Itraconazole is a synthetic triazole antifungal agent which is known to be a potent inhibitor of cytochrome P450 (CYP) 3A4, and may cause drug-drug interactions with the many drugs metabolized by this route, including some statins. In this study, the influence of concomitant administration of a single oral dose of pitavastatin with itraconazole at steady state was investigated to determine the potential for pharmacokinetic interaction and any effects on safety. Eighteen subjects were enrolled into the study. The AUC and Cmax of pitavastatin alone were 138 ng h/mL and 63.8 ng/mL, and pitavastatin with itraconazole were 106 ng h/mL and 49.5 ng/mL, respectively. Comparison of the 90% confidence interval of the geometric mean ratio of AUC0-t and Cmax against a standard reference of 0.80-1.25 demonstrated that the lower limit was breached for both pitavastatin and its lactone metabolite (0.71-0.84 and 0.69-0.88 for AUC0-t and Cmax , respectively, for pitavastatin, 0.86-0.97 and 0.76-0.86 for AUC0-t and Cmax , respectively, for pitavastatin lactone). The safety and tolerability of pitavastatin was not affected by co-administration with itraconazole. This study suggests that pitavastatin is not a CYP3A4 substrate in humans.
In Dictyostelium discoideum Ax-2 cells, a specific checkpoint (PS point) from which cells enter the differentiation phase in response to starvation has been specified in the cell cycle. Using the differential display method, we isolated a novel gene, dia1 (differentiation-associated gene 1), that is specifically expressed in cells differentiating from the PS point. The dia1 mRNA has an open reading frame of 1,368 bp and is deduced to code for a 48.6 kDa protein (DIA1). The DIA1 protein is highly serine-rich and the serine residues are predominantly located in the C-terminal region. After the PSORT II search, the protein is predicted to be GPI-anchored at the plasma membrane. Unexpectedly, dia1 overexpression rather impaired the progression of differentiation, possibly coupled with the reduced expression of early genes such as cAMP receptor1 (car1). The inhibitory effect of dia1 expression on early differentiation was almost completely nullified by externally applied cAMP pulses. In contrast to dia1 overexpression, antisense RNA-mediated dia1 inactivation was found to enhance the initial step of cell differentiation, as exemplified by precocious expression of car1 and other early genes. We discuss the unique structure and function of DIA1 in relation to the cooperative development of cells during the establishment of multicellular organization.
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