title: Gemfibrozil significantly lowers cynomolgus monkey plasma lipoprotein[a]-protein and liver apolipoprotein[a] mRNA levels.
abstract: 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.
authors.affiliation: Parke-Davis Pharmaceutical Research, Division of Warner-Lambert Company, Ann Arbor, MI 48105, USA.
authors.forename: R
authors.initials: R
authors.lastname: Ramharack
authors.forename: M A
authors.initials: MA
authors.lastname: Spahr
authors.forename: G W
authors.initials: GW
authors.lastname: Hicks
authors.forename: K A
authors.initials: KA
authors.lastname: Kieft
authors.forename: D W
authors.initials: DW
authors.lastname: Brammer
authors.forename: L L
authors.initials: LL
authors.lastname: Minton
authors.forename: R S
authors.initials: RS
authors.lastname: Newton
mesh_terms: D000818:Animals; D001054:Apolipoproteins A / Q000235:genetics*; D001055:Apolipoproteins B / Q000097:blood; D001483:Base Sequence; D002460:Cell Line; D018076:DNA, Complementary / Q000737:chemistry; D015248:Gemfibrozil / Q000494:pharmacology*; D006801:Humans; D017270:Lipoprotein(a) / Q000097:blood*; D008099:Liver / Q000187:drug effects / Q000378:metabolism*; D008252:Macaca fascicularis; D008297:Male; D008969:Molecular Sequence Data; D012333:RNA, Messenger / Q000378:metabolism*; D012260:Ribonucleases; D014162:Transfection
chemical_list: D001054:Apolipoproteins A; D001055:Apolipoproteins B; D018076:DNA, Complementary; D017270:Lipoprotein(a); D012333:RNA, Messenger; D012260:Ribonucleases; D015248:Gemfibrozil