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The use of verapamil as an absorption enhancer for the paracellular route in-vivo was studied using FITC-labelled dextran (molecular weight 4000) (FD-4) as a hydrophilic model compound for transport enhancement. The kinetics of FD-4 after intravenous doses of 1 or 10 mg could be described by a two-compartment model with a systemic clearance of approximately 2 mL min-1 and a terminal plasma half-life of approximately 36 min. Rectal administration to rats, performed as a rectal infusion of 10 mg FD-4 together with 7 mM verapamil, resulted in a 10-fold increase in the percentage of the dose absorbed over a 5-h period compared with the control and a 6-fold increase compared with a bolus administration, although the total amount absorbed remained relatively low (approx. 3% maximum). Large inter-animal variation in effect values were noted. The data indicate that although verapamil is able to enhance the absorption of hydrophilic compounds in-vivo, practical application of verapamil for this purpose doses not seem feasible.

The absorption across rat intestinal tissue of the model peptide drug 9-desglycinamide, 8-arginine vasopressin from bioadhesive formulations was studied in-vitro, in a chronically isolated internal loop in-situ and after intraduodenal administration in-vivo. A controlled-release bioadhesive drug delivery system was tested, consisting of microspheres of poly(2-hydroxyethyl methacrylate) with a mucoadhesive Polycarbophil-coating, as well as fast-release formulation consisting of an aqueous solution of the peptide in a suspension of Polycarbophil particles. Using the controlled-release system, a slight improvement of peptide absorption was found in-vitro in comparison with a non-adhesive control system, but not in-situ or in-vivo. In contrast, bioavailability was significantly increased in all three models from the Polycarbophil suspension in comparison with a solution of the drug in saline. The effect appeared to be dose-dependent, indicative of intrinsic penetration-enhancing properties of the mucoadhesive polymer. A prolongation of the absorption phase in-vitro and in the chronically isolated loop in-situ suggested that the polymer was able to protect the peptide from proteolytic degradation. This could be confirmed by degradation studies in-vitro. The duration of the penetration enhancing/enzyme inhibiting effect was diminished with increasing complexity of the test model, in the same way as was previously found for the bioadhesive effect. This interrelationship suggests that the observed improvement in peptide absorption and the mucoadhesive properties of this polymer are associated. The development of a fast-release oral dosage form for peptide drugs on the basis of Polycarbophil appears to be possible.

A study has been made to identify the component(s) responsible for the absorption-promoting effect of MGK medium chain glyceride preparation commercially available as a mixture of glyceryl-1-monooctanoate, glyceryl-1,3-dioctanoate, glyceryl-1,2-dioctanoate, glyceryl trioctanoate, octanoic acid and glycerol. The action of the individual constituents has been evaluated on the rectal absorption of cefazolin in conscious rats. The results indicate that the action of MGK can be completely explained by the effect of glyceryl-1-monooctanoate, which both enhanced the extent and rate of cefazolin uptake.

The enhancing effect of the medium chain glyceride preparation MGK on the rectal absorption of the cephalosporin antibiotic cefazolin sodium was evaluated in relation to the rate of delivery. Cefazolin sodium proved to be absorbed to a small extent (15 to 27%) after rectal administration without MGK. Bolus administration with MGK enhanced rate and extent of cefazolin sodium absorption, resulting in a bioavailability of 57 +/- 26%. Linear infusion of 3 mg cefazolin sodium with MGK in 32 min produced complete absorption of the antibiotic (102 +/- 7%), but absorption occurred slower in comparison with bolus delivery. The rate of administration proved to be an important variable of the absorption enhancing effect of MGK.

The promoting action of the calcium chelating compound EDTA on intestinal drug absorption is supposed to be based on Ca2+ depletion, inducing widening of tight junctions. The aim of the present study was to evaluate the effects of the calcium-binding agent 3-amino-1-hydroxypropylidene-1,1-diphosphonate disodium salt (APD) on rectal cefoxitin absorption in rats. The extent of rectal cefoxitin absorption was enhanced by 0.5 to 6% w/v of APD, on rectal infusion as well as on bolus delivery, the latter regimen tending to result in lower bioavailabilities. A maximal cefoxitin bioavailability of 85 +/- 10% was achieved by infusion with 4% w/v of APD, compared with 14 +/- 12% without APD.