Pharmacokinetics of dirithromycin in patients with impaired hepatic function.

Dirithromycin is a new macrolide antibiotic. A non-blinded, non-comparative study was performed in patients with mild, (Pugh and Childs Grade A) chronic, stable, impaired hepatic function (CSIHF) to determine the single- and multiple-dose pharmacokinetics and safety in such patients. Eight volunteers had disease affecting primarily the hepatic parenchyma, eight had primarily biliary system diseases and five healthy volunteers served as the control population. CSIHF patients and healthy volunteers all received a single dose of dirithromycin 500 mg po and 2 weeks later a 10-day course of dirithromycin 500 mg po once a day. Blood and urine samples were obtained with single dose administration and on days 1 and 10 of multiple-dose administration. The area under the serum concentration versus time curve (AUC) was higher with multiple-dose administration than with single-dose administration in all three treatment groups; however, the difference was not statistically significant between the treatment groups. With multiple-dose administration, peak serum concentrations (Cmax) were 0.69 +/- 0.74, 0.34 +/- 0.15, and 0.78 +/- 0.25 mg/L and the AUC0-24 were 6.45 +/- 6.27, 4.05 +/- 1.59, and 6.60 +/- 2.89 mg.h/L in normal, parenchymal, and biliary volunteers, respectively. Cmax and AUC were consistently lower in subjects with parenchymal disease than those with biliary disease or normal volunteers but the reason for this is unclear. Statistically significant differences in clearance, due to lower non-renal and renal clearances in the biliary volunteers with single- or multiple-dose administration were found between the groups but these differences were not thought to be clinically or pharmacokinetically relevant for short-term antibiotic administration. With dirithromycin administered for 14 days or less, no dosage adjustment should be necessary in patients with mild hepatic insufficiency.

Regulation of gene expression and synthesis and degradation of 3-hydroxy-3-methylglutaryl coenzyme A reductase by micellar cholesterolin CaCo-2 cells.

To investigate whether, and by what mechanisms, luminal (dietary) cholesterol regulates cholesterol synthesis in human intestinal cells, HMG-CoA reductase activity, gene expression, synthesis, and degradation were investigated in CaCo-2 cells exposed to taurocholate micelles containing cholesterol. In cells incubated with cholesterol solubilized in 5 mM taurocholate and 30 microM monoolein, HMG-CoA reductase activity was decreased. 25-Hydroxycholesterol, delivered to the cells in the same manner as native cholesterol, was significantly more potent in inhibiting reductase activity and was used, therefore, to investigate mechanisms for sterol regulation. Cells incubated with taurocholate micelles without cholesterol lost cellular cholesterol into the medium causing an increase in HMG-CoA reductase activity and enzyme mass. Although steady-state levels of HMG-CoA reductase mRNA were increased under conditions of cholesterol efflux, synthesis rates of reductase protein were not increased. An increase in activity and enzyme mass in cells incubated with micelles alone, however, was accompanied by a significant decrease in the rate of degradation of reductase protein. In contrast, sterol influx from taurocholate micelles was associated with a marked decrease in HMG-CoA reductase activity and mass without altering mRNA levels except at high concentrations of the polar sterol which did decrease reductase mRNA levels by 50%. The absorption of apical sterol resulted in a significant decrease in the translational efficiency of reductase mRNA and a modest increase in the rate of degradation of the enzyme. Thus, although the primary function of the enterocyte is to transport luminal (dietary) cholesterol to other tissues of the body, apically derived cholesterol enters metabolic pools within the cell which regulates its own cholesterol synthesis. Dietary cholesterol, therefore, will regulate the contribution to the total body cholesterol pool of endogenously derived cholesterol from the intestine. The mechanism for this regulation of intestinal HMG-CoA reductase by luminal cholesterol occurs primarily at the post-transcriptional level.