Mai Hashimoto1, Kazuaki Taguchi1, Takako Ishiguro1, Satoru Kohgo2, Shuhei Imoto1, Keishi Yamasaki1,3, Hiroaki Mitsuya2,4,5, Masaki Otagiri1,3. 1. Faculty of Pharmaceutical Sciences, Sojo University, Kumamoto, Japan. 2. Center for Clinical Sciences, National Center for Global Health and Medicine, Shinjuku, Japan. 3. DDS Research Institutes, Sojo University, Kumamoto, Japan. 4. Department of Infectious Diseases and Hematology, Kumamoto University School of Medicine, Kumamoto, Japan. 5. Experimental Retrovirology Section, HIV and AIDS Malignancy Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA.
Abstract
OBJECTIVES: 4'-cyano-2'-deoxyguanosine (CdG), a novel nucleoside analogue, has a high degree of antiviral activity against the chronic hepatitis B virus (HBV). The objective of this study was to develop an analytical method for quantitatively determining CdG levels in biological samples by liquid chromatography-mass spectrometry (LC/MS) and to investigate the pharmacokinetic properties of CdG in rats after intravenous and oral administration. METHODS: An analytical method using a UPLC system interfaced with a TOF-MS system was developed and validated. The pharmacokinetic properties after the intravenous and oral administration of CdG to rats were evaluated. In vivo pharmacokinetic interactions between CdG and entecavir were also investigated. KEY FINDINGS: A rapid, simple and selective method for the quantification of CdG in biological samples was established using LC/MS with solid-phase extraction. In vivo pharmacokinetic studies of CdG in rats demonstrated that CdG is highly bioavailable, is rapidly absorbed from the intestinal tract, is then distributed to the liver rather than kidney and is ultimately excreted via the urine in an unchanged form. The co-administration of CdG and entecavir led to pharmacokinetic interactions with each other. CONCLUSIONS: The data generated in this study provide support for the clinical development of CdG for use in the treatment of HBV.
OBJECTIVES:4'-cyano-2'-deoxyguanosine (CdG), a novel nucleoside analogue, has a high degree of antiviral activity against the chronic hepatitis B virus (HBV). The objective of this study was to develop an analytical method for quantitatively determining CdG levels in biological samples by liquid chromatography-mass spectrometry (LC/MS) and to investigate the pharmacokinetic properties of CdG in rats after intravenous and oral administration. METHODS: An analytical method using a UPLC system interfaced with a TOF-MS system was developed and validated. The pharmacokinetic properties after the intravenous and oral administration of CdG to rats were evaluated. In vivo pharmacokinetic interactions between CdG and entecavir were also investigated. KEY FINDINGS: A rapid, simple and selective method for the quantification of CdG in biological samples was established using LC/MS with solid-phase extraction. In vivo pharmacokinetic studies of CdG in rats demonstrated that CdG is highly bioavailable, is rapidly absorbed from the intestinal tract, is then distributed to the liver rather than kidney and is ultimately excreted via the urine in an unchanged form. The co-administration of CdG and entecavir led to pharmacokinetic interactions with each other. CONCLUSIONS: The data generated in this study provide support for the clinical development of CdG for use in the treatment of HBV.
Authors: S F Innaimo; M Seifer; G S Bisacchi; D N Standring; R Zahler; R J Colonno Journal: Antimicrob Agents Chemother Date: 1997-07 Impact factor: 5.938