Enhancing the uptake of dextromethorphan in the CNS of rats by concomitant administration of the P-gp inhibitor verapamil

Marier, Jean‐François; Deschênes, Jean-Luc; Hage, Amal; Seliniotakis, Eleftheria; Gritsas, Ari; Flarakos, Themis; Beaudry, Francis; Vachon, Pascal

doi:10.1016/j.lfs.2005.04.025

Cited by 27 publications

(18 citation statements)

References 30 publications

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“…In present study verapamil was used as a P-gp inhibitor regarding to the selectivity of the inhibitory action of the drug on P-gp compared to the cytochrome P450 isoenzyme 2D6, the main enzyme responsible for tramadol metabolism. The dose of verapamil was selected based on the expected plasma concentration and the IC 50 of the inhibitor as well as the experiences in similar studies (33).…”

Section: Resultsmentioning

confidence: 99%

Lack of Evidence for Involvement of P-Glycoprotein in Brain Uptake of the Centrally Acting Analgesic, Tramadol in the Rat

et al. 2012

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-Purpose. Tramadol Hydrochloride is a widely-used centrally acting analgesic drug, which has some features of being a P-gp substrate. The present study evaluates the functional involvement of Pgp in CNS distribution of tramadol. Methods. The possibe involvement of P-glycoprotein in brain distribution of tramadol was evaluated using a pharmacokinetic approach in two groups of Pgp-inhibited and control rats. Six male Sprague-Dawley rats were used in each group to collect plasma and brain at 1, 5, 10, and 30 min following two tramadol doses of 1 and 10 mg/kg. Results. The brain uptake clearances of tramadol in Pgp-inhibited and control rats were 2.47±0.56 and 2.34±0.56 ml min , respectively, for 10 mg/kg dose. The brain-to-plasma concentration ratio (Kp,app) of more than 1 in all the time points following both the high and low dose cases (sometimes more than 3) indicated the brain accumulation of the drug. Linear correlation was found between tramadol dose and both corresponding plasma and brain concentrations, but the presence of a dose-dependency was not confirmed by the data obtained for brain-to-plasma concentration ratio. Conclusion. Considering the results of the previous studies and the present research, it seems that the brain accumulation of tramadol is not affected by P-gp inhibition which implies that there may be some other transport mechanisms involved in BBB transport of tramadol.

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Section: Resultsmentioning

confidence: 99%

Lack of Evidence for Involvement of P-Glycoprotein in Brain Uptake of the Centrally Acting Analgesic, Tramadol in the Rat

et al. 2012

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“…This was also supported by the results obtained with verapamil and probenecid. Although verapamil inhibits P-gp (18) and MRPs (5), MRP-mediated transport can be excluded since probenecid, a highly effective inhibitor of MRPs (26), did not significantly affect the transport of MXF. Statistical analysis of MXF permeability values in the presence of PSC-833 showed no difference in the secretory and absorptive directions.…”

Section: Discussionmentioning

confidence: 99%

P-Glycoprotein-Mediated Transport of Moxifloxacin in a Calu-3 Lung Epithelial Cell Model

