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Exploration of Antiemetics for Osteoporosis Therapy-Induced Nausea and Vomiting Using PET Molecular Imaging Analysis to Gastrointestinal Pharmacokinetics

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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-[18F]fluoro-d-glucose ([18F]FDG) under free moving conditions in vivo. The effect of teriparatide on the permeability of Caco-2 cell membranes to [18F]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 [18F]FDG.

Results

Teriparatide delayed the time-radioactivity profile of [18F]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 [18F]FDG to control levels. Teriparatide had no effect on Caco-2 membrane permeability to [18F]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.

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Abbreviations

[18F]FDG:

2-deoxy-2-[18F]fluoro-d-glucose

AUC:

Area under the concentration-time curve

CL:

Oral elimination clearance

GI:

Gastrointestinal

IA:

Injected radioactivity

ka :

Absorption rate constant

k Duo :

Rate constant for the elimination from the duodenum

kel :

Elimination rate constant

k GE :

Gastric emptying rate constant in the stomach

k in :

Rate constant for intestinal transit from the duodenum to the jejunum

k out :

Rate constant for the elimination from the small intestine

MIP:

Maximum intensity projection

MRT:

Mean residence time

NCA:

Non-compartmental analysis

Papp :

Apparent permeability

PET:

Positron emission tomography

PTH:

Parathyroid hormone

ROIs:

Regions of interest

SUV:

Standard uptake value

TACs:

Time-activity curves

Vd :

Volume of distribution

VOIs:

Volumetric regions of interest

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ACKNOWLEDGMENTS AND DISCLOSURES

We thank Masahiro Sasaki, Ph.D. of the Institute of Biomedical Research and Innovation for supplying [18F]FDG. We thank Dr. Naoto Kato for fruitful discussions. The authors declare that this study had the funding support of the Asahi Kasei Pharma Corporation, and that T. Takashima, who worked for RIKEN, is currently an employee of the Asahi Kasei Pharma Corporation.

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Authors and Affiliations

  1. RIKEN Center for Life Science Technologies, 6-7-3 Minatojima-minamimachi, Chuo-ku, Kobe, Hyogo, 650-0047, Japan

    Tomotaka Shingaki, Yumiko Katayama, Takayoshi Nakaoka, Kayo Onoe, Takashi Okauchi, Emi Hayashinaka, Yasuhiro Wada, Yilong Cui & Yasuyoshi Watanabe

  2. RIKEN Center for Molecular Imaging Sciences, reorganized to RIKEN Center for Life Science Technologies, 6-7-3 Minatojima-minamimachi, Chuo-ku, Kobe, Hyogo, Japan

    Tadayuki Takashima

Authors
  1. Tomotaka Shingaki
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  2. Yumiko Katayama
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  3. Takayoshi Nakaoka
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  4. Tadayuki Takashima
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  5. Kayo Onoe
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  9. Yilong Cui
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  10. Yasuyoshi Watanabe
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Correspondence to Tomotaka Shingaki.

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Shingaki, T., Katayama, Y., Nakaoka, T. et al. Exploration of Antiemetics for Osteoporosis Therapy-Induced Nausea and Vomiting Using PET Molecular Imaging Analysis to Gastrointestinal Pharmacokinetics. Pharm Res 33, 1235–1248 (2016). https://doi.org/10.1007/s11095-016-1868-6

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  • DOI: https://doi.org/10.1007/s11095-016-1868-6

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