Ewoud J. van Hoogdalem

Rate-controlled Absorption Enhancement of Rectally Administered Cefazolin in Rats by a Glyceride Mixture (MGK)

Abstract— 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.

Absorption enhancement of rectally infused cefoxitin sodium by medium-chain fatty acids in conscious rats: concentration-effect relationship

The objective of this study was to assess the relative absorption promoting potency in terms of concentration–effect relationships of the medium-chain fatty acids hexanoic acid, octanoic acid, decanoic acid, and dodecanoic acid in conscious rats, using cefoxitin sodium as the rectally delivered model compound. Rectal uptake of cefoxitin, which was absorbed to a limited extent without enhancer (30 ± 25%), proved to be significantly enhanced by 2.0 M sodium hexanoate, 0.69 M sodium octanoate, and 0.22 M sodium decanoate, resulting in mean bioavailabilities of 102 ± 24, 68 ± 25, and 68 ± 10%, respectively. Thus, increasing fatty acid chain length results in increased enhancing potency from hexanoic acid to decanoic acid. However, using dodecanoate a statistically significant effect could not be reached, because of its limited aqueous solubility. Optimal chain length for absorption enhancement by medium-chain fatty acids is probably determined by interplay of intrinsic effects on mucosal permeability and solubility of the medium-chain fatty acid.

Absorption Enhancement of Rectally Infused Insulin by Sodium Tauro-24,25-Dihydrofusidate (STDHF) in Rats

The bile salt derivative sodium tauro-24,25-dihydrofusidate (STDHF) has been reported to promote nasal absorption of insulin. In the present study the effect of STDHF on rectal insulin absorption was investigated in rats. At concentrations of 1 and 4% (w/v) it enhanced insulin bioavailability from 0.2 ± 0.2 (control) to 4.2 ± 3.2 and 6.7 ± 2.1%, respectively, as assessed by radioimmunoassay. Insulin preparations with STDHF reduced blood glucose concentrations considerably in a concentration-dependent way. Coadministration of STDHF with Na2EDTA (0.25%, w/v) tended to increase further insulin bioavailability and hypoglycemic response. Varying the site of rectal administration did not influence these parameters.

3‐Amino‐1‐hydroxypropylidene‐1,1‐diphosphonate (APD): a novel enhancer of rectal cefoxitin absorption in rats

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.

Rectal absorption enhancement of des-enkephalin-γ-endorphin (DEγE) by medium-chain glycerides and EDTA in conscious rats

The stability of the neuroleptic peptide des-enkephalin-γ-endorphin (DEγE; Org 5878) in the rectal lumen and the rectal bioavailability of DEγE were investigated in conscious rats. Furthermore, the influence of peptidase inhibition, peptidase saturation, and absorption enhancement on DEγE bio-availability were evaluated. Na2EDTA (0.25%, w/v) prolonged the degradation half-life of DEγE in the ligated colon from 33 ± 7 to 93 ± 45 min. Without adjuvant, tritium-labeled DEγE was absorbed from the rat rectum to a very low extent (0–4%). After administration of an excess of unlabeled DEγE or with Na2EDTA, comparable results were obtained. The medium-chain glyceride preparation MGK markedly enhanced the rectal DEγE bioavailability, up to 8–20%, which was further increased to 10–44% by coadministration of Na2EDTA. No substantial influence of varying the rectal delivery rate was observed. The results suggest that absorption enhancement and enzyme inhibition both are essential for effective increase of rectal peptide bioavailability.

The influence of components on the rectal absorption of cefazolin in rats

Abstract— 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.

In-vitro Metabolism of YM17E, an Inhibitor of Acyl Coenzyme A: Cholesterol Acyltransferase, by Liver Microsomes in Man

Because YM17E (1,3‐bis[[1‐cycloheptyl‐3‐(p‐dimethylaminophenyl)ureido]methyl]benzene dihydrochloride) inhibits acyl coenzyme A:cholesterol acyltransferase (ACAT) it has potential application in the treatment of hypercholesterolaemia. In man and animals YM17E is extensively metabolized, via N‐demethylation, to five active metabolites (M1, M2‐a, M2‐b, M3 and M4). The main objectives of this study were to examine inhibition of YM17E metabolism by the products and identify the cytochrome P450 isoforms in liver microsomes which catalyse in‐vitro YM17E metabolism in man.