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
Creators: name: Giri, Poonam
name: Delvadia, Prashant
name: Lakshmikant Gupta
name: Priyal Trivedi
name: Patel, Nirmal
name: Sharma, Manoranjan
name: Jaideep Singh
name: Abhijit Chatterjee
name: Kadam, Shekhar
name: Nuggehally R. Srinivas
Publisher: name: Taylor & Francis
Year: 2018
Subjects: subject: Biochemistry
subject: Medicine
subject: Microbiology
subject: FOS: Biological sciences
subject: FOS: Biological sciences
subject: Genetics
subject: Physiology
subject: Pharmacology
subject: 59999 Environmental Sciences not elsewhere classified
subject: FOS: Earth and related environmental sciences
subject: FOS: Earth and related environmental sciences
subject: 39999 Chemical Sciences not elsewhere classified
subject: FOS: Chemical sciences
subject: FOS: Chemical sciences
subject: Ecology
subject: Science Policy
subject: Immunology
subject: FOS: Clinical medicine
subject: FOS: Clinical medicine
subject: Cancer

description: 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.<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.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.The findings may have implications in the clinical therapy of arthritis patients who are concomitantly given voriconazole for the management of fungal infections. 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. <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. 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. The findings may have implications in the clinical therapy of arthritis patients who are concomitantly given voriconazole for the management of fungal infections.