MDR1 genotype-related pharmacokinetics of digoxin after single oral administration in healthy Japanese subjects.

PURPOSE: To evaluate the MDR1 genotype frequency in the Japanese population and to study the relationship between the MDR1 genotype and the pharmacokinetics of digoxin after single oral administration in healthy subjects. METHODS: The MDR1 genotype at exon 26 was determined in 114 healthy volunteers by polymerase chain reaction-restriction fragment length polymorphism. The serum concentration-time profile of digoxin was examined after single oral administration at a dose of 0.25 mg. RESULTS: It was found that 35.1 % (40/114) of subjects were homozygous for the wild-type allele (C/C). 52.6% (60/114) were compound heterozygotes with a mutant T-allele (C3435T) (C/T), and 12.3% (14/114) were homozygous for the mutant allele (T/T). There was no effect of gender or age on the distribution. The serum concentration of digoxin after a single oral administration increased rapidly, attaining a steady state in all subjects; however, it was lower in the subjects harboring the T-allele. AUC0-4 h values (+/-SD) were 4.11 +/- 0.57, 3.20 +/- 0.49. and 3.27 +/- 0.58 ng h/ml, respectively, with a significant difference between C/C and C/T or T/T. CONCLUSIONS: The serum concentration of digoxin after single oral administration was lower in the subjects harboring a mutant allele (C3435T) at exon 26 of the MDR1 gene.

Reversal effects of antifungal drugs on multidrug resistance in MDR1-overexpressing HeLa cells.

In this study, the antiproliferative effects of vinblastine (VLB), paclitaxel (TXL), doxorubicin (DXR), daunorubicin (DNR) and 5-fluorouracil (5-FU) were assessed in the human cervical carcinoma cell line HeLa-Ohio (HeLa) and Hvr100-6 cells, established by growing the parental HeLa cells in the presence of progressively greater concentrations of VLB in the culture medium. Flow cytometric analysis indicated the induction of MDR1 (P-glycoprotein) in Hvr100-6 cells with no alterations in levels of multidrug resistance-associated protein (MRP). Resistance to VLB, TXL, DXR and DNR was found in Hvr100-6 cells with relative resistances of ca. 300, 4000, 50 and 200, respectively, whereas no resistance was found to 5-FU. The reversal effects of antifungal drugs, fluconazole, itraconazole, ketoconazole, miconazole and amphotericin B on multidrug resistance were also assessed using Hvr100-6 cells. Itraconazole was found to have potent reversal effect on the resistance to VLB and TXL, but the others had no such effect. This reversal effect of itraconazole was concentration-dependent, with dose modifying factors of 3.2, 10.1 and 435.7 at 0.1, 0.25 and 0.5 microM of itraconazole, respectively. In addition, this reversal effect of itraconazole was explained by the inhibition of accumulation of the anticancer drugs.

Effects of propofol on hemodynamic and inflammatory responses to endotoxemia in rats.

OBJECTIVE: To document the effects of propofol on the hemodynamic and inflammatory responses to endotoxemia in an animal model. DESIGN: Randomized, prospective laboratory study. SETTING: University experimental laboratory. SUBJECTS: Thirty-two male rats. INTERVENTIONS: The animals were randomly assigned to one of four groups: a) endotoxemia group (n = 8), which received intravenous Escherichia coli endotoxin (15 mg/kg over 2 mins); b) control group (n = 8), which was treated identically to the endotoxemia group except for the substitution of 0.9% saline for endotoxin; c) propofol group (n = 8), which was treated identically to the control group but also received propofol (10 mg/kg bolus, followed by infusion at 10 mg/kg/hr) immediately after the injection of 0.9% saline; and d) propofol-endotoxemia group (n = 8), which was treated identically to the endotoxemia group with the additional administration of propofol (10 mg/kg bolus, followed by infusion at 10 mg/kg/hr) immediately after endotoxin injection. MEASUREMENTS AND MAIN RESULTS: Hemodynamics, arterial blood gases, and acid-base status were recorded and the blood propofol concentrations and plasma cytokine concentrations were measured during the 5-hr observation. Microscopic findings of lung tissue for each group were obtained at necropsy. The systolic arterial pressure and heart rate of the propofol-endotoxemia group were similar to those of the endotoxemia group. The increases in the plasma cytokine (tumor necrosis factor, interleukin-6, and interleukin-10) concentrations, in the base deficit, and in the infiltration of neutrophils in the air space or vessel walls of the lungs were attenuated in the propofol-endotoxemia group compared with the endotoxemia group. CONCLUSIONS: Propofol attenuated cytokine responses, base deficit, and activation of neutrophils to endotoxemia. These findings suggest that propofol may inhibit inflammatory response and prevent the development of metabolic acidosis during endotoxemia.

Non-enzymatic oligomerization of racemic adenosine 5'-phosphorimidazolide on Na(+)-montmorillonite.

In this study, we have investigated non-enzymatic oligomerization of an activated racemic mononucleotide in the presence of Na(+)-montmorillonite. Oligomers up to the decamer in length were formed by oligomerization reactions of activated D- and L-mononucleotides. Similarly, oligomerization of an activated racemic mononucleotide results in the formation of oligomers up to the octamer. These results suggest that montmorillonite catalysis is quite efficient for the oligomerization of racemic monomers, though it is somewhat less efficient than that of D- and L-monomers.