Interaction of angiotensin II type 1 receptor blockers with P-gp substrates in Caco-2 cells and hMDR1-expressing membranes

Kamiyama, Emi; Nakai, Daisuke; Mikkaichi, Tsuyoshi; Okudaira, Noriko; Okazaki, Osamu

doi:10.1016/j.lfs.2009.11.006

Cited by 30 publications

(17 citation statements)

References 22 publications

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“…Since many P-gp related drug-drug interactions have been reported, 15,16) P-gp is considered to be the most important ABC transporter with regard to drug efficacy. Therefore, it is thought that information on the changes in P-gp expression and localization induced by diseases would be useful for clinicians performing drug therapy.…”

Section: Discussionmentioning

confidence: 99%

Changes in the Localization of Ileal P-Glycoprotein Induced by Intestinal Ischemia/Reperfusion

Takizawa

Kishimoto

Kitazato

et al. 2011

Biological & Pharmaceutical Bulletin

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ATP binding cassette (ABC) transporters form one of the largest families of membrane transport proteins and are expressed in all organisms. They have been studied extensively and play a vital role in many cellular processes. ABC transporters are responsible for the multidrug resistance of cancer cells 1) but may also be capable of transporting several substrates such as metal ions, peptides, amino acids, sugars, and a large number of hydrophobic compounds and metabolites across the plasma membrane as well as intracellular membranes.2) ABC transporters play important roles in the defense mechanisms of several tissues through the excretion of toxic compounds and their metabolites. 3,4) In addition, the expression levels of the transporters are tightly regulated during tissue defense. 5)P-Glycoprotein (P-gp) is a typical ABC transporter. P-gp, which plays a very important role in drug therapy, was first discovered in 1976 as an efflux pump in a colchicine-resistant cell line, and 10 years later, the gene for P-gp was encoded. It is the most extensively studied of all of the ABC transporters.During small intestine grafting, rejection and ischemia/ reperfusion (I/R) injury are important problems. Immunosuppressive therapy is always required after transplantation. Since transplantation depends on a delicate balance between immunosuppression and rejection, the maintenance of adequate blood concentrations of immunosuppressants is critical. Cyclosporine A and tacrolimus are representative P-gp substrates. Therefore, P-gp controls the efficacies of these immunosuppressants. Information about the changes in P-gp induced by intestinal I/R would be useful for clinicians performing immunosuppressive therapy. We previously reported in in vitro 6) and in vivo 7-9) studies that I/R influences the function and expression of P-gp. In these reports, a correlation was found between the function of P-gp 1 h after reperfusion and the expression level of P-gp, but no such relationship was recognized 24 h after reperfusion. 7,8) It was suggested that this was due to functional abnormalities or abnormal localization of P-gp.In the present study, we examined whether abnormal P-gp localization is induced by intestinal I/R. Moreover, the mechanism and factors responsible for this phenomenon were also examined. MATERIALS AND METHODS MaterialsAll reagents were of analytical grade or better. Animals and Experimental Design Male Wistar/ST rats (8 weeks old) were purchased from Japan SLC Ltd. (Shizuoka, Japan). All animal experiments were performed according to the guidelines of Tokyo University of Pharmacy and Life Sciences. The animals were fasted for 18 h before the start of the experiment. Water was given freely during fasting. We have previously reported an in vivo intestinal I/R model that was produced using a spring scale and surgical sutures.7-9) Briefly, the superior mesenteric artery and vein in rats were occluded by lifting them using surgical-sutures (Natsume No. 3) connected to a spring balance for 1 h (ischemia condition), before r...

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Section: Discussionmentioning

confidence: 99%

Changes in the Localization of Ileal P-Glycoprotein Induced by Intestinal Ischemia/Reperfusion

Takizawa

Kishimoto

Kitazato

et al. 2011

Biological & Pharmaceutical Bulletin

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“…Moreover, some ARBs are inhibitors of P-gp that may lead to drug-drug interactions (see Section VI.G). Thus, telmisartan was shown to block digoxin transport in vitro with an IC 50 of 2.19 mM (Kamiyama et al, 2010), whereas candesartan cilexetil and irbesartan were less potent (IC 50 14.7 and 34 mM, respectively), and losartan, eprosartan, and candesartan did not inhibit P-gp (Kamiyama et al, 2010;Weiss et al, 2010). Given the intestinal concentration of telmisartan, telmisartan is potent enough to be expected to affect oral bioavailability of P-gp substrates in the intestine.…”

Section: B Transporter Molecules Involved In Tissue Distributionmentioning

confidence: 99%

A Systematic Comparison of the Properties of Clinically Used Angiotensin II Type 1 Receptor Antagonists

et al. 2013

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“…This may be an explanation for our observations. Angiotensin II type 1 receptor blockers of telmisartan, candesartan cilexetil (not candesartan itself) and irbesartan were demonstrated to have the potential to inhibit the transport of various drugs via P-gp [23]. However, Weiss et al [24] elucidated the inhibitory effect of angiotensin receptor type 1 blockers (telmisartan, candesartan, candesartan cilexetil, irbesartan, losartan, eprosartan, olmesartan and olmesartan medoxomil) on ATP-binding cassette transporter activity in vitro, including P-gp; no potential inhibition of losartan on P-gp was reported.…”

Section: Discussionmentioning

confidence: 99%

In vitro and in vivo Drug-Drug Interaction of Losartan and Glimepiride in Rats and Its Possible Mechanism

et al. 2015

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Background: Losartan and glimepiride are commonly used drugs to treat chronic diseases of hypertension and diabetes; they are both substrates of CYP2C9. The aim of the present study was to investigate the possible interaction of losartan and glimepiride both in vitro (rat liver microsomes) and in vivo (healthy Sprague-Dawley rats). Methods: In rat liver microsomes, 1-10 μmol/l losartan and glimepiride were coincubated, and the inhibitory effect was analyzed. In the subsequent pharmacokinetic study, 15 healthy Sprague-Dawley rats received administrations of 5 mg/kg losartan or 1 mg/kg glimepiride or a coadministration. Results: In the rat liver microsome system, glimepiride showed a slight inhibition of losartan at concentrations of 1-10 μmol/l, whereas losartan exhibited no inhibitory effect on glimepiride. In vivo, glimepiride did not modify the plasma concentration of losartan and its metabolite E-3174. The alteration of an increased AUC and C_max was observed in the pharmacokinetic parameters of glimepiride and hydroxy glimepiride. Conclusions: Glimepiride did not affect losartan pharmacokinetics in rats, while losartan potently altered glimepiride metabolism; this result was inconsistent with the in vitro outcome. The mechanism requires further investigation. In clinical settings, attention should be paid to the interaction of these two drugs in the human body as well as the possible adverse reactions of glimepiride.

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Interaction of angiotensin II type 1 receptor blockers with P-gp substrates in Caco-2 cells and hMDR1-expressing membranes

Cited by 30 publications

References 22 publications

Changes in the Localization of Ileal P-Glycoprotein Induced by Intestinal Ischemia/Reperfusion

Changes in the Localization of Ileal P-Glycoprotein Induced by Intestinal Ischemia/Reperfusion

A Systematic Comparison of the Properties of Clinically Used Angiotensin II Type 1 Receptor Antagonists

In vitro and in vivo Drug-Drug Interaction of Losartan and Glimepiride in Rats and Its Possible Mechanism

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