doi-asserted-by":"publisher","DOI":"10.1093\/oxfordjournals.bmb.a069388"},{"key":"e_1_2_7_69_1","doi-asserted-by":"publisher","DOI":"10.1007\/978-3-642-72873-0"},{"issue":"1","key":"e_1_2_7_70_1","first-page":"1","article-title":"The intravenous administration of a high concentration of Para\u2010aminosalicylic acid (PAS)","volume":"7","author":"Naito M","year":"1957","journal-title":"Acta Tuberc Jpn"},{"issue":"6","key":"e_1_2_7_71_1","first-page":"849","article-title":"Comparison of single and divided daily dosages of isoniazid and PAS in the treatment of pulmonary tuberculosis. XV. A report of the veterans administration\u2010armed forces cooperative. Study on the chemotherapy of tuberculosis","volume":"94","author":"Reisner D","year":"1966","journal-title":"Am Rev Respir Dis"},{"key":"e_1_2_7_72_1","first-page":"81","article-title":"Continued studies on the problems of PAS dosage","volume":"39","author":"Bang HO","year":"1960","journal-title":"Acta Tuberc Scand"},{"key":"e_1_2_7_73_1","doi-asserted-by":"publisher","DOI":"10.1164\/ajrccm.159.3.9807131"},{"key":"e_1_2_7_74_1","first-page":"756","article-title":"Single daily dose regimen of isoniazid and PAS in the treatment of pulmonary tuberculosis","volume":"89","author":"Wilson JL","year":"1964","journal-title":"Am Rev Respir Dis"},{"key":"e_1_2_7_75_1","doi-asserted-by":"publisher","DOI":"10.1002\/jcph.1542"},{"key":"e_1_2_7_76_1","unstructured":"WHO treatment guidelines for drug\u2010 resistant tuberculosis October 2016 Revision."},{"key":"e_1_2_7_77_1","doi-asserted-by":"publisher","DOI":"10.12659\/MSM.904682"},{"key":"e_1_2_7_78_1","doi-asserted-by":"publisher","DOI":"10.1164\/rccm.201502-0372LE"},{"key":"e_1_2_7_79_1","doi-asserted-by":"publisher","DOI":"10.1093\/cid\/ciz074"}],"container-title":["British Journal of Clinical Pharmacology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1111\/bcp.14395","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/full-xml\/10.1111\/bcp.14395","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/bpspubs.onlinelibrary.wiley.com\/doi\/pdf\/10.1111\/bcp.14395","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,9,4]],"date-time":"2023-09-04T13:01:46Z","timestamp":1693832506000},"score":1,"resource":{"primary":{"URL":"https:\/\/bpspubs.onlinelibrary.wiley.com\/doi\/10.1111\/bcp.14395"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2020,6,21]]},"references-count":78,"journal-issue":{"issue":"11","published-print":{"date-parts":[[2020,11]]}},"alternative-id":["10.1111\/bcp.14395"],"URL":"https:\/\/doi.org\/10.1111\/bcp.14395","archive":["Portico"],"relation":{},"ISSN":["0306-5251","1365-2125"],"issn-type":[{"value":"0306-5251","type":"print"},{"value":"1365-2125","type":"electronic"}],"subject":[],"published":{"date-parts":[[2020,6,21]]}}}