ABSTRACT
High-risk patients with dyslipidemias resistant to diet and single-agent pharmacotherapy may require combination therapy to achieve target levels of low density lipoprotein, triglycerides, and high density lipoprotein. Combinations of fibrates and 3-hydroxy-3-methylglutaryl-coenzyme A reductase inhibitors are effective, but because of safety concerns related to myopathy and rhabdomyolysis, it is important to consider the possibility of pharmacokinetic interactions when such combinations are used. In this study, the area under the curve, maximum plasma concentration, and time to maximum concentration for fluvastatin and gemfibrozil are compared, when used alone and in combination, in patients with hyperlipidemia and either coronary or carotid atherosclerosis, or a family history of coronary artery disease. A total of 17 patients were studied in a random sequence, open-label, crossover study of fluvastatin at 20 mg twice daily, gemfibrozil at 600 mg twice daily, and the combination of the 2 drugs. No significant difference was observed in area under the curve, maximum plasma concentration, and time to maximum concentration when comparing the combination with each drug alone. These pharmacokinetic data add support to the clinical observations that the combination of fluvastatin and gemfibrozil is both effective and safe.
Subject(s)
Anticholesteremic Agents/pharmacokinetics , Fatty Acids, Monounsaturated/pharmacokinetics , Gemfibrozil/pharmacokinetics , Hydroxymethylglutaryl CoA Reductases/pharmacokinetics , Hydroxymethylglutaryl-CoA Reductase Inhibitors , Hyperlipidemias/drug therapy , Indoles/pharmacokinetics , Anticholesteremic Agents/administration & dosage , Anticholesteremic Agents/therapeutic use , Arteriosclerosis/blood , Arteriosclerosis/complications , Carotid Stenosis/blood , Carotid Stenosis/complications , Coronary Artery Disease/blood , Coronary Artery Disease/complications , Coronary Disease/blood , Coronary Disease/genetics , Cross-Over Studies , Drug Combinations , Fatty Acids, Monounsaturated/administration & dosage , Fatty Acids, Monounsaturated/therapeutic use , Female , Fluvastatin , Gemfibrozil/administration & dosage , Gemfibrozil/therapeutic use , Humans , Hydroxymethylglutaryl CoA Reductases/administration & dosage , Hydroxymethylglutaryl CoA Reductases/therapeutic use , Indoles/administration & dosage , Indoles/therapeutic use , Lipoproteins, HDL/blood , Lipoproteins, LDL/blood , Male , Middle Aged , Pilot Projects , Placebos , Safety , Triglycerides/bloodABSTRACT
The isolation and characterization of a flavanone-specific 7-O-glucosyltransferase and its resolution from other glucosyltransferases in Citrus paradisi (grapefruit) seedlings is described. This new enzyme in the subclass 2.4.1 catalyzes the glucosylation of the 7-OH group of naringenin (4',5',7-trihydroxyflavanone) to prunin and has been purified (943-fold) by fractional precipitation with ammonium sulfate and successive chromatography on Sephadex G-100, hydroxyapatite, UDP-glucuronic acid agarose, Mono Q, and Mono P columns. It has a pH optimum of 7.5-8.0, an apparent pI of 4.3, and an apparent Mr of 54,900. This glucosyltransferase has an expressed specificity for the 7-position of the flavanones naringenin (Kmapp 62 microM; Kmapp UDPG 51 microM) and hesperetin (Kmapp 124 microM; Kmapp UDPG 243 microM) and did not accept other flavone or flavonol aglycones. Characteristics of other flavonoid glucosyltransferase activities found in grapefruit seedlings are also described.
Subject(s)
Glucosyltransferases/isolation & purification , Plants/enzymology , Ammonium Sulfate , Chromatography , Chromatography, Affinity , Chromatography, Gel , Chromatography, Ion Exchange , Durapatite , Electrophoresis, Polyacrylamide Gel , Fruit , Glucosyltransferases/metabolism , Hydroxyapatites , Kinetics , Molecular Weight , Substrate SpecificityABSTRACT
A monoclonal antibody to a partially purified preparation of 2'-O-glucosyltransferase was produced by in vitro immunization of spleen cells from BALB/c mice, followed by fusion with mouse myeloma cells. Hybridoma culture supernatants were screened by enzyme-linked immunosorbent assay for (i) their ability to produce immunoglobulins and (ii) their immunoreactivity with a partially purified enzyme preparation. The majority of the immunoglobulin-producing hybridomas were IgM secretors. Two highly immunoreactive IgM-secreting clones were chosen for further characterization. The supernatant fraction from a culture of one of these clones displayed 50% inhibition of the 2'-O-glucosyltransferase activity. The native form of the 2'-O-glucosyltransferase was essential for recognition, suggesting that the epitope recognized by the antibody is a conformational discontiguous one.
