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Quantitative Assessment of Intestinal First-pass Metabolism of Oral Drugs Using Portal-vein Cannulated Rats

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Abstract

Purpose

To evaluate the impact of intestinal first-pass metabolism (Fg) by cytochrome P4503A (CYP3A) and uridine 5’-diphosphate-glucuronosyltransferases (UGT) on in vivo oral absorption of their substrate drugs.

Methods

CYP3A and UGT substrates were orally administered to portal-vein cannulated (PV) rats to evaluate their intestinal availability (Fa · Fg). In the case of CYP3A substrates, vehicle or 1-aminobenzotriazole (ABT), a potent inhibitor of CYP enzymes, was pretreated to assess Fg separately from Fa (Enzyme-inhibition method). On the other hand, since potent inhibitors of UGT have not been identified, Fg of UGT substrate was calculated from total amount of metabolites generated in enterocytes (Metabolite-distribution method).

Results

After oral administration of CYP3A substrates in ABT-pretreated rats, the portal and systemic plasma concentrations of the metabolite were nearly the same, indicating almost complete inhibition of intestinal CYP3A-mediated metabolism. Using Enzyme-inhibition method, Fg of midazolam (1 mg/kg) was calculated as 0.71. Additionally, total amount of raloxifene-6-glucuronide generated in enterocytes after oral administration of raloxifene was estimated using Metabolite-distribution method and Fg of raloxifene (0.98 μmol/kg) was calculated as 0.21.

Conclusions

PV rats enabled in vivo quantitative assessment of intestinal first-pass metabolism by CYP3A and UGT. This method is useful for clarifying the cause of low bioavailability.

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Abbreviations

ABT:

1-Aminobenzotriazole

ANT:

Antipyrine

BUS:

Buspirone

CYP:

Cytochrome P450

D-FEL:

Dehydrofelodipine

FEX:

Fexofenadine

FEL:

Felodipine

MDZ:

Midazolam

6-OH-BUS:

6-Hydroxybuspirone

1-OH-MDZ:

1-Hydroxy-midazolam

4-OH-MDZ:

4-Hydroxy-midazolam

P-gp:

P-glycoprotein

PV rats:

Portal vein-cannulated rats

RLX:

Raloxifene

R4’G:

Raloxifene-4’-glucuronide

R6G:

Raloxifene-6-glucuronide

UGT:

Uridine 5’-diphosphate –glucuronosyltransferase

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ACKNOWLEDGMENTS & DISCLOSURES

We thank Kunihiko Morisaki (Charles River Laboratories Japan), Dr. Jiro Kuze (Taiho Pharmaceutical Co. Ltd.), and Dr. Toshiyuki Kume (Mitsubishi Tanabe Pharma Corporation) for useful discussions.

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Authors and Affiliations

  1. Pharmacokinetics and Safety Research Department, Central Research Laboratories, Kaken Pharmaceutical Co., Ltd, 14 Shinomiya Minamigawara-cho, Yamashina-ku, Kyoto, 607-8042, Japan

    Yoshiki Matsuda, Yoshihiro Konno, Takashi Hashimoto, Mika Nagai, Takayuki Taguchi & Masahiro Satsukawa

  2. Faculty of Pharmaceutical Sciences, Setsunan University, 45-1 Nagaotobe-cho, Hirakata, 573-0101, Osaka, Japan

    Shinji Yamashita

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  1. Yoshiki Matsuda
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  2. Yoshihiro Konno
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  4. Mika Nagai
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  6. Masahiro Satsukawa
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Correspondence to Yoshiki Matsuda.

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Matsuda, Y., Konno, Y., Hashimoto, T. et al. Quantitative Assessment of Intestinal First-pass Metabolism of Oral Drugs Using Portal-vein Cannulated Rats. Pharm Res 32, 604–616 (2015). https://doi.org/10.1007/s11095-014-1489-x

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  • DOI: https://doi.org/10.1007/s11095-014-1489-x

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