Ramharack R, Spahr M A, Hicks G W, Kieft K A, Brammer D W, Minton L L, Newton R S
Parke-Davis Pharmaceutical Research, Division of Warner-Lambert Company, Ann Arbor, MI 48105, USA.
J Lipid Res. 1995 Jun;36(6):1294-304.
Eight male cynomolgus monkeys (Macaca fascicularis) on a normal chow diet were orally administered gemfibrozil daily using a weekly rising dose protocol for 3 weeks (50, 125, and 200 mg/kg per day). At these drug doses, Lp[a] levels were reduced: 83.7% +/- 3.2 (SEM), (P < 0.024); 63.7% +/- 4.1 (P < 0.013); and 36.2% +/- 1.1 (P < 0.002), respectively, of pretreatment values. Lp[a] reduction was directly related to blood gemfibrozil concentration (range 36-428 microM, r = 0.969) and occurred without concomitant changes in apolipoprotein B. Three weeks posttreatment Lp[a] levels returned to pretreatment values. A specific ribonuclease protection assay demonstrated that liver apolipoprotein[a] (apo[a]) mRNA expression was decreased in all animals to an average of 19.1% +/- 3.0 (P < 0.0026), of pretreatment values after the 200 mg/kg treatment, whereas, albumin, apolipoprotein A-I, apolipoprotein E, and glyceraldehyde-3-phosphate dehydrogenase mRNAs were unchanged. Lp[a] levels were unaffected by gemfibrozil in HepG2 cells permanently transfected with an apo[a] 10-kringle cDNA construct containing partial 5'- and 3'-untranslated sequences and under control of a constitutive CMV promoter. However, both Lp[a] and apo[a] mRNA in primary cynomolgus monkey hepatocytes were coordinately lowered in a dose-dependent fashion by gemfibrozil. Thus, Lp[a] can be regulated by gemfibrozil at the level of apo[a] mRNA expression.
八只正常饮食的雄性食蟹猴（猕猴），按照每周递增剂量方案，连续3周每日口服吉非贝齐（剂量分别为50、125和200mg/kg/天）。在这些药物剂量下，脂蛋白[a]（Lp[a]）水平降低：分别为治疗前值的83.7%±3.2（标准误），（P<0.024）；63.7%±4.1（P<0.013）；以及36.2%±1.1（P<0.002）。Lp[a]的降低与血液中吉非贝齐浓度直接相关（范围为36 - 428μM，r = 0.969），且载脂蛋白B无伴随变化。治疗3周后，Lp[a]水平恢复至治疗前值。一种特异性核糖核酸酶保护试验表明，在200mg/kg治疗后，所有动物肝脏载脂蛋白[a]（apo[a]）mRNA表达均降低至治疗前值的平均19.1%±3.0（P<0.0026），而白蛋白、载脂蛋白A-I、载脂蛋白E和甘油醛-3-磷酸脱氢酶mRNA未发生变化。在稳定转染了包含部分5'和3'非翻译序列且受组成型巨细胞病毒启动子控制的apo[a] 10 - kringle cDNA构建体的HepG2细胞中，吉非贝齐对Lp[a]水平无影响。然而，在原代食蟹猴肝细胞中，吉非贝齐以剂量依赖方式使Lp[a]和apo[a] mRNA协同降低。因此，吉非贝齐可在apo[a] mRNA表达水平调节Lp[a]。
