Role of P-Glycoprotein as a Secretory Mechanism in Quinidine Absorption from Rat Small Intestine

doi:10.1021/js970294v

Journal of Pharmaceutical Sciences

Volume 87, Issue 3, March 1998, Pages 295-299

https://doi.org/10.1021/js970294v Get rights and content

Abstract

□ The intestinal transport of quinidine was characterized in rat small intestine, using the Ussing-type chamber under short-circuited conditions. In the short-circuited condition, quinidine transport was predominantly secretory and the transport rate in jejunum was 3.5 times larger in the secretory direction than that in the absorptive direction. The secretion of quinidine was found to be dependent upon its concentration and to be via a carrier-mediated system in both jejunum and ileum. Although the kinetic characteristic of the carrier-mediated secretion of quinidine was very similar in jejunum and ileum, its contribution was much greater in jejunum because of a higher passive diffusion component in ileum. The secretion of quinidine, well-known as an inhibitor of P-glycoprotein, was inhibited significantly and its absorption was enhanced significantly by several substrates of P-glycoprotein including verapamil, diltiazem, and digitoxin in jejunum. These phenomena were also observed by the addition of 2,4-dinitrophenol. Furthermore, the voltage-clamp studies indicated that the inhibition of quinidine secretion occurred in the transcellular pathway. On the other hand, neither tetraethylammonium nor p-aminohippuric acid affected the transport of quinidine. Quinidine was also recognized to inhibit the secretion and to promote the absorption of substrates of P-glycoprotein, chlorpromazine, and verapamil. These results strongly suggest that quinidine is not only an inhibitor but also a substrate of P-glycoprotein and that the P-glycoprotein-mediated secretory flux acts as a barrier to quinidine absorption in the small intestine, especially jejunum.

References and Notes (29)

V.J. Wacher et al.
Active secretion and enterocytic drug metabolism barriers to drug absorption
Adv. Drug Deliv. Rev.
(1996)
Y. Kamimoto et al.
The function of Gp170, the multidrug resistance gene product, in rat liver canalicular membrane vesicles
J. Biol. Chem.
(1989)
T. Watanabe et al.
Kinetic analysis of hepatobiliary transport of vincristine in perfused rat liver
J. Hepatol.
(1992)
A. Tsuji et al.
Restricted transport of cyclosporin A across the blood-brain barrier by a multidrug transporter
P-glycoprotein. Biochem. Pharmacol.
(1993)
S. Hsing et al.
The function of Gp170, the multidrug-resistance gene product, in the brush border of rat intestinal mucosa
Gastroenterology
(1992)
K.V. Chin et al.
Function and regulation of the human multidrug resistance gene
Adv. Cancer Res.
(1993)
F. Thiebaut et al.
Cellular localization of the multidrug-resistance gene product P-glycoprotein in normal human tissues
Proc. Natl. Acad. Sci. U.S.A.
(1987)
C. Cordon-Cardo et al.
Expression of the multidrug resistance gene product (P-glycoprotein) in human normal and tumor tissues
J. Histochem. Cytochem.
(1990)
R. Hori et al.
Role of P-glycoprotein in renal tubular secretion of digoxin in the isolated perfused rat kidney
J. Pharmacol. Exp. Ther.
(1993)
N. Okamura et al.
Hori. R. Digoxin-cyclosporin A interaction: Modulation of the multidrug transporter P-glycoprotein in the kidney
J. Pharmacol. Exp. Ther.
(1993)

A.H. Shinkel et al.

Disruption of the mouse mdr1a P-glycoprotein gene leads to a deficiency in the blood-brain barrier and to increased sensitivity to drugs

Cell

(1994)

D. Leveque et al.

P-glycoprotein and pharmacokinetics

Anticancer Res.

(1995)

T. Terao et al.

Active secretion of drugs from the small intestinal epithelium in rats by P-glycoprotein functioning as an absorption barrier

J. Pharm. Pharmacol.

(1996)

H. Saitoh et al.

Possible involvement of multiple P-glycoprotein-mediated efflux systems in the transport of verapamil and other organic cations across rat intestine

Pharm. Res.

