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Mihara, Kiyoshi; Matsumura, Mina; Yoshioka, Eiji; Hanada, Kazuhiko; Nakasa, Hiromitsu; Ohmori, Shigeru; Kitada, Munehiro; Ogata, Hiroyasu

doi:10.1023/a:1010922925928

Cited by 23 publications

(3 citation statements)

References 18 publications

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“…[18][19][20] However, in situ or in vivo drug permeability in the monkey intestine has not been reported yet because in situ intestinal perfusion method is usually applied to the small animals such as rat. 5,6,21,22) In order to consider the differences in the intestinal drug absorption between cynomolgus monkeys and humans, the same quality of permeability data should be necessary for both species.…”

Section: Discussionmentioning

confidence: 99%

“…32,33) On the other hand, simultaneous perfusion method of the intestinal tract and the mesenteric vein have often been used to evaluate directly the intestinal first-pass metabolism in rats. 5,6) However, since the method requires complicated operations and is difficult to apply to the big animals such as monkeys, in this study, we have measured the concentration of drugs in both portal and peripheral veins during the intestinal perfusion to calculate Fg value. In our method, amount of the drug metabolized in the intestinal epithelial cells are calculated as the difference between the eliminated amount from the intestinal tract and the absorbed amount into the portal vein.…”

Section: Discussionmentioning

confidence: 99%

“…Also, Mihara et al evaluated quantitatively the first-pass metabolism of eperison in rats by using the similar perfusion method. 6) Although the simultaneous perfusion method is useful to assess the intestinal metabolism of drugs, this method requires complicated operations of the mesenteric vein and is difficult to perform in cynomolgus monkeys. Moreover, perfusion of the mesenteric vein might affect the absorption and metabolism of drugs in the intestine.…”

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confidence: 99%

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Investigation of the Intestinal Permeability and First-Pass Metabolism of Drugs in Cynomolgus Monkeys Using Single-Pass Intestinal Perfusion

Takahashi

Washio

Suzuki

et al. 2010

Biological & Pharmaceutical Bulletin

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where Fa is the fraction of dose absorbed from the gastrointestinal (GI) tract, Fg is the intestinal availability, that correspondent to the fraction of dose not metabolized in the intestinal wall during the absorption process and Fh is the fraction of dose not metabolized in the liver before reaching the systemic circulation. Therefore, the values of (1ϪFg) and (1ϪFh) mean the first-pass metabolism of orally administered drugs in GI tract and the liver, respectively. In order to select the appropriate candidates for oral drug product, quantitative assessments on each process are highly required.Recently, not only the small animals such as mice and rats, but also cynomolgus monkeys are often used as an animal model for PK studies in the drug discovery stage. However, lower oral BAs of test compounds were often observed in cynomolgus monkeys compared with those in other animals.1,2) Also in our previous study, various marketed drugs showed low oral BAs in cynomolgus monkeys than those in humans. From the kinetic analysis of the plasma concentrations of drugs after intravenous and oral administration, it was indicated that the low oral BAs in cynomolgus monkeys are mostly attributed to the low value of Fa*Fg.3,4) However, only from the in vivo PK analysis, it is theoretically impossible to evaluate Fa and Fg separately, resulting the confusion in the contribution of intestinal absorption on the oral BA of various drugs.Tamura et al. investigated the mechanisms of intestinal absorption of tacrolims by using the simultaneous perfusion method of intestinal lumen and mesenteric veins in rats. 5)They have calculated the fraction of metabolized in the intestinal cells from the difference between eliminated amount of the drug from the intestinal lumen and absorbed amount into the blood perfusate. Also, Mihara et al. evaluated quantitatively the first-pass metabolism of eperison in rats by using the similar perfusion method. 6) Although the simultaneous perfusion method is useful to assess the intestinal metabolism of drugs, this method requires complicated operations of the mesenteric vein and is difficult to perform in cynomolgus monkeys. Moreover, perfusion of the mesenteric vein might affect the absorption and metabolism of drugs in the intestine.The present study is performed 1) to establish the experimental method to evaluate the drug permeability and the metabolism in the intestine of cynomolgus monkeys and then 2) to clarify the causes of low BA of drugs in cynomolgus monkeys. For these purposes, an in situ single-pass intestinal perfusion method was performed with blood sampling from both portal and peripheral veins, instead of the perfusion of the mesenteric vein. The intestinal permeability of drugs (P eff ) is calculated from the decrease in drug concentration in the perfusate after single pass perfusion through the intestinal tract. The intestinal metabolism during the absorption process (1ϪFg) is calculated from the difference between drug amounts that disappeared from the perfusate and absorbed into the por...

