The studies proposed involve clinical and laboratory investigations in adult patients with heterozygous familial hypercholesterolemia (HFH). Mevinolin is a specific competitive inhibitor of HMG CoA reductase, the rate limiting enzyme in cholesterol biosynthesis, and has been shown to be a hypolipidemic agent in previously refractory patients. We plan to examine changes in the plasma concentrations of mevalonic acid in patients with HFH given single oral doses of mevinolin and to determine whether a single oral dose of mevinolin given in the evening will abolish the nocturnal increase in mevalonic acid concentrations previously reported in normal subjects. Changes in the 24-hour excretion of mevalonic acid will also be examined in patients treated with increasing doses of mevinolin (5 mg b.i.d. up to 40 mg b.i.d.) and the urinary excretion of mevalonic acid correlated with changes in the concentrations of LDL cholesterol. Changes in the composition of LDL and the distribution and composition of LDL in distinct subfractions, the latter isolated by density gradient ultracentrifugation will also be examined in patients with HFH studied on no medications, mevinolin alone, and mevinolin plus colestipol. In these same patients we will also assess changes in the concentrations of apoprotein AI, B, CIII, and E in plasma. Metabolic studies will be conducted in a subset of patients and will examine the turnover of 125I-LDL, whole body cholesterol synthesis assessed by the sterol balance technique, and the 24-hour excretion of mevalonic acid. These studies will be conducted under steady state conditions on 4 regimens: a) diet only, b) diet plus mevinolin (5 mg b.i.d.), c) diet plus 20 mg b.i.d. of mevinolin, and d) diet plus 20 mg b.i.d. of mevinolin plus colestipol. Kinetic studies also aim to examine the metabolism of two distinct subfractions in patients with HFH and the influence of single drug therapy with mevinolin on these parameters. Separate studies in 8-10 patients will also determine whether clinically effective doses (20-40 mg b.i.d.) influence the adrenal response to prolonged (36 hours) stimulation with ACTH. Does hypocholesterolemic therapy of HFH patients with an inhibitor of HMG CoA reductase influence the ability of the adrenal cortex to produce cortisol under conditions of maximal stimulation? Overall these studies should provide new information on the effects of mevinolin on cholesterol homeostasis, low density lipoprotein metabolism, and adrenal corticosteroid production in adult patients with HFH.
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