Gopaul V Sashi, Pieterman Elsbet J, Princen Hans M G, Bergenholm Linnéa, Lundborg Eva, Cavallin Anders, Johansson Magnus J, Hawthorne Glen, Björkbom Anders, Hammarberg Maria, Li XueQing, Jarke Annica, Bright Jonathan, Svensson Lena, Jansson-Löfmark Rasmus, Abrahamsson Bertil, Agrawal Rahul, Hurt-Camejo Eva
Early CVRM, BioPharmaceuticals R&D, AstraZeneca, Gothenburg, Sweden.
The Netherlands Organization for Applied Scientific Research (TNO)-Metabolic Health Research, Leiden, Netherlands.
Eur J Pharm Sci. 2021 Jun 1;161:105776. doi: 10.1016/j.ejps.2021.105776. Epub 2021 Mar 2.
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 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.
我们在动物模型中研究了矿物油对他汀类药物药代动力学和炎症标志物的影响。一种新的合成策略产生了区域异构体，有助于在C57BL/6NCrl小鼠中表征亲脂性他汀类药物阿托伐他汀的主要代谢物（M1）。小鼠体内M1的化学结构被确认为邻羟基β-氧化阿托伐他汀。在给予5mg/kg/天或10mg/kg/天阿托伐他汀的C57BL6/J小鼠中，评估阿托伐他汀和M1的药代动力学及炎症标志物，给药方式为单次给药或连续21天给药，同时给予或不给予10μL或30μL矿物油。在给予或不给予矿物油的情况下，对阿托伐他汀进行单次或重复给药后，未观察到小鼠体内阿托伐他汀或M1的血浆暴露存在一致差异。然而，连续21天给予10mg/kg阿托伐他汀并同时给予30μL矿物油的小鼠，其血清淀粉样蛋白A的血浆水平显著升高（平均值9.6μg/mL，无矿物油时为7.9μg/mL；p<0.01），C62L B细胞比例显著增加（平均值18%，无矿物油时为12%；p = 0.04）。对于评估的其他炎症标志物，未发现统计学上的显著差异。在犬类中，单次给予10mg阿托伐他汀加40mg普伐他汀（一种亲水性他汀类药物）并同时给予或不给予2g矿物油后，评估阿托伐他汀、其两种羟基代谢物和普伐他汀的药代动力学。在犬类中，给予或不给予矿物油进行单次给药后，阿托伐他汀、羟基化阿托伐他汀代谢物或普伐他汀的药代动力学无显著差异。总体而言，小鼠和犬类的研究结果表明，矿物油不影响阿托伐他汀或普伐他汀的药代动力学，但长期口服可能会引起低度炎症，这值得进一步研究。
