We showed the difference between the acid and lactone forms in terms of drug interaction. The lipophilicity could be one of the important factors for inhibitory effects. In the case of statins, it is important to examine the effects of both forms to understand the events found in clinical settings, including the pleiotropic effects.

The effects of micafungin on cytochrome P450 3A4 (CYP3A4) metabolic and multidrug resistance protein 1 (MDR1) transport activities were investigated and compared with those of amphotericin B and four azole antifungal drugs (ketoconazole, itraconazole, fluconazole and miconazole). The effects on the metabolic activity of CYP3A4 were examined by measuring nifedipine oxidase activity in human liver microsomes and the effects on MDR1 transport activity were evaluated using [3H]digoxin in MDR1-overexpressing LLC-GA5-COL150 cells. An inhibitory effect on CYP3A4 activity was found for ketoconazole, itraconazole and miconazole, with 50% inhibitory concentrations of 11.7, 32.6 and 74.2 nM, respectively. Fluconazole and micafungin had only slight inhibitory effects and amphotericin B had no effect. The MDR1-mediated transport of [3H]digoxin was inhibited by ketoconazole and itraconazole, and slightly by miconazole. It is suggested that micafungin and amphotericin B would be unlikely to cause drug-drug interactions by inhibition of CYP3A4 and MDR1. A positive correlation between the inhibitory effects on CYP3A4 and MDR1 activities was observed, and the physicochemical mechanisms involved and impact on clinical treatment should be studied further.

To clarify the effect of therapeutic moderate hypothermia on drug distribution, transepithelial transport via multi-drug resistance protein 1 (MDR1) (also called P-glycoprotein or ABCB1) was evaluated at various temperatures in vitro using LLC-GA5-COL150 cells, which were established by transfecting human MDR1 complementary deoxyribonucleic acid into kidney epithelial LLC-PK 1 cells and express MDR1 on the apical membrane. MDR1 is expressed in the blood-brain barrier to limit drug distribution to the brain by exporting exogenous substances including calcium blockers and antiarrhythmic drugs. Digoxin was used as a typical substrate, as well as the non-substrate tetracycline and paracellular marker inulin. MDR1-mediated transport of digoxin decreased at lower temperatures. Transport of tetracycline also decreased at lower temperatures, probably due to changes in membrane fluidity. However, no change was found at over 329 C, suggesting that passive diffusion does not change during moderate hypothermia. The distribution of MDR1 substrates should be considered during hypothermic conditions, as the clinical outcome could be affected.