Studies on Intestinal Absorption of Sulpiride. (1): Carrier-Mediated Uptake of Sulpiride in the Human Intestinal Cell Line Caco-2.

Watanabe, Kimitsuna; Sawano, Tetsuya; Terada, Kazuaya; Endo, Tokiko; Sakata, Masakatsu; Sato, Juichi

doi:10.1248/bpb.25.885

Cited by 47 publications

(32 citation statements)

References 31 publications

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“…The low F a ⅐ F g of sulpiride and fexofenadine was probably due to brush-border P-glycoprotein efflux (Watanabe et al, 2002;Kamath et al, 2005). In addition, the low F h of fexofenadine is probably due to excretion of bile in the liver (Kamath et al, 2005).…”

Section: Discussionmentioning

confidence: 98%

Assessment of Intestinal Availability of Various Drugs in the Oral Absorption Process Using Portal Vein-Cannulated Rats

Matsuda

Konno

Satsukawa

et al. 2012

Drug Metabolism and Disposition

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ABSTRACT:To understand the rate-limiting process of oral drug absorption, not only total bioavailability (F) but also intestinal (F a ⅐ F g ) and hepatic (F h ) availability after oral administration should be evaluated. Usually, F a ⅐ F g of drug is calculated from pharmacokinetic parameters after intravenous and oral administration. This approach is influenced markedly by the estimated value of F h , which varies with the hepatic blood flow used in the calculations. In this study, portal vein-cannulated rats were used to calculate the F a ⅐ F g of drugs from a single oral dosing experiment without data from intravenous injection. Portal vein-cannulated rats were prepared by a new operative method that enables stable portal vein blood flow. This surgery had no effects on hepatic blood flow and metabolic activity. Our method for calculating F a ⅐ F g was validated by determining both portal and systemic plasma concentration profiles of various drugs possessing different pharmacokinetic properties after oral administration to the portal vein-cannulated rats. Simulation of portal and systemic plasma concentrations by physiologically based pharmacokinetic modeling indicated that the balance of the absorption rate constant (k a ) and elimination rate constant (k e ) resulted in different patterns in portal and systemic plasma concentration-time profiles. This study is expected to provide a new experimental animal model that enables identification of the factors that limit oral bioavailability and to provide pharmacokinetic information on the oral absorption process of drugs during drug discovery.

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Section: Discussionmentioning

confidence: 98%

Assessment of Intestinal Availability of Various Drugs in the Oral Absorption Process Using Portal Vein-Cannulated Rats

Matsuda

Konno

Satsukawa

et al. 2012

Drug Metabolism and Disposition

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“…Conditions for High-Performance Liquid Chromatography (HPLC) HPLC 6) was carried out using a model CCPM pump (Tosoh, Tokyo, Japan) equipped with an RF-530 fluorescence detector (Shimadzu, Kyoto, Japan). The excitation and emission wavelengths were set at 307 and 358 nm, respectively.…”

Section: Methodsmentioning

confidence: 99%

Studies on Intestinal Absorption of Sulpiride (3): Intestinal Absorption of Sulpiride in Rats

