{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2023,9,13]],"date-time":"2023-09-13T16:32:19Z","timestamp":1694622739045},"reference-count":15,"publisher":"American Society for Microbiology","issue":"4","license":[{"start":{"date-parts":[[2000,4,1]],"date-time":"2000-04-01T00:00:00Z","timestamp":954547200000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/journals.asm.org\/non-commercial-tdm-license"}],"content-domain":{"domain":["journals.asm.org"],"crossmark-restriction":true},"short-container-title":["Antimicrob Agents Chemother"],"published-print":{"date-parts":[[2000,4]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n          <jats:p>\n            The pharmacokinetics and distribution in tissue of several novel triazole antifungal agents were studied in different animal species in order to select an appropriate lead compound. The purpose of the study was also to determine species differences in pharmacokinetics for SYN azoles to select the most appropriate species for secondary efficacy and toxicological evaluation of the selected compound. SYN-2836, SYN-2869, SYN-2903, and SYN-2921 were rapidly absorbed into the systemic circulation and reached maximum concentrations (\n            <jats:italic>C<\/jats:italic>\n            <jats:sub>max<\/jats:sub>\n            s) of 7.31 \u00b1 2.53, 6.29 \u00b1 0.85, 6.16 \u00b1 0.39, and 3.41 \u00b1 0.34 \u03bcg\/ml, respectively, in BALB\/c mice after administration of an oral dose of 50 mg\/kg of body weight, with bioavailability being greater than 45% in all mice. The areas under the concentration-time curve from time zero to infinity (AUC\n            <jats:sub>0\u2013\u221e<\/jats:sub>\n            s) after administration of a single intravenous dose of 20 mg\/kg to mice varied between 25.0 and 63.6 \u03bcg \u00b7 h\/ml. The half-life was in the range of 4.5 to 6 h. In Sprague-Dawley rats there was no significant difference in AUC\n            <jats:sub>0\u2013\u221e<\/jats:sub>\n            after administration of a single intravenous dose of 20 mg\/kg, but on oral administration, the bioavailability of SYN-2836 was extremely low, while that of SYN-2869 was only 14.7%. In New Zealand White rabbits the\n            <jats:italic>C<\/jats:italic>\n            <jats:sub>max<\/jats:sub>\n            and the time to reach\n            <jats:italic>C<\/jats:italic>\n            <jats:sub>max<\/jats:sub>\n            for SYN-2836 and SYN-2869 after administration of a single oral dose of 50 mg\/kg were similar. There were significant differences in AUC\n            <jats:sub>0\u2013\u221e<\/jats:sub>\n            and half-life between SYN-2836 and SYN-2869. On the other hand, in beagle dogs the\n            <jats:italic>C<\/jats:italic>\n            <jats:sub>max<\/jats:sub>\n            and AUC\n            <jats:sub>0\u2013\u221e<\/jats:sub>\n            of SYN-2836 after administration of a single oral dose of 30 mg\/kg were 4.82 \u00b1 1.54 \u03bcg\/ml and 41.8 \u00b1 15.7 \u03bcg \u00b7 h\/ml, respectively, which were threefold higher than those of SYN-2869. The concentrations of the SYN compounds in tissue indicated that the AUC\n            <jats:sub>0\u2013\u221e<\/jats:sub>\n            s of SYN-2836, SYN-2869, SYN-2903, and SYN-2921 in mouse lungs were significantly different from each other. The ratios of the concentrations of the SYN azoles in lungs to those in plasma were also significantly different from those for itraconazole. Among the SYN azoles the highest concentration in the lungs was found for SYN-2869. The higher level of distribution of SYN-2869 into lung tissue was considered to contribute to the potent efficacy in respiratory tract infection models compared with the potency of itraconazole. Significant differences in the pharmacokinetics of these compounds were observed in different animal species, and selection of an animal model for further evaluation was based on results obtained from these studies.\n          <\/jats:p>","DOI":"10.1128\/aac.44.4.910-915.2000","type":"journal-article","created":{"date-parts":[[2002,7,27]],"date-time":"2002-07-27T10:06:42Z","timestamp":1027764402000},"page":"910-915","update-policy":"http:\/\/dx.doi.org\/10.1128\/asmj-crossmark-policy-page","source":"Crossref","is-referenced-by-count":6,"title":["Interspecies Comparison of Pharmacokinetics of the Novel Triazole Antifungal Agent SYN-2869 and Its Derivatives"],"prefix":"10.1128","volume":"44","author":[{"given":"Jehangir K.","family":"Khan","sequence":"first","affiliation":[{"name":"<!--label omitted: 1-->Division of Biopharmaceutics and Pharmacokinetics, NAEJA Pharmaceutical Inc., Edmonton, Alberta T6E 5V2, Canada"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Hashem","family":"Montaseri","sequence":"additional","affiliation":[{"name":"<!