Biomedical subjects

Yoshihiko Tsunenari

Publications and source records attributed to Yoshihiko Tsunenari.

4 recordsLinked to original sources

PubMed2004

Effect of gemfibrozil on the metabolism of pitavastatin--determining the best animal model for human CYP and UGT activities.

A series of studies was conducted to determine the best animal model for human CYP and UGT activities. The investigation focused primarily on the interactions occurring in the CYP- or UGT-mediated metabolism of pitavastatin, and involved in vitro and in vivo experiments. We found that the best animal models for human CYP-mediated hydroxylation and UGT-mediated lactonization of pitavastatin were rats and dogs, respectively. In addition, a large difference in the metabolic properties of pitavastatin was found between monkeys and humans. In the presence of gemfibrozil, the CYP- or UGT-mediated metabolism of pitavastatin was inhibited in vitro. However, gemfibrozil treatment had no inhibitory effect on the AUC of pitavastatin and its lactone form in rats and dogs. We conclude that the plasma level of pitavastatin would not be increased by co-administration of gemfibrozil in humans.

Animals↗

PubMed2003

Interaction between several medicines and statins.

To gain a better understanding of drug-drug interaction between various medicinal substances and statins, in vitro experiments using human hepatic microsomes were performed. The metabolic clearance of atorvastatin (CAS 134523-00-5) was about 32 microliters/min/mg protein, some 15-fold greater than that of pitavastatin (CAS 147526-32-7). On co-incubation with several medicinal substances, metabolic inhibition of pitavastatin was negligible in human hepatic microsomes. However, a remarkable metabolic inhibition of atorvastatin was noted in the presence of various medicinal substances. The intrinsic clearance of atorvastatin lactone was 20-fold greater than that of its acid form, whereas no marked difference was noted between pitavastatin and its lactone form. Pitavastatin lactone showed no inhibitory effect on CYP3A4-mediated metabolism of testosterone in contrast to atorvastatin lactone. These results suggest that pitavastatin and its lactone form will be highly unlikely to interact with other drugs in clinical practice.

Acids↗

PubMed2003

Studies on the interaction between fibrates and statins using human hepatic microsomes.

To gain a better understanding of the mechanism of drug-drug interaction between fibrates and statins, several in vitro experiments were performed. On coincubation with several fibrates, pitavastatin (CAS 147526-32-7) did not displace fibrates from their protein binding in human plasma. The presence of gemfibrozil (CAS 25812-30-0) inhibited the metabolism of statins (cerivastatin (CAS 145599-86-6) and atorvastatin (CAS 134523-00-5)) remarkably. However, the increase of the unchanged form was fairly small for pitavastatin. The metabolic profile of gemfibrozil was also investigated. The cytochrome P (CYP) enzyme CYP2C9 plays a major role in the metabolism of gemfibrozil. Gemfibrozil showed a high affinity for CYP enzymes and a relatively high metabolism velocity. Moreover, several inhibitory effects of gemfibrozil on CYP-mediated metabolism were detected--in contrast to other fibrates. Although the mechanism of the drug-drug interaction was not completely clarified, it is suggested that the increase of plasma concentration caused by the co-administration of gemfibrozil and statins is at least partially due to the inhibition of the CYP-mediated metabolism.

Antibodies, Blocking↗

PubMed2003

Interaction between fibrates and statins--metabolic interactions with gemfibrozil.

An in vitro study was carried out in order to examine the metabolic basis of the interaction between fibrates and statins. Metabolic inhibition of statins was noted in the presence of gemfibrozil. However, increase in the unchanged form was fairly small for pitavastatin, compared with other statins. Several CYP enzymes were shown to be principally responsible for the metabolism of gemfibrozil in contrast to other fibrates. In the presence of gemfibrozil, a focal point was obtained in Dixon plots, demonstrating that there was inhibition of CYP2C8-, CYP2C9- and CYP3A4-mediated metabolism. We propose that the increase of plasma concentration caused by co-administration of gemfibrozil and statins is at least partially due to CYP-mediated inhibition.

Atorvastatin↗