Utility of Biomarker-Informed Drug Interaction Evaluation in Drug Development and Regulatory Decision Making.

The measurement of endogenous biomarkers in plasma and urine before and after administration of an investigational drug in a clinical study may provide an early indication of its drug-drug interaction (DDI) potential via a specific pathway. In the first international harmonized guideline on drug interaction studies, the International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH) M12, endogenous biomarkers have been recognized as an emerging approach in the transporter- and enzyme-based DDI risk assessment. Clinical Pharmacology Roundtable Conference 2024 held at Pharmaceuticals and Medical Devices Agency (PMDA) brought together experts from regulatory agencies, academia, and industries to discuss potential advantages and challenges of the biomarkers approach in drug development and regulatory decision making.

A Mechanism by which Ergosterol Inhibits the Promotion of Bladder Carcinogenesis in Rats.

We previously showed that ergosterol has an inhibitory effect on bladder carcinogenesis. In this study, we aimed to elucidate the molecular mechanism by which ergosterol inhibits bladder carcinogenesis using a rat model of N-butyl-N-(4-hydroxybutyl)nitrosamine-induced bladder cancer. The messenger ribonucleic acid (mRNA) expression level of the cell cycle-related gene cyclin D1 and inflammation-related gene cyclooxygenase-2 in bladder epithelial cells was significantly increased in the carcinogenesis group compared with the control group.

Inhibitory effect of ergosterol on bladder carcinogenesis is due to androgen signaling inhibition by brassicasterol, a metabolite of ergosterol.

We previously revealed that Choreito, a traditional Kampo medicine, strongly inhibits bladder carcinogenesis promotion. We have also shown that Polyporus sclerotium, which is one of the crude drugs in Choreito, has the strongest bladder carcinogenesis inhibitory effect and that the ergosterol contained in Polyporus sclerotium is the main active component. In this study, we analyzed the mechanism by which ergosterol inhibits bladder carcinogenesis.

Effects of menthol on the pharmacokinetics of triazolam and phenytoin.

We have previously shown that menthol attenuates the anticoagulant effect of warfarin by increasing the expression levels of CYP3A and CYP2C in the liver. This study evaluated the effects of menthol on the pharmacokinetics of the CYP3A substrate triazolam and the CYP2C substrate phenytoin. Menthol was orally administered to mice for 7 d.

Menthol reduces the anticoagulant effect of warfarin by inducing cytochrome P450 2C expression.

Recently, it was reported that the anticoagulant effect of warfarin was reduced when patients receiving warfarin also took menthol. The purpose of this study is to reveal the mechanism of this reduced anticoagulant effect of warfarin from the pharmacokinetic point of view. Warfarin was orally administered to mice 24h after the administration of menthol for 2 days, and the plasma warfarin concentration was measured.

Inhibition of aquaporin-3 water channel in the colon induces diarrhea.

Aquaporin (AQP) 3, which is predominantly expressed in the colon, is considered to play an important role in regulating the fecal water content in the colon. In this study, the role of AQP3 in the colon was examined using HgCl(2) and CuSO(4), which are known to inhibit AQP3 function. The fecal water content was measured up to 1 h after the rectal administration of HgCl(2) or CuSO(4) to rats.