Effect of P-glycoprotein inhibitor, verapamil, on oral bioavailability and pharmacokinetics of irinotecan in rats

Bansal, Tripta; Mishra, Gautam; Jaggi, Manu; Khar, Roop K.; Talegaonkar, Sushama

doi:10.1016/j.ejps.2008.12.005

Cited by 121 publications

(98 citation statements)

References 30 publications

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“…The ability of this drug in enhancing the tissue concentrations and effectiveness of other drug molecules via P-gp inhibition has been widely studied (30)(31)(32). 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.…”

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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“…Although drug-drug interactions of irinotecan and SN-38 with verapamil have already been described in previous works using Caco2 cells model and in vivo in rats (8), applying the improved in situ model provided two main additions, the first, is that it allowed the determination of the intestinal permeability of the parent drug, which is, to our best knowledge, the first published work providing the P eff of irinotecan, the second, is that it allowed the quantification of SN-38 exposure at the site where toxicity takes place.…”

Section: Discussionmentioning

confidence: 99%

“…Drug efflux transporters mainly (p-gp) play a major role in the disposition of both CPT-11 and SN-38 (7), thus, inhibition of those intestinal efflux pumps would be a rational way to improve oral bioavailability and ameliorate intestinal toxicity of irinotecan, due to the potential of these inhibitors such as verapamil to inhibit the exsorption of both irinotecan and SN-38 to the lumen of the gut (5). The oral route of irinotecan administration has been the subject of extensive research recently due to the promising results for overcoming the poor and erratic oral bioavailability by the action of drug efflux transport inhibitors (8,9).…”

Section: Introductionmentioning

confidence: 99%

In Situ Intestinal Perfusion of Irinotecan: Application to P-gp Mediated Drug Interaction and Introduction of an Improved HPLC Assay

Rabba

Xue

et al. 2011

J Pharm Pharm Sci

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-Purpose:To determine experimentally the intestinal permeability of the anticancer prodrug irinotecan, and to quantify the amount of its cytotoxic metabolite SN-38 that is intestinally excreted (exsorbed) as a predictor of intestinal toxicity, and to assess the effect of p-glycoprotein (p-gp) inhibitors (verapamil as a model) on the permeability and toxicity of irinotecan. Methods: Single pass intestinal perfusion of rat's whole length small intestines is applied to assess the permeability of the parent drug and quantify the intestinally excreted metabolite. The perfusion solution contained 30μg/ml of irinotecan (control group) without or with verapamil (verapamil group). A simple reversed phase HPLC method with UV detection is developed and validated for simultaneous determination of irinotecan and SN-38 using camptothecin as an internal standard. Results: HPLC-UV method found to be simple, specific, accurate, and precise. Effective permeability coefficient of irinotecan found to be 4.9±1.7  10 -3 mm/min and was doubled in verapamil group (P=0.007). Average cumulative amount of SN-38 exsorbed found to be 29 ng/cm over 2 hours perfusion time which was decreased to 15 ng/cm in verapamil group (P=0.016). Conculsions: in situ intestinal perfusion method was successfully applied to quantify the permeability of irinotecan and the exsorption of SN-38 in the same experiment, in a manner that robustly reflects real in vivo situation. P-gp inhibition using verapamil found to significantly enhance the intestinal permeability of irinotecan and potentially decrease the intestinal toxicity due to SN-38 exposure.

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“…Verapamil increased the absolute bioavailability (F) of irinotecan by 4.3 fold and decreased its biliary excretion. It appears that the concomitant and synergistic inhibition of P-gp present in rat intestine and liver is a plausible explanation for prominent increase in oral bioavailability of irinotecan [5]. However, in view of narrow therapeutic index, the co-administration of irinotecan and verapamil may result in unanticipated toxicities.…”

Section: Introductionmentioning

confidence: 99%

P-glycoprotein-dependent pharmacokinetics of irinotecan and its active metabolite, SN-38 in rats: Effect of verapamil

Garg¹,

Jagg²,

Khar³

et al. 2015

ADMET DMPK

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We have recently demonstrated that the oral bioavailability of irinotecan (80 mg/kg) can be increased at least 7-fold by co-administration of the P-gp blocker verapamil (25 mg/kg, Oral). As a result, co-treatment with P-gp inhibitor could be a useful strategy for bioavailability enhancement. However, in view of narrow therapeutic index, the co-administration of irinotecan and verapamil may result in unanticipated toxicities. Therefore, dose optimisation studies of irinotecan were performed when it is given in conjunction with a P-gp inhibitor. For dose optimization study, the bioavailability and pharmacokinetic parameters were studied in rats after oral administration of irinotecan at three doses (i.e. 20, 40 and 80 mg/kg) alone and in combination with verapamil (25 mg/kg, oral 7.84 ± 1.20, 19.94 ± 2.39 and 61.71 ± 15.0 h µg/ml, respectively. In

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Effect of P-glycoprotein inhibitor, verapamil, on oral bioavailability and pharmacokinetics of irinotecan in rats

Cited by 121 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

In Situ Intestinal Perfusion of Irinotecan: Application to P-gp Mediated Drug Interaction and Introduction of an Improved HPLC Assay

P-glycoprotein-dependent pharmacokinetics of irinotecan and its active metabolite, SN-38 in rats: Effect of verapamil

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