Fujita KI

References (2)

Title : Variants of carboxylesterase 1 have no impact on capecitabine pharmacokinetics and toxicity in capecitabine plus oxaliplatin treated-colorectal cancer patients - Matsumoto_2020_Cancer.Chemother.Pharmacol__
Author(s) : Matsumoto N , Kubota Y , Ishida H , Sekido M , Ohkuma R , Ishiguro T , Hirasawa Y , Ariizumi H , Tsunoda T , Ikusue T , Kobayashi K , Hisamatsu A , Toshima H , Shimada K , Fujita KI
Ref : Cancer Chemother Pharmacol , : , 2020
Abstract : PURPOSE: Capecitabine is a prodrug that undergoes metabolism in three steps to form an active 5-fluorouracil (5-FU). The first step is primarily catalyzed by liver carboxylesterases (CES) 1. Here, we examined the effects of CES1 variants on pharmacokinetics and toxicity of capecitabine. METHODS: We enrolled postoperative colorectal cancer (CRC) patients administered with adjuvant capecitabine plus oxaliplatin (CapeOX) and metastatic CRC patients receiving CapeOX. The pharmacokinetic analysis of the first capecitabine dose (1000 mg/m(2)) was done on day 1, and oxaliplatin administration was shifted to day 2. Plasma concentrations of capecitabine, 5'-deoxy-5-fluorocytidine, 5'-deoxy-5-fluorouridine (5'-DFUR), and 5-FU were analyzed by high-performance liquid chromatography. CES1 polymorphisms (rs3217164, rs2244614, rs2244613, rs7187684, and rs11861118) and the functional CES1 genes (1A1, var1A1, 1A2, and pseudo 1A3) in their diplotype configurations were analyzed by direct sequencing. RESULTS: Thirty-seven patients were enrolled from September 2017 to February 2020. Patients with a higher area under the plasma concentration-time curve to capecitabine dose ratio (AUC/dose) of 5'-DFUR than its mean showed a higher frequency of overall >/= grade 3 toxicity and lower relative dose intensity (RDI) of capecitabine than those with a lower ratio. Higher CES1 activity expressed as a metabolic ratio (AUC of capecitabine/sum of three AUCs of each metabolite) lower than its mean was associated with higher 5'-DFUR AUC/dose and lower RDI, indicating essential roles of CES1 in capecitabine activation to produce 5'-DFUR. However, the association between CES1 variants and capecitabine pharmacokinetics and toxicity was not significant. CONCLUSION: CES1 variants are not associated with capecitabine pharmacokinetics and toxicity.
ESTHER : Matsumoto_2020_Cancer.Chemother.Pharmacol__
PubMedSearch : Matsumoto_2020_Cancer.Chemother.Pharmacol__
PubMedID: 32458030

Title : 123I-iomazenil whole-body imaging to detect hepatic carboxylesterase drug-metabolizing enzyme activity - Mizutani_2018_Nucl.Med.Commun_39_825
Author(s) : Mizutani A , Kobayashi M , Fujita KI , Takahashi K , Hokama T , Takasu H , Nishi K , Nishii R , Shikano N , Fukuchi K , Kawai K
Ref : Nucl Med Commun , 39 :825 , 2018
Abstract : OBJECTIVES: Drugs are mainly metabolized by hepatic enzymes, the activity of which can differ between individuals. Although it is ideal to measure the hepatic clearance of liver-targeted drugs in individualized medicine, blood enzyme tests typically measure metabolic drug clearance in the entire body, and not just in the liver. We investigated whether I-iomazenil imaging can directly assess and quantify the activity of hepatic drug-metabolizing enzymes. MATERIALS AND METHODS: Hepatic enzymes that metabolize I-iomazenil were identified by thin-layer chromatography in mouse liver homogenates with bis(4-nitrophenyl) phosphate (BNPP) inhibitor for carboxylesterase enzymes and nicotinamide adenine dinucleotide phosphate (NADPH) generator for cytochrome P450 enzymes. Whole-body images of mice were acquired using I-iomazenil with and without BNPP, and the distribution was also obtained. The metabolism of I-iomazenil in the blood, liver, gall bladder, and bladder was investigated by thin-layer chromatography. RESULTS: From the in-vitro metabolism of I-iomazenil using BNPP, the enzyme converting I-iomazenil to I-R-COOH was identified as carboxylesterase, and that converting I-iomazenil to M2 was identified as cytochrome P450 in experiments with and without an NADPH generator. The biological distribution and whole-body imaging showed increased accumulation in the liver of mice administered BNPP compared with normal mice, but decreased levels in the gall bladder and small intestine. The main fraction in bile and urine was I-R-COOH, with two unknown metabolites (M1 and M2), I, and I-iomazenil also being present. CONCLUSION: I-iomazenil whole-body imaging has good possibility of direct measurement of hepatic carboxylesterase activity as accumulation of I-R-COOH in the gall bladder through bile and in the bladder through urine.
ESTHER : Mizutani_2018_Nucl.Med.Commun_39_825
PubMedSearch : Mizutani_2018_Nucl.Med.Commun_39_825
PubMedID: 29877992