Pre‐clinical evidence of enhanced oral bioavailability of the P‐glycoprotein substrate talinolol in combination with morin

Pathak, Shriram M.; Udupa, N.

doi:10.1002/bdd.703

Cited by 21 publications

(11 citation statements)

References 23 publications

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“…These results indicated that some flavones could enhance the absorption of drugs co-administered with low bioavailabilities, and thus enhance their efficacy. On the other side, the drug–drug interactions are common in clinical, and can cause toxic side effects if they increased drug levels reaching above toxic threshold [ 22 ]. We should aware the potential interaction of a drug with a narrow therapeutic index.…”

Section: Discussionmentioning

confidence: 99%

The Pharmacokinetics of Raloxifene and Its Interaction with Apigenin in Rat

et al. 2010

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Purpose: Raloxifene is a selective estrogen receptor modulator which is structurally similar to tamoxifen. As flavonoids can interact with raloxifene in vitro, we evaluated the in vivo pharmacokinetics of raloxifene in rats when co-administered with apigenin. Methods: The pharmacokinetics of raloxifene in the absence or presence of apigenin was investigated in rats after different dosage regimens. The plasma concentrations before and after enzymatic hydrolysis were analyzed by HPLC, and the pharmacokinetic profiles of raloxifene administered alone and in combination with apigenin were compared. Results: Co-administration of apigenin with raloxifene in a 1:2 ratio by weight resulted in a 55% and 37% increase in the Cmax and AUC of intact raloxifene, respectively. When equal proportions of raloxifene and apigenin (1:1) were administered, the Cmax and AUC of intact raloxifene were increased by 173% and 97% respectively. This increase in intact raloxifene was not associated with an increase in total raloxifene (intact plus conjugated raloxifene) because AUC and Cmax of total raloxifene when administered alone or in combination with apigenin were found to be similar. The results indicated that apigenin inhibited the glucuronidation and sulfation of raloxifene in the intestine bringing about an increased bioavailability of the drug. Conclusions: The results showed that apigenin decreased the first-pass metabolism of raloxifene but did not increase its absorption from the gastrointestinal tract.

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Section: Discussionmentioning

confidence: 99%

The Pharmacokinetics of Raloxifene and Its Interaction with Apigenin in Rat

et al. 2010

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“…The chambers were screwed tight and the entire assembly was maintained at 37°C. For the inhibitory studies, verapamil, a validated P‐gp inhibitor (Varma & Panchagnula, 2005; Pathak & Udupa, 2010), was added to the mucosal side at the final concentration of 200 μ m . The interest of investigating the effect of verapamil in bidirectional transport of drugs across jejunum segments has increased widely because it is a well‐known inhibitor of P‐gp (Saitoh et al., 2003; Watanabe et al., 2004; Varma & Panchagnula, 2005; International Transporter Consortium, 2010; Pathak & Udupa, 2010; Sajeesh et al., 2010).…”

Section: Methodsmentioning

confidence: 99%

“…For the inhibitory studies, verapamil, a validated P‐gp inhibitor (Varma & Panchagnula, 2005; Pathak & Udupa, 2010), was added to the mucosal side at the final concentration of 200 μ m . The interest of investigating the effect of verapamil in bidirectional transport of drugs across jejunum segments has increased widely because it is a well‐known inhibitor of P‐gp (Saitoh et al., 2003; Watanabe et al., 2004; Varma & Panchagnula, 2005; International Transporter Consortium, 2010; Pathak & Udupa, 2010; Sajeesh et al., 2010). Its concentration was defined according to previous studies and, in order to be equimolar, to that of the test compounds (Annaert et al., 2000; Pan et al., 2002; Varma & Panchagnula, 2005; Pathak & Udupa, 2010).…”

Section: Methodsmentioning

confidence: 99%

Evaluation of the permeability and P‐glycoprotein efflux of carbamazepine and several derivatives across mouse small intestine by the Ussing chamber technique