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

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Investigation of the Intestinal Permeability and First-Pass Metabolism of Drugs in Cynomolgus Monkeys Using Single-Pass Intestinal Perfusion

Takahashi

Washio

Suzuki

et al. 2010

Biological & Pharmaceutical Bulletin

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Pharmacokinetics of eperisone following oral administration in healthy Korean volunteers

Baek

Back

Chae

et al. 2021

Biopharm & Drug Disp

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Eperisone is an oral muscle relaxant used to treat musculoskeletal diseases, which exhibits high pharmacokinetic (PK) variability in bioequivalence studies. The aim of this study was to characterize the PKs of eperisone following its oral administration to Korean volunteers through the conduct of a noncompartmental and population analysis. A total of 360 concentration‐time measurements collected on two separate occasions from 15 healthy volunteers during a bioequivalent study of eperisone 50 mg (Murex®) were used in the PK analysis. Noncompartmental analysis was performed using WinNonLinTM and population analysis was performed using NONMEM®. The possible influence of thirty demographic and pathophysiological characteristics on the PKs of eperisone were explored. Based on noncompartmental analysis mean eperisone elimination half‐life, apparent clearance (CL/F), and apparent volume of distribution were estimated to be 3.81 h, 39.24 × 103 l/h × 103 L, respectively. During population PK modeling a two‐compartment model with first‐order absorption rate constant (typical population K a = 1.5 h−1) and first‐order elimination (typical population CL/F and apparent volume of distribution in the central compartment [V c/F] = 30.8 × 103 l/h and 86.2 × 103 l, respectively) best described the PKs of eperisone. Interindividual variability in CL/F and V c/F were estimated to be 87.9% and 130.3%, respectively and interoccasion variability in CL/F and V c/F were estimated to be 23.8% and 30.8%, respectively. Aspartate aminotransferase level and smoking status were identified as potential covariates that may influence the CL/F of eperisone. This is the first study to develop a disposition model for eperisone and investigate the potential influence of covariate factors on it PK variability.

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Metabolic routes along digestive system of licorice: multicomponent sequential metabolism method in rat

Zhang

Zhao²,

Yang

et al. 2015

Biomedical Chromatography

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This study was conducted to establish the multicomponent sequential metabolism (MSM) method based on comparative analysis along the digestive system following oral administration of licorice (Glycyrrhiza uralensis Fisch., leguminosae), a traditional Chinese medicine widely used for harmonizing other ingredients in a formulae. The licorice water extract (LWE) dissolved in Krebs-Ringer buffer solution (1 g/mL) was used to carry out the experiments and the comparative analysis was performed using HPLC and LC-MS/MS methods. In vitro incubation, in situ closed-loop and in vivo blood sampling were used to measure the LWE metabolic profile along the digestive system. The incubation experiment showed that the LWE was basically stable in digestive juice. A comparative analysis presented the metabolic profile of each prototype and its corresponding metabolites then. Liver was the major metabolic organ for LWE, and the metabolism by the intestinal flora and gut wall was also an important part of the process. The MSM method was practical and could be a potential method to describe the metabolic routes of multiple components before absorption into the systemic blood stream. Copyright © 2015 John Wiley & Sons, Ltd.

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Abstract: Those data strongly suggest that eperisone may be metabolized to HMO by CYP1A in rat intestinal microsomes during the first-pass through the epithelium of the small intestine.

Cited by 23 publications

References 18 publications

Investigation of the Intestinal Permeability and First-Pass Metabolism of Drugs in Cynomolgus Monkeys Using Single-Pass Intestinal Perfusion

Investigation of the Intestinal Permeability and First-Pass Metabolism of Drugs in Cynomolgus Monkeys Using Single-Pass Intestinal Perfusion

Pharmacokinetics of eperisone following oral administration in healthy Korean volunteers

Metabolic routes along digestive system of licorice: multicomponent sequential metabolism method in rat

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