- 著者
- Kiyoshi FUKUHARA Akiko OHNO Yosuke ANDO Takashi YAMOTO Haruhiro OKUDA
- 出版者
- 日本薬物動態学会 会長/日本薬物動態学会 DMPK編集委員長
- 雑誌
- Drug Metabolism and Pharmacokinetics (ISSN:13474367)
- 巻号頁・発行日
- vol.26, no.4, pp.399-406, 2011 (Released:2011-09-02)
- 参考文献数
- 23
- 被引用文献数
- 18
The widely used analgesic-antipyretic drug acetaminophen (APAP) is known to cause serious liver necrosis at high doses in man and experimental animals. For studies of toxic processes, 1H NMR spectroscopy of biofluids allows monitoring of endogenous metabolite profiles that alter characteristically in response to changes in physiological status. Herein, a 1H NMR metabolomics approach was applied to the investigation of APAP toxicity in rats and the effect of phenobarbital (PB) on APAP-induced hepatotoxicity. Metabolite differences due to hepatotoxicity were observed in 1H NMR spectra of serum and urine, and enhanced APAP hepatotoxicity by pretreatment with PB was clearly shown by a principal components analysis of the spectral data. NMR spectra of APAP-dosed rat urine provided profiles of APAP-related compounds together with endogenous metabolites. By comparison of endogenous and APAP-related metabolite spectra with those from rats pretreated with PB, it was possible to show the importance of oxidative metabolism of APAP to N-acetyl-p-benzoquinone, an essential step in APAP hepatotoxicity.
- 著者
- Yasuhiro Abe Eiichi Yamamoto Hiroyuki Yoshida Akiko Usui Naomi Tomita Hitomi Kanno Sayaka Masada Hidetomo Yokoo Genichiro Tsuji Nahoko Uchiyama Takashi Hakamatsuka Yosuke Demizu Ken-ichi Izutsu Yukihiro Goda Haruhiro Okuda
- 出版者
- The Pharmaceutical Society of Japan
- 雑誌
- Chemical and Pharmaceutical Bulletin (ISSN:00092363)
- 巻号頁・発行日
- pp.c20-00431, (Released:2020-08-08)
- 参考文献数
- 28
- 被引用文献数
- 20
The purpose of this study was to elucidate the effect of high-temperature storage on the stability of ranitidine, specifically with respect to the potential formation of N-nitrosodimethylamine (NDMA), which is classified as a probable human carcinogen. Commercially available ranitidine reagent powders and formulations were stored under various conditions, and subjected to LC-MS/MS analysis. When ranitidine tablets from two different brands (designated as tablet A and tablet B) were stored under accelerated condition (40°C with 75% relative humidity), following the drug stability guidelines issued by the International Conference on Harmonisation (ICH-Q1A), for up to 8 weeks, the amount of NDMA in them substantially increased from 0.19 to 116 ppm and from 2.89 to 18 ppm, respectively. The formation of NDMA that exceeded the acceptable daily intake limit (0.32 ppm) at the temperature used under accelerated storage conditions clearly highlights the risk of NDMA formation in ranitidine formulations when extrapolated to storage under ambient conditions. A forced-degradation study under the stress condition (60°C for 1 week) strongly suggested that environmental factors such as moisture and oxygen are involved in the formation of NDMA in ranitidine formulations. Storage of ranitidine tablets and reagent powders at the high temperatures also increased the amount of nitrite, which is considered one of the factors influencing NDMA formation. These data indicate the necessity of controlling/monitoring stability-related factors, in addition to controlling impurities during the manufacturing process, in order to mitigate nitrosamine-related health risks of certain pharmaceuticals.