Print Email Facebook Twitter Effects of mineral oil administration on the pharmacokinetics, metabolism and pharmacodynamics of atorvastatin and pravastatin in mice and dogs Title Effects of mineral oil administration on the pharmacokinetics, metabolism and pharmacodynamics of atorvastatin and pravastatin in mice and dogs Author Gopaul, V.S. Pieterman, E.J. Princen, H.M.G. Bergenholm, L. Lundborg, E. Cavallin, A. Johansson, M.J. Hawthorne, G. Björkbom, A. Hammarberg, M. Li, X. Jarke, A. Bright, J. Svensson, L. Jansson-Löfmark, R. Abrahamsson, B. Agrawal, R. 1 Hurt-Camejo, E. Publication year 2021 Abstract We investigated the effects of mineral oil on statin pharmacokinetics and inflammatory markers in animal models. A new synthesis strategy produced regioisomers that facilitated the characterization of the main metabolite (M1) of atorvastatin, a lipophilic statin, in C57BL/6NCrl mice. The chemical structure of M1 in mice was confirmed as ortho-hydroxy β-oxidized atorvastatin. Atorvastatin and M1 pharmacokinetics and inflammatory markers were assessed in C57BL6/J mice given atorvastatin 5 mg/kg/day or 10 mg/kg/day, as a single dose or for 21 days, with or without 10 µL or 30 µL mineral oil. No consistent differences in plasma exposure of atorvastatin or M1 were observed in mice after single or repeat dosing of atorvastatin with or without mineral oil. However, mice administered atorvastatin 10 mg/kg with 30 µL mineral oil for 21 days had significantly increased plasma levels of serum amyloid A (mean 9.6 µg/mL vs 7.9 µg/mL without mineral oil; p < 0.01) and significantly increased proportions of C62Lhigh B cells (mean 18% vs 12% without mineral oil; p = 0.04). There were no statistically significant differences for other inflammatory markers assessed. In dogs, pharmacokinetics of atorvastatin, its two hydroxy metabolites and pravastatin (a hydrophilic statin) were evaluated after single administration of atorvastatin 10 mg plus pravastatin 40 mg with or without 2 g mineral oil. Pharmacokinetics of atorvastatin, hydroxylated atorvastatin metabolites or pravastatin were not significantly different after single dosing with or without mineral oil in dogs. Collectively, the results in mice and dogs indicate that mineral oil does not affect atorvastatin or pravastatin pharmacokinetics, but could cause low-grade inflammation with chronic oral administration, which warrants further investigation. Subject AtorvastatinInflammatory markersMineral oilPharmacodynamicsPharmacokineticsPravastatinPreclinicalBiomedical InnovationHealthy LivingLifeMHR - Metabolic Health ResearchELSS - Earth, Life and Social Sciences To reference this document use: http://resolver.tudelft.nl/uuid:df4e4610-8c7a-4313-8188-30d5b28d5689 DOI https://doi.org/10.1016/j.ejps.2021.105776 TNO identifier 952971 Source European Journal of Pharmaceutical Science, 161 (161) Document type article Files To receive the publication files, please send an e-mail request to TNO Library.