Tomotaka Shingaki1, Yumiko Katayama2, Takayoshi Nakaoka2, Tadayuki Takashima3, Kayo Onoe2, Takashi Okauchi2, Emi Hayashinaka2, Yasuhiro Wada2, Yilong Cui2, Yasuyoshi Watanabe2. 1. RIKEN Center for Life Science Technologies, 6-7-3 Minatojima-minamimachi, Chuo-ku, Kobe, Hyogo, 650-0047, Japan. tshingaki@riken.jp. 2. RIKEN Center for Life Science Technologies, 6-7-3 Minatojima-minamimachi, Chuo-ku, Kobe, Hyogo, 650-0047, Japan. 3. RIKEN Center for Molecular Imaging Sciences, reorganized to RIKEN Center for Life Science Technologies, 6-7-3 Minatojima-minamimachi, Chuo-ku, Kobe, Hyogo, Japan.
Abstract
PURPOSE: To select appropriate antiemetics relieving teriparatide-induced nausea and vomiting during osteoporosis treatment using PET molecular imaging and pharmacokinetic analysis. METHODS: Rats were pretreated with subcutaneous teriparatide, followed by oral administration of antiemetics with different pharmacological effects. The pharmacokinetics of antiemetics were assessed by oral administration of 2-deoxy-2-[(18)F]fluoro-D-glucose ([(18)F]FDG) under free moving conditions in vivo. The effect of teriparatide on the permeability of Caco-2 cell membranes to [(18)F]FDG was assessed in vitro. The effects of antiemetics on teriparatide-induced suppression of gastrointestinal motility in vivo was assayed by positron emission tomography (PET) using orally administered [(18)F]FDG. RESULTS: Teriparatide delayed the time-radioactivity profile of [(18)F]FDG in blood and significantly reduced its absorption rate constant (k a ), determined from non-compartmental analysis, to 60% of control. In contrast, co-administration of granisetron or mosapride restored the time-radioactivity profile and k a of [(18)F]FDG to control levels. Teriparatide had no effect on Caco-2 membrane permeability to [(18)F]FDG. Pharmacokinetic PET imaging data analysis quantitatively showed the pharmacological effects of teriparatide-induced suppression of upper gastrointestinal motility and its restoration by granisetron and mosapride. CONCLUSIONS: Teriparatide-induced abdominal discomfort might be attributed to GI motility, and PET imaging analysis is a useful tool to for the selection of appropriate antiemetics.
PURPOSE: To select appropriate antiemetics relieving teriparatide-induced nausea and vomiting during osteoporosis treatment using PET molecular imaging and pharmacokinetic analysis. METHODS:Rats were pretreated with subcutaneous teriparatide, followed by oral administration of antiemetics with different pharmacological effects. The pharmacokinetics of antiemetics were assessed by oral administration of 2-deoxy-2-[(18)F]fluoro-D-glucose ([(18)F]FDG) under free moving conditions in vivo. The effect of teriparatide on the permeability of Caco-2 cell membranes to [(18)F]FDG was assessed in vitro. The effects of antiemetics on teriparatide-induced suppression of gastrointestinal motility in vivo was assayed by positron emission tomography (PET) using orally administered [(18)F]FDG. RESULTS:Teriparatide delayed the time-radioactivity profile of [(18)F]FDG in blood and significantly reduced its absorption rate constant (k a ), determined from non-compartmental analysis, to 60% of control. In contrast, co-administration of granisetron or mosapride restored the time-radioactivity profile and k a of [(18)F]FDG to control levels. Teriparatide had no effect on Caco-2 membrane permeability to [(18)F]FDG. Pharmacokinetic PET imaging data analysis quantitatively showed the pharmacological effects of teriparatide-induced suppression of upper gastrointestinal motility and its restoration by granisetron and mosapride. CONCLUSIONS:Teriparatide-induced abdominal discomfort might be attributed to GI motility, and PET imaging analysis is a useful tool to for the selection of appropriate antiemetics.