(1995)

Cited by (64)

Inhalable spray dried lipidnanoparticles for the co-delivery of paclitaxel and doxorubicin in lung cancer
2020, Journal of Drug Delivery Science and Technology
Citation Excerpt :
Drug resistance is connected with elevated expression of proteins associated with ATP-binding cassette (ABC) transporter involving P-glycoprotein (P-gp), multidrug resistance proteins (MRP) and breast cancer resistance protein (BCRP) [8]. P-gp efflux is reported to increase within most ofthe drug resistance cancerous cells including cancer-associated with lung, liver, pancreas, and ovaries [9]. These proteins bind to the multiple compounds which have structurally dissimilarity; eventually mediate drug efflux from cancerous cells, leading to a sub-therapeutic concentration of drug inside cancer cells which ultimately causes a decrease in therapeutic value [10].
The present study aimed to develop and evaluate inhalable nanocarriers using different surfactants for enhancing the antitumor efficacy of chemotherapeutics. Surfactants (Cremophor EL, Tween 80 and Tween 20) loaded nano-lipid carriers (NLCs) containing Paclitaxel (PTX) and Doxorubicin (DOX) were prepared through solvent evaporation followed by spray drying technique. The prepared inhalable nanoaggregates were evaluated for various pharmaceutical and aerodynamic properties. Animal model was used to determine in-vivo drug distribution, and safety profile of optimized formulations. Particle size distribution analysis indicated that Cremophor EL based nanocarriers have smallest particle size distribution (394.1 ± 5.6 nm) compared to Tween 80 and Tween 20 characterized by size values, 575.6 ± 3.3 nm and 460.7 ± 2.6 nm, respectively. DSCand XRD analysis show no characteristic change in solid state properties of drugs in optimized formulation. Organ distribution studies demonstrated Cremophor EL DPIs show higher drug distribution in the lungs compared to other experimental formulations and plain drugs. Further animals treated with experimental DPIs show no sign of tissue damage with usual feeding and drinking behaviour after 24 h of treatment. In this study, spray-dried nanoaggregates composed of Cremophor EL encapsulating PTX and DOX offer a possible strategy to reverse the growing concern of drug resistance for improved therapeutic adherence.
Effects of Polyoxyethylene Alkyl Ethers on the Intestinal Transport and Absorption of Rhodamine 123: A P-glycoprotein Substrate by in Vitro and in Vivo Studies
2016, Journal of Pharmaceutical Sciences
Citation Excerpt :
P-gp is expressed in various normal tissues, including the intestinal brush border membranes, brain, liver, kidney, testis, and adrenal glands, and is also extensively expressed in tumor cells. It can actively pump a wide range of drugs such as digoxin, vinca alkaloids, and β-adrenergic agonists out of cells and thus reduce the oral bioavailability of these drugs.6,7 Therefore, the intestinal P-gp, an ATP-dependent multidrug efflux pump, can affect the absorption, distribution, and elimination of its substrates.8,9
We examined the effects of polyoxyethylene alkyl ethers (Brijs) on the intestinal transport and absorption of rhodamine 123, a P-glycoprotein (P-gp) substrate, by in vitro and in vivo studies. Brijs increased the absorptive transport of rhodamine 123 and decreased its secretory transport in the in vitro diffusion chamber method. However, Brijs did not change the transport of 5(6)-carboxyfluorescein, a non-P-gp substrate, indicating that the effect of Brijs on the transport of drugs was P-gp substrate-specific. The effects of Brijs on rhodamine 123 transport across Caco-2 cell monolayers were also examined. Secretory transport of rhodamine 123 was enhanced and its absorptive transport was significantly reduced in the presence of Brijs. Furthermore, in the in vivo studies, Brijs also enhanced the intestinal absorption of rhodamine 123 in rats. The intestinal membrane damage produced by Brijs was also evaluated by measuring the activity of lactate dehydrogenase and the release of protein. We found almost no intestinal damage in the presence of various Brijs. These findings suggest that Brijs might inhibit the function of intestinal P-gp, thereby increasing the intestinal transport and absorption of P-gp substrates without serious intestinal membrane damage.
Coexisted components of Salvia miltiorrhiza enhance intestinal absorption of cryptotanshinone via inhibition of the intestinal P-gp
2012, Phytomedicine
