Akira Touchi

Investigation of drug–drug interaction via mechanism‐based inhibition of cytochrome P450 3A by macrolides in dexamethasone‐treated female rats

The in vitro and in vivo inhibition of cytochrome P450 (CYP) 3A with mechanism‐based inhibition (MBI) by macrolides was investigated using dexamethasone‐treated female rats (DEX‐female rats). In the in vitro CYP inhibition studies using erythromycin (ERM) and clarithromycin (CAM), similar inhibition responses were observed between human and DEX‐female rat liver microsomes, however, there were fewer effects in intact male rats. The ex vivo study showed that midazolam (MDZ) metabolism in liver microsomes of DEX‐female rats was reduced by ERM administration and the inhibitory effect was increased with increasing ERM doses, indicating that metabolite intermediate complex formation caused irreversible inhibition of CYP3A activity in DEX‐female rats as well as in humans. In the in vivo studies, ERM and CAM significantly increased the area under the plasma concentration–time curve of MDZ and decreased the total clearance in DEX‐female rats. It was concluded that the DDIs via MBI of CYP3A following macrolide administration in humans could be reproduced in female rats, suggesting that DEX‐female rats can serve as an in vivo model for assessing this DDI in humans. Copyright

Synthesis and activities of oxidative metabolites of the anti-arthritic drug candidate S-2474

We have synthesized and characterized some oxidative metabolites of S-2474. In this study, we discovered a novel skeleton, the 2,3-dihydrobenzofuran derivative, which inhibited PGE(2) production at a very low concentration and was effective in the anti-carrageenin footpad edema assay.

ELUCIDATION OF METABOLIC PATHWAY OF THROMBOXANE A2 RECEPTORANT ANTAGONIST, (+)-S-145, IN RAT

Metabolism of (+)-S-145 was investigated within vitro studies to elucidate the metabolic pathway and responsible enzymes therein. Co-factor requirements and subcellular distribution indicated that a-side chain of (+)-S-145 was β-oxidized by peroxisomal enzymes, and that hydroxylation at C-5 or C-6 position of bicyclo-ring was catalyzed by cytochrome P-450s in microsomes. Results of these studies revealed that the most of (+)-S 145 incorporated into liver was activated to its acyl-CoA ester, and that β-oxidation was major pathway in metabolism of (+)-S-145. In peroxisome, there were two independent pathways in β-oxidation, thus (+)-S 145-CoA was generally β-oxidized to Bisnor-(+)S-145 and Tetranor-(+)-S 145, meanwhile its a-side chain was saturated by Δ5-reduction to form DH(+)-S-145 by NADPH dependent manner, then it was β-oxidized to DH-bisnor-(+)-S-145. As OH-(+)S-145 could never be n-oxidized, it was concluded that OH-Tetranor-(+)-S-145, one of major metabolites in vivo, was produced in the hydroxylation of Tetranor-(+)-S-145 catalyzed mainly by P-450 3A1/2.