10.6084/m9.figshare.6876728.v1 Poonam Giri Poonam Giri Prashant Delvadia Prashant Delvadia Lakshmikant Gupta Lakshmikant Gupta Priyal Trivedi Priyal Trivedi Nirmal Patel Nirmal Patel Manoranjan Sharma Manoranjan Sharma Jaideep Singh Jaideep Singh Abhijit Chatterjee Abhijit Chatterjee Shekhar Kadam Shekhar Kadam Nuggehally R. Srinivas Nuggehally R. Srinivas Impact of collagen-induced arthritis on the pharmacokinetic disposition of voriconazole, a widely used antifungal agent: <i>in vitro</i> and <i>in vivo</i> investigations in DBA/1J mice Taylor & Francis Group 2018 Collagen-induced arthritis DBA/1J mice gut first-pass effect presystemic metabolism pharmacokinetics voriconazole fungal infection 2018-07-30 11:33:10 Journal contribution https://tandf.figshare.com/articles/journal_contribution/Impact_of_collagen-induced_arthritis_on_the_pharmacokinetic_disposition_of_voriconazole_a_widely_used_antifungal_agent_i_in_vitro_i_and_i_in_vivo_i_investigations_in_DBA_1J_mice/6876728 <p></p><p>Pharmacokinetics of voriconazole, an anti-fungal agent, was determined in collagen-induced arthritic (CIA) and healthy DBA/1J mice. CIA was confirmed in DBA/1J mice by clinical scoring and histological analysis.</p><p><i>In vivo</i> oral pharmacokinetic study (3 mg/kg) and <i>in vitro</i> stability assessment in liver microsomes were performed in CIA vs. healthy DBA/1J mice. Additionally, hepatic portal vein cannulated (HPVC) CIA and healthy mice were used to clarify the role of gut first-pass effect. Voriconazole/N-oxide metabolite was measured in plasma and <i>in vitro</i> samples using liquid chromatography tandem-mass spectrometry method.</p><p>Voriconazole exposure was reduced in CIA by 27% as compared to healthy mice. Formation of voriconazole N-oxide was higher in CIA mice as evidenced by higher molar C<sub>max</sub> ratio (i.e. metabolite/parent) of 2.08 vs. 1.66 in healthy mice. Because voriconazole was stable in microsomes, involvement of presystemic gut metabolism was suspected for decreased voriconazole exposure and formation of higher molar ratio of metabolite. HPVC work revealed higher formation of voriconazole N-oxide in CIA relative to healthy mice resulting in C<sub>max</sub>/AUC ratios of 0.41/0.54 and 0.08/0.17, respectively, confirming first-pass effect.</p><p>The findings may have implications in the clinical therapy of arthritis patients who are concomitantly given voriconazole for the management of fungal infections.</p><p></p> <p>Pharmacokinetics of voriconazole, an anti-fungal agent, was determined in collagen-induced arthritic (CIA) and healthy DBA/1J mice. CIA was confirmed in DBA/1J mice by clinical scoring and histological analysis.</p> <p><i>In vivo</i> oral pharmacokinetic study (3 mg/kg) and <i>in vitro</i> stability assessment in liver microsomes were performed in CIA vs. healthy DBA/1J mice. Additionally, hepatic portal vein cannulated (HPVC) CIA and healthy mice were used to clarify the role of gut first-pass effect. Voriconazole/N-oxide metabolite was measured in plasma and <i>in vitro</i> samples using liquid chromatography tandem-mass spectrometry method.</p> <p>Voriconazole exposure was reduced in CIA by 27% as compared to healthy mice. Formation of voriconazole N-oxide was higher in CIA mice as evidenced by higher molar C<sub>max</sub> ratio (i.e. metabolite/parent) of 2.08 vs. 1.66 in healthy mice. Because voriconazole was stable in microsomes, involvement of presystemic gut metabolism was suspected for decreased voriconazole exposure and formation of higher molar ratio of metabolite. HPVC work revealed higher formation of voriconazole N-oxide in CIA relative to healthy mice resulting in C<sub>max</sub>/AUC ratios of 0.41/0.54 and 0.08/0.17, respectively, confirming first-pass effect.</p> <p>The findings may have implications in the clinical therapy of arthritis patients who are concomitantly given voriconazole for the management of fungal infections.</p>