In vivo approach for the evaluation of mechanism-based inhibition of cytochrome P450 3A in rats.

1. There have been no reports showing that the area under the concentration-time curve (AUC) of a probe drug is elevated due to mechanism-based inhibition (MBI) of drug-metabolizing enzymes in animals. This study ascertained that mechanism-based inhibitors reported to induce drug-drug interactions (DDIs) in humans also caused MBI in rats. 2. Midazolam (MDZ), mainly metabolized by cytochrome P450 3A in rats, and mibefradil, which showed the most intense time-dependent inhibition among the inhibitors tested, were selected as the probe and the inhibitor, respectively. Following pretreatment of mibefradil at 24 h before MDZ administration in rats, the C(max) and AUC values of MDZ were significantly elevated in comparison with the control. The free plasma concentration of mibefradil was substantially lower than the IC(50) value observed in the in vitro inhibition study, suggesting that the DDI was due to MBI. 3. It is concluded that the evaluation of MBI in rats in vivo in combination with in vitro data using human enzymes could be useful to evaluate risk in clinical studies.

Antiatherogenic effects of the antioxidant BO-653 in three different animal models.

Antioxidants have been proposed to have antiatherogenic potential by their inhibition of low density lipoprotein (LDL) oxidation. Here, we report an antioxidant, BO-653 (2,3-dihydro-5-hydroxy-2, 2-dipentyl-4,6-di-tert-butylbenzofuran), designed to exhibit antioxidative potency comparable to that of alpha-tocopherol, but yet possess a high degree of lipophilicity comparable to that of probucol. BO-653 exhibits a high affinity for LDL and is well distributed in aortic vessels in vivo. In atherosclerosis models of rabbits and mice, BO-653 has been shown to be able to suppress the formation of atherosclerotic lesions without untoward side effects. Specifically, there was no reduction of high density lipoprotein levels. This antioxidant provides additional evidence in support of the oxidized-LDL hypothesis, and itself is a promising candidate antioxidant for clinical use.

[Recovered state of iron in female blood donors--after taking an iron supplement].

An iron supplement was given to female blood donors to prevent iron deficiency after blood donation. The levels of items related to red blood cells and serum ferritin (S-Fer) among 17 iron-takers and 31 non-iron-takers were analyzed continuously. In most of the non-iron-takers, the S-Fer levels did not recover within four weeks after the donation of 200ml or 400ml of blood. In the approximately half of the donors, hemoglobin (Hb) levels did not recover either. However, in 59% of those taking iron supplements three times the amount of iron lost by donation, the levels of Hb and S-Fer recovered within two weeks. In the remaining 41%, the Hb levels recovered within four weeks by taking the iron supplement. Four weeks after blood donation, the incidence of iron deficiency anemia among the non-iron-takers increased from 13% to 23% and the incidence of latent iron deficiency among the non-iron-takers increased from 32% to 42%. However, the incidence of iron deficiency anemia among the iron-takers remained 0% and the incidence of latent iron deficiency among the iron-takers decreased from 12% to 6%.