Cryptotanshinone, derived from the roots of Salvia miltiorrhiza Bge and Salvia przewalskii Maxim, is the major active component and possesses significant antibacterial, antidermatophytic, antioxidant, anti-inflammatory and anticancer activities. The objective of this study was to investigate the intestinal absorptive characteristics of cryptotanshinone as well as the absorptive behavior influenced by co-administration of the diterpenoid tanshinones and danxingfang using an in vitro everted rat gut sac model. The results showed a good linear correlation between cryptotanshinone of absorption and the incubation time from 10 to 70 min. The concentration dependence showed that a non-linear correlation existed between the cryptotanshinone absorption and the concentration at 100 μg/ml. Coexisting diterpenoid tanshinones and danxingfang could significantly enhance the absorption of cryptotanshinone. Coexisting diterpenoid tanshinones and danxingfang, which influenced cryptotanshinone's absorption, manifested as similar to that of the P-glycoprotein inhibitor. The underlying mechanism of the improvement of oral bioavailability was proposed that coexisting diterpenoid tanshinones and danxingfang could decrease the efflux transport of cryptotanshinone by P-glycoprotein.
The effects of notoginsenoside R <inf>1</inf> on the intestinal absorption of geniposide by the everted rat gut sac model
2012, Journal of Ethnopharmacology
Geniposide is derived from Gardenia jasminoides Ellis (Rubiaceae). Its anti-inflammatory, antithrombotic effects as well as its preventive effect against ischemic stroke have been reported. Radix notoginseng (Chinese name tienchi or sanqi) is the dried root of Panax notoginseng (Burk.) F.H. Chen, an herb noted for its promotion of blood circulation, blood stasis removal and pain alleviation, and has been widely utilized for the prevention and treatment of microcirculatory disturbances in China and other Asian countries for many years. Notoginsenoside R₁ is an effective and structurally representative bioactive constituent of R. notoginseng. In our preliminary study, notoginsenoside R₁ was able significantly to improve the bioavailability of geniposide in beagle dogs, but the underlying mechanisms remain unknown.
The present study aimed to investigate the intestinal kinetic absorptive characteristics of geniposide as well as the absorptive behavior influenced by the co-administration of notoginsenoside R₁ using an in vitro everted rat gut sac model.
The results showed good linear correlation between the geniposide absorption in sac contents and the incubation time from 0 to 120 min. The concentration dependence showed a non-linear correlation between the geniposide absorption and the concentrations 0.356–1.424 mg/mL, the absorption was saturated about 1.424 mg/mL. Notoginsenoside R₁ at 0.1 and 0.2 mg/mL concentrations was able significantly to enhance the absorption of geniposide (1.424 mg/mL) by 1.7- and 1.4-fold. Moreover, verapamil, a well-known P-glycoprotein inhibitor, was able significantly to elevate the absorption of geniposide 2.4-fold. Notoginsenoside R₁ influenced geniposide's absorption in a way similar to that of a P-glycoprotein inhibitor.
In conclusion, notoginsenoside R₁ significantly enhances the intestinal absorption of geniposide. As for the mechanism underlying the improvement of geniposide's bioavailability, it is proposed that notoginsenoside R₁ was able to decrease the efflux transport of geniposide by P-glycoproteins.
Quinidine
2010, xPharm: The Comprehensive Pharmacology Reference
Xenopus laevis oocytes expressing human P-glycoprotein: Probing trans- and cis-inhibitory effects on [<sup>3</sup>H]vinblastine and [<sup>3</sup>H]digoxin efflux
2010, Pharmacological Research
P-glycoprotein (P-gp; MDR1) recognizes and actively transports many structurally diverse compounds (hydrophobic neutral and cationic). We studied MDR1-mediated drug transport using a high-throughput (96-well) oocyte expression system. MDR1-expressing oocytes contained sufficient ATP levels to conduct fundamental efflux studies; the optimal experimental temperature was 25 °C. [³H]Vinblastine efflux by MDR1-expressing oocytes was detectable and afforded a K_m of 145.5 ± 25.4 μM. [³H]Vinblastine (5.6 ± 0.3 μM) and [³H]digoxin (1.0 ± 0.1 μM) were individually injected into MDR1-expressing oocytes and their efflux monitored. Quinidine and verapamil, known MDR1 substrates/inhibitors, showed trans-inhibition on MDR1-mediated [³H]vinblastine and [³H]digoxin efflux. Conversely, doxorubicin demonstrated cis-inhibition without trans-inhibition on MDR1-mediated [³H]vinblastine efflux. The MDR1-expressing oocyte system offers researchers with an alternative in vitro method to screen compounds and may allow one to probe P-gp drug–drug and/or drug–inhibitor interactions.

View all citing articles on Scopus

View full text

Role of P-Glycoprotein as a Secretory Mechanism in Quinidine Absorption from Rat Small Intestine

Abstract

Adv. Drug Deliv. Rev.

J. Biol. Chem.

J. Hepatol.

P-glycoprotein. Biochem. Pharmacol.

Gastroenterology

Function and regulation of the human multidrug resistance gene

Adv. Cancer Res.

Cellular localization of the multidrug-resistance gene product P-glycoprotein in normal human tissues

Proc. Natl. Acad. Sci. U.S.A.

Expression of the multidrug resistance gene product (P-glycoprotein) in human normal and tumor tissues

J. Histochem. Cytochem.

Role of P-glycoprotein in renal tubular secretion of digoxin in the isolated perfused rat kidney

J. Pharmacol. Exp. Ther.

Hori. R. Digoxin-cyclosporin A interaction: Modulation of the multidrug transporter P-glycoprotein in the kidney