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>