Assessment and modulation of acamprosate intestinal absorption: comparative studies using in situ, in vitro (CACO-2 cell monolayers) and in vivo models

Zornoza, Teodoro; Cano-Cebrián, M. J.; Nalda-Molina, Ricardo; Guerri, Consuelo; Granero, Luis; Polache, Ana

doi:10.1016/j.ejps.2004.04.004

Cited by 28 publications

(31 citation statements)

References 28 publications

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“…The P eff -value of FTA was enhanced as the concentration of sodium caprate was increased, exhibiting a clear concentration-dependent effect. [26] reported that the absorption enhancing effect of sodium caprate for acamprosate showed a clear concentration-dependent effect. Therefore, our present results are consistent with the previous report.…”

Section: Discussionmentioning

confidence: 99%

“…This physicochemical property of the drug led us to postulate that the low permeability of the drug in the intestinal mucosa was one important reason for its reported low bioavailability. The Food and Drug Administration (FDA) also recognises that the poor permeation of drugs across the intestinal mucosa (usually due to their high hydrophilicity) was one of the common factors leading to failed absorption and thus to low drug BA [14] . Whether the improvement of the lipid solubility of FTA can increase its oral BA and whether other infl uencing factors such as effl ux transporters, P-glycoprotein (P-gp), multidrug resistance related proteins (MRPs) also decrease the bioavailability of FTA are yet to be investigated.…”

Section: Introductionmentioning

confidence: 99%

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Intestinal absorption of forsythoside A in in situ single-pass intestinal perfusion and in vitro Caco-2 cell models

Wang

Shan

et al. 2012

Acta Pharmacol Sin

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Aim: To investigate the mechanisms underlying the intestinal absorption of the major bioactive component forsythoside A (FTA) extracted from Forsythiae fructus. Methods: An in vitro Caco-2 cell model and a single-pass intestinal perfusion in situ model in SD rats were used. Results: In the in vitro Caco-2 cell model, the mean apparent permeability value (P app -value) was 4.15×10 -7 cm/s in the apical-tobasolateral (AP-BL) direction. At the concentrations of 2.6-10.4 μg/mL, the effl ux ratio of FTA in the bi-directional transport experiments was approximately 1.00. After the transport, >96% of the apically loaded FTA was retained on the apical side, while >97% of the basolaterally loaded FTA was retained on the basolateral side. The P app -values of FTA were inversely correlated with the transepithelial electrical resistance. The paracellular permeability enhancers sodium caprate and EDTA, the P-gp inhibitor verapamil and the multidrug resistance related protein (MRP) inhibitors cyclosporine and MK571 could concentration-dependently increase the Papp-values, while the uptake (OATP) transporter inhibitors diclofenac sodium and indomethacin could concentration-dependently decrease the P app -values. The intake transporter SGLT1 inhibitor mannitol did not cause signifi cant change in the P app -values. In the in situ intestinal perfusion model, both the absorption rate constant (K a ) and the effective permeability (P eff -values) following perfusion of FTA 2.6, 5.2, and 10.4 μg/mL via the duodenum, jejunum and ileum had no signifi cant difference, although the values were slightly higher for the duodenum as compared to those in the jejunum and ileum. The low, medium and high concentrations of verapamil caused the largest increase in the P eff -values for duodenum, jejunum and ileum, respectively. Sodium caprate, EDTA and cyclosporine resulted in concentration-dependent increase in the P eff -values. Diclofenac sodium and indomethacin caused concentration-dependent decrease in the Peff-values. Mannitol did not cause signifi cant change in the P app -values for the duodenum, jejunum or ileum. Conclusion:The results suggest that the intestinal absorption of FTA may occur through passive diffusion, and the predominant absorption site may be in the upper part of small intestine. Paracellular transport route is also involved. P-gp, MRPs and OATP may participate in the absorption of FTA in the intestine. The low permeability of FTA contributes to its low oral bioavailability.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Intestinal absorption of forsythoside A in in situ single-pass intestinal perfusion and in vitro Caco-2 cell models

Wang

Shan

et al. 2012

Acta Pharmacol Sin

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“…A previous paper [13] showed, using in situ, in vitro (Caco-2 cells monolayer) and in vivo models that acamprosate intestinal absorption likely occurs via the paracellular pathway and its bioavailability in rats after oral administration is around 20%. Moreover, using an in situ rat gut technique, the intestinal absorption rate constant of the drug (k a ) was calculated.…”

Section: Introductionmentioning

confidence: 98%

Evidence of a flip‐flop phenomenon in acamprosate pharmacokinetics: an in vivo study in rats

Zornoza

Cano-Cebrián

Hipólito

et al. 2006

Biopharm & Drug Disp

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The pharmacokinetics of acamprosate were examined in the rat after oral and intravenous administration in order to detect the possible presence of a flip-flop phenomenon. Rats received 9.3 or 73.3 mg/kg of the drug as an intravenous bolus. The same doses were orally administered via gastric intubation. Plasma samples were taken from the jugular vein for determination of acamprosate concentration by liquid scintillation counting. The drug content was also quantified in urine and faeces. The acamprosate bioavailability was close to 20%, the amount recovered in the faeces being around 80% of the administered dose. The terminal slope of the oral plasma curve was significantly lower than that obtained after intravenous administration of the drug at both doses tested (p<2 x 10(-6) in both cases). Moreover, the downward slope after oral administration (lambda2=0.006 +/- 0.001 min(-1)) practically coincided with the first-order absorption rate constant, previously reported by us, obtained using an in situ rat gut technique. It is concluded that the acamprosate absorption rate is considerably slower than its elimination rate so that the drug exhibits flip-flop pharmacokinetics after oral administration. The lower intrinsic first-order absorption rate constant, ka, is responsible for this phenomenon.

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“…The bioavailability of heparin in rats could be increased almost 3-fold with C10 in solution with a C10 dose of 100 mg/kg (Motlekar et al, 2005). On the contrary, Zornoza et al (2004) state that C10 did not improve the oral bioavailability of acamprosate in rats. Improved intestinal absorption of a model decapeptide by co-administration of C10 could be demonstrated after intrajejunal instillation (Chao et al, 1999).…”

Section: Discussionmentioning

confidence: 83%

Thiolated polycarbophil/glutathione: Defining its potential as a permeation enhancer for oral drug administration in comparison to sodium caprate

et al. 2011

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Assessment and modulation of acamprosate intestinal absorption: comparative studies using in situ, in vitro (CACO-2 cell monolayers) and in vivo models

Cited by 28 publications

References 28 publications

Intestinal absorption of forsythoside A in in situ single-pass intestinal perfusion and in vitro Caco-2 cell models

Intestinal absorption of forsythoside A in in situ single-pass intestinal perfusion and in vitro Caco-2 cell models

Evidence of a flip‐flop phenomenon in acamprosate pharmacokinetics: an in vivo study in rats

Thiolated polycarbophil/glutathione: Defining its potential as a permeation enhancer for oral drug administration in comparison to sodium caprate

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