Peroral delivery of hydrophilic drugs is one of the greatest challenges in biopharmaceutical research. Hydrophilic drugs usually present low bioavailability after oral administration. One of the causes of this low bioavailability is their poor intestinal permeation through the paracellular pathway. This pathway is actually restricted by the presence of tight junctions at the apical side of the enterocytes. In the last few years, great interest has been focused on the structure and cellular regulation of tight junctions, materializing in more in-depth knowledge of this intestinal barrier. Simultaneously, and on the basis of this understanding, continuous efforts are being made to develop agents that can modulate tight junctions and magnify the paracellular permeability of hydrophilic compounds without causing significant intestinal damage. This review focuses on strategies to improve the paracellular permeation of poorly absorbed drugs as a way to enhance their bioavailability after oral administration. Most of the research on this subject has been carried out using in vitro models (mainly Caco-2 cell monolayers), which yield useful information on the potential effects and mechanisms of action of absorption-enhancing compounds. However, in vivo studies, which are much more scarce, are needed to confirm the effects of potential enhancers and to evaluate the suitability of including these compounds as excipients in drug formulation. We review the in vitro and in situ studies involving the most promising paracellular permeation enhancers (e.g., medium chain fatty acids and chitosan and its derivatives), analyzing the degree of drug absorption enhancement achieved, as well as the potential associated toxicity. The few studies performed in vivo are also presented. In addition, the findings of recent absorption enhancers, such as zonula occludens toxin or thiolated polymers, are reviewed.

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This paper reviews the empirical methods of quantitative microdialysis that have been used to interpret the results obtained from pharmacokinetic studies. The concept of extraction efficiency or recovery and the properties of recovery in vivo (variation with flow rate, time dependency and influence of the mode of administration) are considered. The most frequently used methods for determining recovery in vivo are described and evaluated in the light of recent theoretical studies. Specifically, we review the variation of flow rate method, the very slow flow method, the no net flux method and the delivery and retrodialysis methods. Special emphasis is placed on the description of each method, demonstrating its applicability to pharmacokinetic studies conducted under steady-state or transient conditions, and also its limitations. Finally, the more relevant studies that have compared the suitability of these methods are reviewed.

The effects of acamprosate on the in vivo dopamine extracellular levels in the nucleus accumbens and the involvement of N-methyl-D-aspartate (NMDA) receptors in these effects were investigated. Microdialysis in freely moving rats was used to assess dopamine levels before and during simultaneous perfusion of acamprosate and/or different agonists or antagonists of NMDA receptors. Perfusion with acamprosate at concentrations of 0.5 and 5 mM provoked a concentration-dependent increase in extracellular dopamine in nucleus accumbens. The lowest concentration of acamprosate assayed (0.05 mM) had no effect on dopamine levels. Infusion of NMDA (25 and 500 microM) and the glutamate uptake blocker, L-trans-pyrrolidine-2,4-dicarboxilic acid (PDC) (0.5 mM) into the NAc caused a significant increase in DA, whereas acamprosate (0.05 mM) co-infusion with these compounds blocked or attenuated the NMDA and PDC-induced increases in DA levels. Co-infusion of the selective antagonist of NMDA receptors, DL-2-amino-5-phosphonopentanoic acid (AP5) (400 microM) with acamprosate (0.5 mM), did not reduce the increase of DA levels induced by acamprosate. These results demonstrate that acamprosate is able to modulate DA extracellular levels in NAc via NMDA receptors and suggest that acamprosate acts as an antagonist of NMDA receptors.

Opioid antagonists are licensed drugs for treating alcohol use disorders; nonetheless, clinical studies have evidenced their limited effectiveness. Preclinical findings indicate that opioid receptor (OR) antagonists, such as naltrexone (NTX), reduce the alcohol deprivation effect (ADE). However, a detailed analysis of published data shows the existence of a delayed increase in ethanol consumption after continuous OR blockade, a phenomenon originally called as 'delayed ADE'. We have recently reported that D-penicillamine (DP) is able to prevent ADE through a mechanism dependent on the inactivation of acetaldehyde, the main metabolite of ethanol. Hypothetically, OR activation would be triggered by acetaldehyde after ethanol consumption. Hence, we conjecture that the combination of NTX and DP, due to their distinct but complementary mechanisms to impede OR activation, may be more efficacious in the prevention of the ADE and, specifically, the 'delayed ADE'. Herein, we compare the effects of the combination NTX/DP (NTX: 2×5 mg/kg SC injection daily/DP: SC infusion (0.25 mg/h)) versus NTX on the ADE in long-term ethanol-experienced rats. As expected, NTXtreated animals displayed a delayed ADE. However, NTX/DP treatment prevented this delayed effect. Our present data indicate that this combination therapy shows an adequate anti-relapse preclinical efficacy being able to overcome the preclinical limitations of NTX alone.