First-pass of GTS-21 on canine gut wall and liver determined by portal–systemic concentration difference

Azuma, Ryotaro; Hirota, Tomio; Manabe, Hiroshi; Komuro, Masahito; Kojima, Hiroshi

doi:10.1016/s0928-0987(01)00166-x

Cited by 7 publications

(9 citation statements)

References 19 publications

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“…The first-pass effects of the stomach, intestine and liver can be evaluated by comparing the absolute bioavailability (F po , F id and F pv respectively), which are calculated by dividing the area under the serum concentration versus time curve (AUC) after po, id, and pv administration by the AUC after iv administration [12,13] . Because PNS is used more widely in practice than Rg 1 alone, both Rg 1 and PNS (Rg 1 content of 27.36%) are investigated in the present study.…”

Section: Introductionmentioning

confidence: 99%

Difference in oral absorption of ginsenoside Rg1 between in vitro and in vivo models

Han

Fang

2006

Acta Pharmacologica Sinica

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Aim: To clarify the cause of poor oral absorption of ginsenoside Rg 1 (Rg 1 ), the active ingredient in Panax notoginseng saponins (PNS) used for treating hemorrhage. Methods: Caco-2 cell monolayers were used as an in vitro model to study the transport mechanism of Rg 1 across the intestinal mucosa. Moreover, the serum concentration-time profiles after peroral (po), intraduodenal (id), portal venous (pv) and tail venous (iv) administration of Rg 1 in rats were compared to evaluate the first-pass effects in the stomach, intestine, and liver. Results: Uptake of Rg 1 by Caco-2 cell monolayers was temperature-dependent, but was not influenced by cyclosporin A. The change in the apical pH produced no obvious effect on the uptake of Rg 1 . The uptake and transport of Rg 1 was non-saturable; whereas the flux from the apical compartment to the basolateral compartment (A− B) increased in a linear manner with the increase in concentration, indicating passive transport. An apparent permeability coefficient of (2.59±0.17)×10-7 cm/s (C 0 =1 mg/mL) predicted incomplete absorption. A significant difference was observed between the po (F po was 3.29% at a dose of 1500 mg/kg), id (F id was 6.60% at a dose of 1200 mg/kg) and pv (F pv was 50.56%) administration methods, and the barrier function of the intestine was more significant than those of the stomach and liver in the absorption process. Conclusion: Elimination in the stomach, large intestine and liver contributed to the low oral bioavailability of Rg 1 , but low membrane permeability might be a more important factor in determining the extent of absorption.

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Section: Introductionmentioning

confidence: 99%

Difference in oral absorption of ginsenoside Rg1 between in vitro and in vivo models

Han

Fang

2006

Acta Pharmacologica Sinica

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“…An in situ intestinal drug perfusion method may provide the best to understand the absorption of the drugs which is very close to intact blood circulation may increase the drug uptake and drug metabolites disposals [16]. The blood drawing through jejunal vein is to determine the drug absorptions [17,18] and the first-pass metabolism in the liver as well as in the intestine [19,20]. It is known as the drug metabolizing enzyme cytochrome P450 located in the liver and the P-gp transporter proteins present in the intestine, liver, lungs, and cardiovascular 1.9 1.9 1.8 1.9 systems, in our results, the curcumin coadministration is modulated the metabolizing enzyme CYP3A4 and efflux drug transporters P-gP expressions in liver and intestine and increased the bioavailability of imatinib, which reveals the previous study reports [21,22].…”

Section: Discussionmentioning

confidence: 99%

Influence of P-Glycoprotein and Cytochrome Isoenzyme-P3a4 on Bioavailability of Anticancer Drugs With Curcumin by in Situ Intestinal Perfusion in Male Wistar Rats