--label omitted: 1-->Division of Biopharmaceutics and Pharmacokinetics, NAEJA Pharmaceutical Inc., Edmonton, Alberta T6E 5V2, Canada"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Marzena","family":"Poglod","sequence":"additional","affiliation":[{"name":"<!--label omitted: 1-->Division of Biopharmaceutics and Pharmacokinetics, NAEJA Pharmaceutical Inc., Edmonton, Alberta T6E 5V2, Canada"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Hai-Zhi","family":"Bu","sequence":"additional","affiliation":[{"name":"<!--label omitted: 1-->Division of Biopharmaceutics and Pharmacokinetics, NAEJA Pharmaceutical Inc., Edmonton, Alberta T6E 5V2, Canada"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Zhong","family":"Zuo","sequence":"additional","affiliation":[{"name":"<!--label omitted: 1-->Division of Biopharmaceutics and Pharmacokinetics, NAEJA Pharmaceutical Inc., Edmonton, Alberta T6E 5V2, Canada"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sameeh M.","family":"Salama","sequence":"additional","affiliation":[{"name":"<!--label omitted: 1-->Division of Biopharmaceutics and Pharmacokinetics, NAEJA Pharmaceutical Inc., Edmonton, Alberta T6E 5V2, Canada"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Mohsen","family":"Daneshtalab","sequence":"additional","affiliation":[{"name":"<!--label omitted: 1-->Division of Biopharmaceutics and Pharmacokinetics, NAEJA Pharmaceutical Inc., Edmonton, Alberta T6E 5V2, Canada"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ronald G.","family":"Micetich","sequence":"additional","affiliation":[{"name":"<!--label omitted: 1-->Division of Biopharmaceutics and Pharmacokinetics, NAEJA Pharmaceutical Inc., Edmonton, Alberta T6E 5V2, Canada"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"235","reference":[{"key":"e_1_3_1_2_2","first-page":"567","article-title":"Treatment of oral candidosis with itraconazole: a review.","volume":"23","author":"Blachford N. R.","year":"1990","unstructured":"Blachford N. R. Treatment of oral candidosis with itraconazole: a review. J. Am. Acad. Dermatol. 23 1990 567 570","journal-title":"J. Am. Acad. Dermatol."},{"key":"e_1_3_1_3_2","doi-asserted-by":"crossref","first-page":"S318","DOI":"10.1093\/clinids\/12.Supplement_3.S318","article-title":"Pharmacokinetics and tissue penetration of Fluconazole in humans.","volume":"12","author":"Brammer K. W.","year":"1990","unstructured":"Brammer K. W. Farrow P. R. Faulkner J. K. Pharmacokinetics and tissue penetration of Fluconazole in humans. Rev. Infect. Dis. 12 (Suppl. 3) 1990 S318 S326","journal-title":"Rev. Infect. Dis."},{"key":"e_1_3_1_4_2","first-page":"S-40","article-title":"Identification of the phase I metabolites of novel antifungal agents SYN-2836, SYN-2869, SYN-2903 and SYN-2921 in liver microsomes using electrospray HPLC\/MS\/MS: interspecies comparison and role of CYP3A4.","volume":"1","author":"Bu H. Z.","year":"1998","unstructured":"Bu H. Z. Khan J. K. Montaseri H. Micetich R. G. Daneshtalab M. Identification of the phase I metabolites of novel antifungal agents SYN-2836, SYN-2869, SYN-2903 and SYN-2921 in liver microsomes using electrospray HPLC\/MS\/MS: interspecies comparison and role of CYP3A4. Pharm. Sci. 1 (Suppl. 1) 1998 S-40","journal-title":"Pharm. Sci."},{"key":"e_1_3_1_5_2","doi-asserted-by":"crossref","first-page":"1185","DOI":"10.1002\/(SICI)1096-9888(199911)34:11<1185::AID-JMS879>3.0.CO;2-R","article-title":"Structure elucidation of three isomeric metabolites of SYN-2836, a novel antifungal agent, in dogs via LC\/MS and LC\/MS\/MS methodologies.","volume":"34","author":"Bu H. Z.","year":"1999","unstructured":"Bu H. Z. Poglod M. Micetich R. G. Khan J. K. Structure elucidation of three isomeric metabolites of SYN-2836, a novel antifungal agent, in dogs via LC\/MS and LC\/MS\/MS methodologies. J. Mass Spectrom. 34 1999 1185 1194","journal-title":"J. Mass Spectrom."},{"key":"e_1_3_1_6_2","unstructured":"Bu H. Z. M. Poglod R. G. Micetich and J. K. Khan. Novel sample preparation method facilitating identification of urinary drug metabolites by liquid chromatography-tandem mass spectrometry. J. Chromatogr. B in press."},{"key":"e_1_3_1_7_2","first-page":"27","article-title":"Pharmacokinetics of itraconazole.","volume":"37","author":"Cauwenbergh G.","year":"1994","unstructured":"Cauwenbergh G. Pharmacokinetics of itraconazole. Mycoses 37 (Suppl.) 1994 27 33","journal-title":"Mycoses"},{"key":"e_1_3_1_8_2","first-page":"5-22N","article-title":"Amphotericin B revisited: reassessment of toxicity.","volume":"88","author":"Clements J. S.","year":"1990","unstructured":"Clements J. S. Jr. Peacock J. E. Jr. Amphotericin B revisited: reassessment of toxicity. Am. J. Med. 88 1990 5-22N 5-27N","journal-title":"Am. J. 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