Simultaneous determination of gemfibrozil and its metabolites in plasma and urine by a fully automated high performance liquid chromatographic system

Nakagawa, Akihiko; Shigeta, Akemi; Iwabuchi, Haruo; Horiguchi, Masaaki; Nakamura, Kenji; Takahagi, Hidekuni

doi:10.1002/bmc.1130050205

Cited by 31 publications

(19 citation statements)

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“…1), is a fibric acid derivative widely used as a lipid-regulating agent. Gemfibrozil undergoes extensive glucuronidation and oxidative metabolism (Nakagawa et al, 1991), with gemfibrozil 1-O-␤-glucuronide as one of the major metabolites in humans. Studies show that 32% of a gemfibrozil dose is excreted as a gemfibrozil conjugate in urine by 24 h after administration (Nakagawa et al, 1991).…”

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confidence: 99%

“…Gemfibrozil undergoes extensive glucuronidation and oxidative metabolism (Nakagawa et al, 1991), with gemfibrozil 1-O-␤-glucuronide as one of the major metabolites in humans. Studies show that 32% of a gemfibrozil dose is excreted as a gemfibrozil conjugate in urine by 24 h after administration (Nakagawa et al, 1991). A recent report showed that the gemfibrozil glucuronide time-dependently inhibits CYP2C8 in vitro (Ogilvie et al, 2006).…”

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confidence: 99%

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The UDP-Glucuronosyltransferase 2B7 Isozyme Is Responsible for Gemfibrozil Glucuronidation in the Human Liver

Mano¹,

Usui²,

Kamimura³

2007

Drug Metab Dispos

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ABSTRACT:Gemfibrozil, a fibrate hypolipidemic agent, is eliminated in humans by glucuronidation. A gemfibrozil glucuronide has been reported to show time-dependent inhibition of cytochrome P450 2C8. Comprehensive assessment of the drug interaction between gemfibrozil and cytochrome P450 2C8 substrates requires a clear understanding of gemfibrozil glucuronidation. However, the primary UDPglucuronosyltransferase (UGT) isozymes responsible for gemfibrozil glucuronidation remain to be determined. Here, we identified the main UGT isozymes involved in gemfibrozil glucuronidation. Evaluation of 12 recombinant human UGT isozymes shows gemfibrozil glucuronidation activity in UGT1A1, UGT1A3, UGT1A9, UGT2B4, UGT2B7, and UGT2B17, with UGT2B7 showing the highest activity. The kinetics of gemfibrozil glucuronidation in pooled human liver microsomes (HLMs) follows Michaelis-Menten kinetics with high and low affinity components. The high affinity K m value was 2.5 M, which is similar to the K m value of gemfibrozil glucuronidation in recombinant UGT2B7 (2.2 M). In 16 HLMs, a significant correlation was observed between gemfibrozil glucuronidation and both morphine 3-OH glucuronidation (r ‫؍‬ 0.966, p < 0.0001) and flurbiprofen glucuronidation (r ‫؍‬ 0.937, p < 0.0001), two reactions mainly catalyzed by UGT2B7, whereas no significant correlation was observed between gemfibrozil glucuronidation and either estradiol 3␤-glucuronidation and propofol glucuronidation, two reactions catalyzed by UGT1A1 and UGT1A9, respectively. Flurbiprofen and mefenamic acid inhibited gemfibrozil glucuronidation in HLMs with similar IC 50 values to those reported in recombinant UGT2B7. These results suggest that UGT2B7 is the main isozyme responsible for gemfibrozil glucuronidation in humans.

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confidence: 99%

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The UDP-Glucuronosyltransferase 2B7 Isozyme Is Responsible for Gemfibrozil Glucuronidation in the Human Liver

Mano¹,

Usui²,

Kamimura³

2007

Drug Metab Dispos

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“…The mechanism of this action is not completely understood but may involve inhibition of peripheral lipolysis; reduced hepatic extraction of free fatty acids, which reduces hepatic triglyceride production; inhibition of synthesis and increased clearance of VLDL carrier, apolipoprotein B, which also reduces VLDL production and according to animal studies, reduced incorporation of longchain fatty acids into newly formed triglycerides, accelerated turnover and removal of cholesterol from the liver (stimulates incorporation of cholesterol precursors into precursors into liver sterols), and increased excretion of cholesterol in the feces [4][5][6][7][8][9] . Gemfibrozil is determined by high performance liquid chromatography (HPLC) [10][11][12][13] , liquid chromatography (LC) 14,15 , gas chromatography (GC) 16 19 , ion exchange 20 , hydrophobicity interaction 21 , and electrostatic interaction [22][23] . To our best knowledge, there are no reports for quantitative determination of gemfibrozil by using poly (gabapentin) film modified glassy carbon electrode.…”