Nalla¹,

Puligilla²

2019

Asian J Pharm Clin Res

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Objectives: An orally administered anticancer drug has been poor drug absorption; drug resistance and metabolism, which alters the bioavailability of drugs. An in situ intestine perfusion technique is developing under the different perfusion rates in the presence of drug inducers and inhibitors of cytochrome isoenzyme-P (CYP)-3A4 and P-glycoprotein (P-gp) for drug concentrations. Materials and Methods: The modified in situ intestinal perfusion technique was developed and followed to obtain the portal and hepatic venous blood samples paralleled at different perfusion time and flow rates of 0.05, 0.1, 0.5, and 1.0 mL/min using the imatinib (1 mg/mL) drug alone and in the presence of drug inducer and drug inhibitor for the period of 3 h. The imatinib drug concentrations were assayed using high-pressure liquid chromatography. Results: The results reveal that the mean imatinib drug concentrations in portal vein were higher than hepatic vein at various perfusion flow rates and time intervals were observed. The area under curve and plasma drug concentrations maximum of imatinib alone absorptions were significantly different between portal and hepatic veins (p<0.05) at the flow rates of 0.5 and 1.0 mL/min and also in the presence of drug inducer and inhibitors that indicating for the considerable hepatic involvement in the presystemic extraction or metabolism of drugs. Conclusions: The in situ perfusions approach could provide the useful tool for improving the basic understanding of absorption kinetics and hepatic metabolism of drugs in the presence of drug inducers and drug inhibitors (CYP3A4 and P-gp) under the development and facilitating the clinical applications.

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“…(4) The predicted values, F H and hepatic clearance (CL H , ml W min W kg), were calculated by applying QPH, plasma unbound fraction ( fu), CLH,int, and a dispersion number (DN) of 0.17 to the dispersion model, 8) Eqs. (5) and (6).…”

Section: Km1mentioning

confidence: 99%

“…The predicted values, FH and CLH, were calculated using a dispersion model of Eqs. (5) and (6). These parameters and F and CLP from the in vivo study are listed in Table 3.…”

Section: Hepatic Clearance and Hepatic Availability Using Amentioning

confidence: 99%

“…1, also referred to as DMXB or DMXBA), (E )-3-(2,4-dimethoxybenzylidene)-3,4,5,6-tetra-hydro-2,3?-bipyridine dihydrochloride, has been developed to treat Alzheimer's disease 4) and schizophrenia. 5) In a previous work, 6) we evaluated the absorption ratio (FA), intestinal availability (FG), and hepatic availability (FH) in three dogs. GTS-21 was completely absorbed but lost byˆrst-pass eŠects of passage through the gut wall and liver.…”

Section: Introductionmentioning

confidence: 99%

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Comparative Analysis of In Vitro and In Vivo Pharmacokinetic Parameters Related to Individual Variability of GTS-21 in Canine

Azuma

Komuro

Kawaguchi

et al. 2002

Drug Metabolism and Pharmacokinetics

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To clarify the cause of the canine individual variability in plasma concentration after oral administration of GTS-21, we evaluated in vitro the metabolism to 4-OH-GTS-21 in liver microsomes of the same individuals from in vivo pharmacokinetic study. First, we applied to the Michaelis-Menten kinetic parameters to a dispersion model, and compared hepatic availability (F(H)) and hepatic clearance (CL(H)) values from in vitro with bioavailability (F), hepatic plasma flow (Q(PH)), and plasma clearance (CL(P)) values from in vivo. The ratios of CL(H) to Q(PH) were ranged 0.74 to 0.94, suggesting that GTS-21 is a hepatic plasma flow-limiting drug. A significant correlation of F(H) and F in the four dogs (r=0.995, p=0.005) indicates that the variability is predominantly caused by GTS-21 O4-demethylase activity. Second, we specified the cytochrome P450 (CYP) enzymes that are involved with the metabolism by chemical inhibition. alpha-Naphthoflavone, furafylline, quinidine, quinine, and troleandomycin significantly inhibited GTS-21 O4-demethylase activity. Thus CYP1A, CYP2D15, and CYP3A12 were involved with O4-demethylation. The variability in control activity decreased on addition of alpha-naphthoflavone and furafylline. Third, we quantified the contents of CYP1A and CYP3A12 by enzyme-linked immunosorbent assay. The content of CYP1A was consistent with GTS-21 O4-demethylase activity. We concluded that canine liver CYP1A causes the individual variability in GTS-21 plasma concentration after oral administration.

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First-pass of GTS-21 on canine gut wall and liver determined by portal–systemic concentration difference

Cited by 7 publications

References 19 publications

Difference in oral absorption of ginsenoside Rg1 between in vitro and in vivo models

Difference in oral absorption of ginsenoside Rg1 between in vitro and in vivo models

Influence of P-Glycoprotein and Cytochrome Isoenzyme-P3a4 on Bioavailability of Anticancer Drugs With Curcumin by in Situ Intestinal Perfusion in Male Wistar Rats

Comparative Analysis of In Vitro and In Vivo Pharmacokinetic Parameters Related to Individual Variability of GTS-21 in Canine

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