Brillault

Castro

Harnois

et al. 2009

Antimicrob Agents Chemother

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Moxifloxacin (MXF) is a fluoroquinolone antibiotic that is effective against respiratory infections. However, the mechanisms of MXF lung diffusion are unknown. Active transport in other tissues has been suggested for several members of the fluoroquinolone family. In this study, transport of MXF was systematically investigated across a Calu-3 lung epithelial cell model. MXF showed polarized transport, with the secretory permeability being twice as high as the absorptive permeability. The secretory permeability was concentration dependent (apparent P max ‫؍‬ 13.6 ؋ 10 ؊6 cm ⅐ s ؊1 ; apparent K m ‫؍‬ 147 M), suggesting saturated transport at concentrations higher than 350 g/ml. The P-glycoprotein inhibitor PSC-833 inhibited MXF transport in both directions, whereas probenecid, a multidrug resistance-related protein inhibitor, appeared to have no effect in the Calu-3 model. Moreover, rifampin, a known inducer of efflux transport proteins, upregulated the expression of P-glycoprotein in Calu-3 cells and enhanced MXF active transport. In conclusion, this study clearly indicates that MXF is subject to P-glycoprotein-mediated active transport in the Calu-3 model. This Pglycoprotein-dependent secretion may lead to higher MXF epithelial lining fluid concentrations than those in plasma. Furthermore, drug-drug interactions may be expected when MXF is combined with other P-glycoprotein substrates or modulators.Fluoroquinolones (FQs) are one of the main classes of antimicrobial agents, with a broad spectrum of activity and a concentration-dependent killing effect (25,29). Moxifloxacin (MXF) is an FQ that has been shown to be effective against respiratory pathogens, including Haemophilus influenzae, Moraxella catarrhalis, and penicillin-resistant strains of Streptococcus pneumoniae (3,24). The use of MXF is recommended as therapy for patients with community-acquired pneumonia, exacerbations of chronic bronchitis, chronic obstructive pulmonary disease, or tuberculosis (21). Pharmacokinetics of FQs have been studied in different tissues, such as the liver, kidney, and intestinal tract, and it appears that multiple transporters contribute to drug disposition (2). Active transport has been suggested for many FQs, involving mainly the ATP-binding cassette (ABC) transporter family (P-glycoprotein [P-gp] and multidrug resistance-related proteins [MRPs]). However, there is a lack of information regarding the mechanisms of MXF lung distribution. To our knowledge, cellular transport of MXF through the lung tissue is still unclear, and an understanding of its mechanisms would help to better predict its pulmonary disposition, which is directly linked to the bacterial killing effect. Moreover, when MXF is used as a second-line therapy or in combination with drugs such as rifampin (22), drug-drug interaction can occur, as presented in some rifampin-MXF interaction studies (23,30). In this particular case, MXF was recommended for the treatment of multidrugresistant tuberculosis and a decrease in MXF plasma concentration was observed in assoc...

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“…In other hands, Verapamil is P-gp inhibitor (Bansal et al, 2009;De Klerk et al, 2010). Administration of verapamil enhanced uptake of dextromethorphan in the CNS of rats (Marier et al, 2005). We demonstrated coadministration of salinomycin and verapamil significantly increased serum level of salinomycin in diabetic rats.…”

Section: Discussionmentioning

confidence: 60%

Effect of Verapamil on Serum Level of Salinomycin in Diabetic Rats

Najafzadeh¹,

Fatemi²,

Ashna³

2011

American Journal of Applied Sciences

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Problem statement:The aim of present study was evaluation function of P-glycoprotein with or without verapamil in normal and diabetic rats; which the function of P-glycoprotein was indirectly evaluated by detection of serum slainomycin concentration with HPLC method. Approach: This study was carried in 4 groups of rats including normal rats which received salinomycin and verapamil together salinomycin; and diabetic rats which received salinomycin and verapamil together salinomycin. Serum concentration of salinomycin was measured by HPLC after 3 h from its administration. Results: Results show the serum concentration of salinomycin significantly elevated in diabetic rats which received verapamil together salinomycin; while this concentration did not significantly change in other groups. Conclusion: Since the p-glycoprotein activity decreases in diabetic conditions and verapamil inhibits it; probably transport of salinomycin from blood to tissues or its elimination was decreased that caused its elevated serum concentration.

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Enhancing the uptake of dextromethorphan in the CNS of rats by concomitant administration of the P-gp inhibitor verapamil

Cited by 27 publications

References 30 publications

Lack of Evidence for Involvement of P-Glycoprotein in Brain Uptake of the Centrally Acting Analgesic, Tramadol in the Rat

Lack of Evidence for Involvement of P-Glycoprotein in Brain Uptake of the Centrally Acting Analgesic, Tramadol in the Rat

P-Glycoprotein-Mediated Transport of Moxifloxacin in a Calu-3 Lung Epithelial Cell Model

Effect of Verapamil on Serum Level of Salinomycin in Diabetic Rats

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