著者

Ayane Mito Keiichi Hirono Haruka Ide Sayaka Ozawa Fukiko Ichida Masato Taguchi

出版者

The Pharmaceutical Society of Japan

雑誌

Biological and Pharmaceutical Bulletin (ISSN:09186158)

巻号頁・発行日

vol.45, no.6, pp.703-708, 2022-06-01 (Released:2022-06-01)

参考文献数

25

---

We encountered cases in which the anticoagulant effects of warfarin (CYP2C9 substrate) were reversibly attenuated by the concomitant administration of rifampicin or bosentan, which are potent pregnane X receptor (PXR) ligands. The purpose of the present study is to report the previous case with rifampicin, and to evaluate the changes in the warfarin anticoagulant effects when withdrawing or switching bosentan treatment. The former is a case study of a 4-year-old girl undergoing warfarin treatment. The latter is a longitudinal study of 20 pediatric patients receiving stable warfarin treatment. The prothrombin time and international normalized ratio (PT-INR) values were extracted from the medical records and normalized by the daily-dose per body size as an index for the warfarin anticoagulant effects. Rifampicin treatment resulted in a 52.0% decrease in the anticoagulant index. On the other hand, 10 of 20 patients started bosentan and their anticoagulant index was reduced by a median of 2.00. Bosentan was withdrawn in 4 of 20 patients and their anticoagulant index increased by a median of 3.67. Six of 20 patients switched from bosentan to macitentan, which is considered not to activate PXR in clinical settings. However, switching from bosentan to macitentan resulted in a median of 2.25 reduction of the anticoagulant index rather than recovery of the response to warfarin. This study suggests not only the possibility of heterogeneity in the response to PXR activation and deactivation, but also the importance of long-term monitoring of drug–drug interactions when switching from bosentan to macitentan.

著者

Nanami Shigetomi Kenta Kamiya Toru Takamori Naoki Yoshimura Sayaka Ozawa Keiichi Hirono Fukiko Ichida Masato Taguchi

出版者

The Pharmaceutical Society of Japan

雑誌

Biological and Pharmaceutical Bulletin (ISSN:09186158)

巻号頁・発行日

vol.42, no.1, pp.110-115, 2019-01-01 (Released:2019-01-01)

参考文献数

23

被引用文献数

2

---

The purpose of this study was to determine the serum protein binding of tadalafil in children with protein-losing enteropathy (PLE) and to evaluate the specific binding of the drug to human serum-derived proteins in vitro. Seventeen serum samples from two PLE patients used after biochemical tests were collected, and the unbound fraction of tadalafil was determined by an ultrafiltration method. The serum albumin concentrations observed in patients #1 and #2 were 2.4–4.2 and 2.9–3.5 g/dL, respectively. The ranges of unbound fraction of tadalafil in patients #1 and #2 were 3.9–13 and 5.0–7.0%, respectively. This suggested that serum albumin was at least a binding carrier for tadalafil because the unbound fraction of tadalafil and serum albumin were slightly correlated. The unbound fraction of tadalafil at the total concentration of 300 ng/mL was negatively dependent on the serum albumin concentration (range: 1.0–5.0 g/dL) in vitro. In the presence of albumin, the additive effect of γ-globulin on the unbound fraction of tadalafil was marginal, but the addition of α1-acid glycoprotein to test samples decreased the unbound fraction of the drug. The decrease in the unbound fraction of tadalafil was greater at low albumin levels (2 g/dL). The addition of lipoprotein to test samples also decreased the unbound fraction of tadalafil, suggesting that lipoprotein was also a binding carrier of the drug. These results suggested that the disposition and/or response to tadalafil in PLE patients was altered by the change in protein bindings of the drug.