PMID- 30972456 OWN - NLM STAT- MEDLINE DCOM- 20200303 LR - 20200303 IS - 1432-0843 (Electronic) IS - 0344-5704 (Linking) VI - 83 IP - 6 DP - 2019 Jun TI - Rabeprazole intake does not affect systemic exposure to capecitabine and its metabolites, 5'-deoxy-5-fluorocytidine, 5'-deoxy-5-fluorouridine, and 5-fluorouracil. PG - 1127-1135 LID - 10.1007/s00280-019-03837-y [doi] AB - PURPOSE: Several retrospective studies have shown that the antitumor efficacy of capecitabine-containing chemotherapy decreases when co-administered with a proton pump inhibitor (PPI). Although a reduction in capecitabine absorption by PPIs was proposed as the underlying mechanism, the effects of PPIs on capecitabine pharmacokinetics remain unclear. We prospectively examined the effects of rabeprazole on the pharmacokinetics of capecitabine and its metabolites. METHODS: We enrolled patients administered adjuvant capecitabine plus oxaliplatin (CapeOX) for postoperative colorectal cancer (CRC) patients and metastatic CRC patients receiving CapeOX with/without bevacizumab. Patients receiving a PPI before registration were allocated to the rabeprazole group, and the PPI was changed to rabeprazole (20 mg/day) at least 1 week before the initiation of capecitabine treatment. On day 1, oral capecitabine (1000 mg/m(2)) was administered 1 h after rabeprazole intake. Oxaliplatin (and bevacizumab) administration on day 1 was shifted to day 2 for pharmacokinetic analysis of the first capecitabine dose. Plasma concentrations of capecitabine, 5'-deoxy-5-fluorocytidine, 5'-deoxy-5-fluorouridine, and 5-fluorouracil were analyzed by high-performance liquid chromatography. Effects of rabeprazole on inhibition of cell proliferation by each capecitabine metabolite were examined with colon cancer cells (COLO205 and HCT116). RESULTS: Five and 9 patients enrolled between September 2017 and July 2018 were allocated to rabeprazole and control groups, respectively. No significant effects of rabeprazole on area under the plasma concentration-time curve divided by capecitabine dose for capecitabine and its three metabolites were observed. Rabeprazole did not affect the proliferation inhibition of colon cancer cells by the respective capecitabine metabolites. CONCLUSION: Rabeprazole does not affect capecitabine pharmacokinetics. FAU - Sekido, Masae AU - Sekido M AD - Division of Cancer Cell Biology, Department of Pharmaceutical Science, Showa University School of Pharmacy, 1-5-8 Hatanodai, Shinagawa-ku, Tokyo, 142-8555, Japan. FAU - Fujita, Ken-Ichi AU - Fujita KI AD - Division of Cancer Cell Biology, Department of Pharmaceutical Science, Showa University School of Pharmacy, 1-5-8 Hatanodai, Shinagawa-ku, Tokyo, 142-8555, Japan. k.fujita@med.showa-u.ac.jp. FAU - Kubota, Yutaro AU - Kubota Y AD - Division of Medical Oncology, Department of Medicine, Showa University School of Medicine, 1-5-8 Hatanodai, Shinagawa-ku, Tokyo, 142-8555, Japan. FAU - Ishida, Hiroo AU - Ishida H AD - Division of Medical Oncology, Department of Medicine, Showa University School of Medicine, 1-5-8 Hatanodai, Shinagawa-ku, Tokyo, 142-8555, Japan. FAU - Takahashi, Takehiro AU - Takahashi T AD - Division of Medical Oncology, Department of Medicine, Showa University School of Medicine, 1-5-8 Hatanodai, Shinagawa-ku, Tokyo, 142-8555, Japan. FAU - Ohkuma, Ryotaro AU - Ohkuma R AD - Division of Medical Oncology, Department of Medicine, Showa University School of Medicine, 1-5-8 Hatanodai, Shinagawa-ku, Tokyo, 142-8555, Japan. FAU - Tsunoda, Takuya AU - Tsunoda T AD - Division of Medical Oncology, Department of Medicine, Showa University School of Medicine, 1-5-8 Hatanodai, Shinagawa-ku, Tokyo, 142-8555, Japan. FAU - Ishikawa, Fumihiro AU - Ishikawa F AD - Division of Cancer Cell Biology, Department of Pharmaceutical Science, Showa University School of Pharmacy, 1-5-8 Hatanodai, Shinagawa-ku, Tokyo, 142-8555, Japan. FAU - Shibanuma, Motoko AU - Shibanuma M AD - Division of Cancer Cell Biology, Department of Pharmaceutical Science, Showa University School of Pharmacy, 1-5-8 Hatanodai, Shinagawa-ku, Tokyo, 142-8555, Japan. FAU - Sasaki, Yasutsuna AU - Sasaki Y AD - Division of Medical Oncology, Department of Medicine, Showa University School of Medicine, 1-5-8 Hatanodai, Shinagawa-ku, Tokyo, 142-8555, Japan. LA - eng SI - JPRN/UMIN000031182 PT - Journal Article DEP - 20190409 PL - Germany TA - Cancer Chemother Pharmacol JT - Cancer chemotherapy and pharmacology JID - 7806519 RN - 0 (Antimetabolites, Antineoplastic) RN - 0 (Proton Pump Inhibitors) RN - 039LU44I5M (Floxuridine) RN - 0W860991D6 (Deoxycytidine) RN - 32828355LL (Rabeprazole) RN - 6804DJ8Z9U (Capecitabine) RN - 8RWB05I6ON (5'-deoxy-5-fluorocytidine) RN - U3P01618RT (Fluorouracil) RN - V1JK16Y2JP (doxifluridine) SB - IM MH - Aged MH - Antimetabolites, Antineoplastic/*administration & dosage/pharmacokinetics MH - Antineoplastic Combined Chemotherapy Protocols MH - Area Under Curve MH - Capecitabine/*administration & dosage/pharmacokinetics MH - Cell Proliferation/drug effects MH - Chromatography, High Pressure Liquid MH - Colorectal Neoplasms/*drug therapy MH - Deoxycytidine/analogs & derivatives/pharmacokinetics MH - Drug Interactions MH - Female MH - Floxuridine/pharmacokinetics MH - Fluorouracil/pharmacokinetics MH - Humans MH - Male MH - Middle Aged MH - Prospective Studies MH - Proton Pump Inhibitors/*administration & dosage/pharmacology MH - Rabeprazole/*administration & dosage/pharmacology OTO - NOTNLM OT - Capecitabine OT - Capecitabine metabolites OT - Colorectal cancer OT - Pharmacokinetics OT - Proton pump inhibitor OT - Rabeprazole EDAT- 2019/04/12 06:00 MHDA- 2020/03/04 06:00 CRDT- 2019/04/12 06:00 PHST- 2019/03/12 00:00 [received] PHST- 2019/04/03 00:00 [accepted] PHST- 2019/04/12 06:00 [pubmed] PHST- 2020/03/04 06:00 [medline] PHST- 2019/04/12 06:00 [entrez] AID - 10.1007/s00280-019-03837-y [pii] AID - 10.1007/s00280-019-03837-y [doi] PST - ppublish SO - Cancer Chemother Pharmacol. 2019 Jun;83(6):1127-1135. doi: 10.1007/s00280-019-03837-y. Epub 2019 Apr 9.