Effects of mineral oil administration on the pharmacokinetics, metabolism and pharmacodynamics of atorvastatin and pravastatin in mice and dogs.

Autor: Gopaul VS; Early CVRM, BioPharmaceuticals R&D, AstraZeneca, Gothenburg, Sweden., Pieterman EJ; The Netherlands Organization for Applied Scientific Research (TNO)-Metabolic Health Research, Leiden, Netherlands., Princen HMG; The Netherlands Organization for Applied Scientific Research (TNO)-Metabolic Health Research, Leiden, Netherlands., Bergenholm L; Early CVRM, BioPharmaceuticals R&D, AstraZeneca, Gothenburg, Sweden., Lundborg E; Advanced Drug Delivery, Pharmaceutical Sciences, BioPharmaceuticals R&D, AstraZeneca, Gothenburg, Sweden., Cavallin A; Early CVRM, BioPharmaceuticals R&D, AstraZeneca, Gothenburg, Sweden., Johansson MJ; Early CVRM, BioPharmaceuticals R&D, AstraZeneca, Gothenburg, Sweden., Hawthorne G; Integrated Bioanalysis, Clinical Pharmacology & Safety Sciences, R&D, AstraZeneca, Cambridge, UK., Björkbom A; Early CVRM, BioPharmaceuticals R&D, AstraZeneca, Gothenburg, Sweden., Hammarberg M; Oral Product Development, Pharmaceutical Technology & Development, Operations, AstraZeneca, Gothenburg, Sweden., Li X; Early CVRM, BioPharmaceuticals R&D, AstraZeneca, Gothenburg, Sweden., Jarke A; Advanced Drug Delivery, Pharmaceutical Sciences, BioPharmaceuticals R&D, AstraZeneca, Gothenburg, Sweden., Bright J; New Modalities and Parenteral Development, Pharmaceutical Technology & Development, Operations, AstraZeneca, Macclesfield, UK., Svensson L; Early CVRM, BioPharmaceuticals R&D, AstraZeneca, Gothenburg, Sweden., Jansson-Löfmark R; Early CVRM, BioPharmaceuticals R&D, AstraZeneca, Gothenburg, Sweden., Abrahamsson B; Oral Product Development, Pharmaceutical Technology & Development, Operations, AstraZeneca, Gothenburg, Sweden. Electronic address: bertil.abrahamsson@AstraZeneca.com., Agrawal R; Global Cardiovascular Renal and Metabolism, BioPharmaceuticals R&D, AstraZeneca, Gothenburg, Sweden., Hurt-Camejo E; Early CVRM, BioPharmaceuticals R&D, AstraZeneca, Gothenburg, Sweden.
Jazyk: angličtina
Zdroj: European journal of pharmaceutical sciences : official journal of the European Federation for Pharmaceutical Sciences [Eur J Pharm Sci] 2021 Jun 01; Vol. 161, pp. 105776. Date of Electronic Publication: 2021 Mar 02.
DOI: 10.1016/j.ejps.2021.105776
Abstrakt: 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 C62L high 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.
(Copyright © 2021. Published by Elsevier B.V.)
Databáze: MEDLINE
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