et al. 2012

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SUMMARYPurpose: The rational discovery and development of new antiepileptic drugs (AEDs) with safer therapeutic index and better pharmacokinetic properties is still warranted nowadays. Because the long-term management of epilepsy is attained by means of orally administered AEDs, investigation of their potential to be well absorbed at the intestinal level is mandatory. Moreover, involvement of the efflux transport mediated by P-glycoprotein (P-gp) may compromise the systemic and central nervous system disposition of AEDs. Therefore, this study aimed at characterizing mouse jejunal passive transport and the possible active efflux mediated by P-gp of a series of dibenz, carbamazepine-10, 11-epoxide[CBZ-E],10,11-trans-dihydroxy-10,11-dihydrocarbamazepine [trans-diol], and BIA 2-024), which comprise some AEDs and metabolites. Methods: Permeation studies were performed with freshly excised mouse jejunum segments mounted in Ussing chambers. Absorptive (M-S) and secretive (S-M) transports were analyzed with and without verapamil, which is a P-gp inhibitor widely recognized. Apparent permeability coefficients (P app ) in both directions and in absence or presence of verapamil were determined for each test compound. The in vitro method was validated using five controls that included high and low permeable markers with known absorption fraction (Fa) and also well-known P-gp substrates. The integrity of intestinal membrane was guaranteed during the assay by measuring the transepithelial electrical resistance. Key Findings: The correlation obtained between P app (M-S) and Fa of references was high (r 2 = 0.9945), and could be used to classify the derivatives according to Biopharmaceutical Classification System: CBZ and OXC were the only classified as highly permeable. The P app (S-M) of OXC, CBZ-E, R-Lic, and BIA 2-024 were significantly higher than their P app (M-S). After verapamil addition, their P app (S-M) lowered while P app (S-M) increased, suggesting the involvement of P-gp on the transport of those compounds across mouse jejunum segments. In opposition, CBZ, S-Lic, and trans-diol presented no statistical differences between the P app values reported in both directions, with or without verapamil. The results reported herein suggest that differences in biodisposition of S-Lic and R-Lic might result from their distinct interaction with P-gp. Significance: The Ussing chamber model used herein showed to be useful for predicting Fa of AEDs and the involvement of efflux transport, namely P-gp, on their absorption. This is an important achievement as compounds that are not transported by P-gp may offer advantages when used in patients with pharmacoresistant epilepsy.

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“…It has also been reported that morin could be a fairly potent P-gp inhibitor (Zhang and Morris, 2003). Morin altered the total areas under the plasma concentration-time curve from time zero to infinity (AUC) of oral diltiazem (Choi and Choi, 2005), etoposide (Li et al, 2007;Suh, 2011), nicardipine , paclitaxel (Choi et al, 2006), talinolol (Pathak and Udupa, 2010), and tamoxifen (Shin et al, 2008) in rats. Thus, it could be expected that morin could also affect the pharmacokinetics of above drugs in tumor rat model.…”

Section: Introductionmentioning

confidence: 96%

Effects of morin on the pharmacokinetics of docetaxel in rats with 7,12-dimethylbenz[a]anthracene (DMBA)-induced mammary tumors

Yang

Lee

et al. 2011

Arch. Pharm. Res.

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Docetaxel is a P-glycoprotein (P-gp) substrate and metabolized via cytochrome P450 (CYP) 3A subfamily in rats. Morin is an inhibitor of both CYPs and P-gp. Hence, the effects of morin on the intravenous and oral pharmacokinetics of docetaxel were investigated using 7,12-dimethylbenz[a]anthracene (DMBA)-induced mammary tumor rats (DMBA rats) as an animal model of human breast cancer. Docetaxel was administered intravenously (4 mg/kg) and orally (20 mg/kg) without and with morin (15 mg/kg) in DMBA rats. After the intravenous administration of docetaxel in control and DMBA rats with and without morin, the values of non-renal clearance and area under the plasma concentration-time (AUC) for docetaxel were comparable. Morin did not increase AUC or the absolute oral bioavailability (F) for docetaxel after the oral administration of docetaxel in control and DMBA rats with and without morin. The inhibition of hepatic and intestinal metabolism of docetaxel by morin and/or DMBA and the effect of intestinal P-gp inhibition by morin on the pharmacokinetics of docetaxel did not seem to be considerable in DMBA-induced mammary tumor rats.

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Pre‐clinical evidence of enhanced oral bioavailability of the P‐glycoprotein substrate talinolol in combination with morin

Cited by 21 publications

References 23 publications

The Pharmacokinetics of Raloxifene and Its Interaction with Apigenin in Rat

The Pharmacokinetics of Raloxifene and Its Interaction with Apigenin in Rat

Evaluation of the permeability and P‐glycoprotein efflux of carbamazepine and several derivatives across mouse small intestine by the Ussing chamber technique

Effects of morin on the pharmacokinetics of docetaxel in rats with 7,12-dimethylbenz[a]anthracene (DMBA)-induced mammary tumors

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