Watanabe

Sawano

Jinriki

et al. 2004

Biological & Pharmaceutical Bulletin

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Sulpiride, a dopamine D 2 receptor antagonist, is widely used for the treatment of schizophrenia, depression, and gastric and duodenal ulcers because it has a much lower incidence of extrapyramidal side effects than any other antagonist of this type.1,2) Optimization of treatment with sulpiride requires knowledge of its bioavailability, pharmacokinetics, and pharmacodynamics in humans. Mizuno et al. showed that the main site of sulpiride absorption is the intestine.3)The bioavailability of sulpiride shows species differences: it is low in some species, a mean of 27% in humans and 15-20% in rat, whereas it is relatively high (44-85%) in dogs. 4)The low bioavailability in humans is probably due to poor absorption.3) Baluom et al. 5) reported that the intestinal absorption of sulpiride was increased when it was concomitantly administered with the substrates of P-glycoprotein, verapamil, and quinidine in rats. They speculated that the poor oral bioavailability of sulpiride was caused by brush border P-glycoprotein efflux.In previous studies, we investigated the transcellular transport of sulpiride using the human intestinal cell line Caco-2. 6,7) Our results indicated that the apical-to-basolateral transport of sulpiride was significantly inhibited by the substrates or inhibitors of peptide transporter PEPT1, and organic cation transporters OCTN1 and/or OCTN2. On the other hand, the basolateral-to-apical transport was significantly inhibited by the substrates or inhibitors of P-glycoprotein on the apical membrane, and basolateral peptide transporter and organic cation transporter OCT1 on the basolateral membrane. From these findings, we speculated that a decrease in the absorption of sulpiride may occur in combination therapy involving the substrates or inhibitors of PEPT1, OCTN1, and OCTN2; conversely, the concomitant administration of the substrates or inhibitors of P-glycoprotein and OCT1 may increase the absorption of sulpiride.To determine the appropriate clinical administration of sulpiride, we consider it essential to investigate its interactions with drug transporters. Drug transporters corresponding to human drug transporters such as P-glycoprotein, organic cation and anion transporters, and peptide transporters are expressed in the rat intestine. The aim of this study was to investigate whether the concomitant administration of sulpiride and the substrates or inhibitors of PEPT1, OCTN1, OCTN2, OCT1, and P-glycoprotein affects the intestinal absorption and the pharmacokinetic behavior of sulpiride after oral administration in rats. MATERIALS AND METHODS MaterialsSulpiride and cephalexin hydrate were purchased from ICN Biomedicals, Inc. (Costa Mesa, CA, U.S.A.). L-Carnitine was purchased from Sigma (St. Louis, MO, U.S.A.). Captopril, carboxymethyl cellulose sodium salt (CMC-Na), choline chloride, cyclosporin A, quinidine, verapamil hydrochloride, and nicotinic acid were purchased from Wako Pure Chemical Industries (Osaka, Japan). Guanidine was purchased from Kanto Chemical (Tokyo, Japan). All chemicals us...

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“…Moreover, they showed that OCTN2 is expressed in another human intestinal cell line (HT-29), suggesting strongly that OCTN2 is expressed in human intestine. Recently, Watanabe et al (52,53) demonstrated that in the presence of some OCTN2 substrates, the apical-to-basolateral transport of sulpiride in Caco-2 cell monolayers was significantly inhibited. These results showed that OCTN2 on the apical membrane in Caco-2 cells takes part in the apical-to-basolateral transport of sulpiride.…”

mentioning

confidence: 99%

Expression and localization of organic cation/carnitine transporter OCTN2 in Caco-2 cells

Elimrani

Lahjouji

Seidman

et al. 2003

American Journal of Physiology-Gastrointestinal and Liver Physi

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Carnitine is derived both from dietary sources and biosynthesis. Dietary carnitine is absorbed in the small intestine and then distributed to other organs. Previous studies using Caco-2 cells demonstrated that the transport of L-carnitine in the intestine involves a carrier-mediated system. The purpose of this study was to determine whether the uptake of L-carnitine in Caco-2 cells is mediated by the recently identified organic cation/carnitine transporter (OCTN2). Kinetics of L-[ 3 H]carnitine uptake were investigated with or without specific inhibitors. L-Carnitine uptake in mature cells was sodium dependent and linear with time. Km and Vmax values for saturable uptake were 14.07 Ϯ 1.70 M and 26.3 Ϯ 0.80 pmol ⅐ mg protein Ϫ1 ⅐ 6 min Ϫ1 , respectively. L-carnitine uptake was inhibited (P Ͻ 0.05-0.01) by valproate and other organic cations. Anti-OCTN2 antibodies recognized a protein in the brush-border membrane (BBM) of Caco-2 cells with an apparent molecular mass of 60 kDa. The OCTN2 expression was confirmed by double immunostaining. Our results demonstrate that L-carnitine uptake in differentiated Caco-2 cells is primarily mediated by OCTN2, located on the BBM. intestine; brush-border membrane; organic cation transport; anti-OCTN2 antibodies; valproate.

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Studies on Intestinal Absorption of Sulpiride. (1): Carrier-Mediated Uptake of Sulpiride in the Human Intestinal Cell Line Caco-2.

Cited by 47 publications

References 31 publications

Assessment of Intestinal Availability of Various Drugs in the Oral Absorption Process Using Portal Vein-Cannulated Rats

Assessment of Intestinal Availability of Various Drugs in the Oral Absorption Process Using Portal Vein-Cannulated Rats

Studies on Intestinal Absorption of Sulpiride (3): Intestinal Absorption of Sulpiride in Rats

Expression and localization of organic cation/carnitine transporter OCTN2 in Caco-2 cells

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