Section: Introductionmentioning

confidence: 99%

Cyclic Voltammetric Studies of Gemfibrozil at Poly (Gabapentin) Film Modified Glassy Carbon Electrode

P¹,

Deepa²,

Naik³

et al. 2012

Int J Pharmceut Chem

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ABSTRACT:A polymerized film of gabapentin was prepared on the surface of a glassy carbon electrode (GCE) in phosphate buffer solution by electropolymerisation method using cyclic voltammetric technique. The poly (gabapentin) film modified glassy carbon electrode was calibrated with standard potassium ferrocyanide solution in 1 M KCl as a supporting electrolyte. This modified electrode used to study the electrochemical behavior of gemfibrozil, a lipid lowering drug in aqueous alcohol medium by cyclic voltammetric technique. It was found that the oxidation peak current of gemfibrozil at the modified GCE was greatly improved compared with that at the bare GCE. The effects of scan rate, pH, supporting electrolyte concentration, % of solvent and concentration of gemfibrozil were examined. With high sensitivity and selectivity, micro molar detection limit, high reproducibility together with ease of preparation and regeneration of the electrode surface make the electrode very stable for the determination of gemfibrozil in pharmaceutical and clinical preparations.

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“…Gem is extensively metabolized and only about 5% of parent compound is retained. Its main metabolites include acyl glucuronide conjugates, accounting for 32% of all of Gem's metabolites in urine after administration [12][13][14]. For CA, 60% of the dose is conjugated as glucuronide metabolites in humans [15].…”

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Metabolism of fibrates by cytochrome P450s and UDP-glycosyltransferases in rat and human liver microsomes

et al. 2012

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Fibrates are widely used for the treatment of dyslipidemia. However, the contributions of the phase I and phase II metabolic pathways to the clearance of fibrates are unclear. In this study, we investigated the metabolism of gemfibrozil (Gem), clofibric acid (CA), fenofibric acid (FA) and bezafibrate (Beza) by cytochrome P450s (P450s) and UDP-glycosyltransferases (UGTs) using a substrate depletion approach. We also compared the metabolic characteristics of rat liver microsomes (RLM) and human liver microsomes (HLM). The intrinsic clearance rates mediated by P450s, UGTs and both were 172 ± 22, 643 ± 26, 798 ± 103 µL min -1 mg -1, respectively, for Gem and 43 ± 11, 88 ± 12, 119 ± 15 µL min -1 mg -1 , respectively, for CA in RLM. The fractions metabolized by P450s and UGTs in RLM were 22% and 81% for Gem, 36% and 74% for CA. The P450-and UGT-mediated depletion rates for Gem were 303 and 1607 nmol min -1 mg -1 in RLM versus 86 and 243 nmol min -1 mg -1 in HLM. The corresponding rates for CA were 1.1 and 1.7 nmol min -1 mg -1 in RLM versus 0.025 and 0.038 nmol min -1 mg -1 in HLM. Accordingly, both P450s and UGTs substantially contribute to the clearance of Gem and CA, with UGTs playing a greater role. To avoid under-estimating the impact of these pathways, it is necessary to measure NADPH-and UDPGA-dependent metabolism. Although the fractions of these two pathways in RLM and HLM were similar, the depletion rate of Gem and CA in RLM was higher than that in HLM. The metabolism of FA and Beza by P450s and UGTs was too low to calculate intrinsic clearance in both RLM and HLM. These results indicate that fibrates are metabolized via similar pathways in rats and humans, and it is applicable to use RLM to predict the clearance of fibrates in human.

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Simultaneous determination of gemfibrozil and its metabolites in plasma and urine by a fully automated high performance liquid chromatographic system

Cited by 31 publications

References 6 publications

The UDP-Glucuronosyltransferase 2B7 Isozyme Is Responsible for Gemfibrozil Glucuronidation in the Human Liver

The UDP-Glucuronosyltransferase 2B7 Isozyme Is Responsible for Gemfibrozil Glucuronidation in the Human Liver

Cyclic Voltammetric Studies of Gemfibrozil at Poly (Gabapentin) Film Modified Glassy Carbon Electrode

Metabolism of fibrates by cytochrome P450s and UDP-glycosyltransferases in rat and human liver microsomes

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