Site specific rectal drug administration in man with an osmotic system: influence on "first-pass" elimination of...

Lidocaine was administered to healthy volunteers at different sites in the rectum. Unchanged drug and monoethylglycinexylidide (MEGX) concentrations were measured in plasma with a newly developed gas chromatographic method. Lidocaine was given rectally by means of an osmotic system (Osmet(®)) which delivered 25 mg/h at zero-order rate. In a pilot experiment in two subjects it was shown that lidocaine administration close to the anus for 5 h resulted in higher lidocaine plasma levels as compared to administration at 15 cm from the anus. Six other subjects participated in three separate experiments, in which lidocaine was administered rectally close to the anus and at 7.5 and 15 cm from the anus. A zero-order infusion plasma level profile was found for both the parent compound and its metabolite. The MEGX/lidocaine plasma concentration ratio was calculated for all experiments. After administration most proximal to the anus the mean metabolite/parent drug concentration ratio was significantly less than that obtained after administration at 15 cm from the anus, whereas at approximately 7.5 cm from the anus the values were in-between. Comparison of the AUC lidocaine/AUC MEGX ratios gave similar results; the highest value, 3.2 ± 1.3 (mean ± S. D.), was found after administration close to the anus, while at 15 cm from the anus the ratio was 1.6 ± 0.3 (p < 0.01). The terminal elimination half-lives of lidocaine and MEGX did not differ for the three sites of administration, and the mean values were 110 and 180 min respectively. The results of this study demonstrate that the site of drug administration in the human rectum determines the degree of hepatic "first-pass" elimination of high-clearance drugs. Maximal avoidance of presystemic elimination is achieved when administration takes place close to the anus.