Aims This study investigated the absorption characteristics and the tolerability of rectally administered ropivacaine, a local anaesthetic, intended as a new local therapy for ulcerative colitis. Methods Thirty-two healthy volunteers participated in a randomized, placebocontrolled study. In study phase 1 ( n = 16, double-blind, crossover) single rectal doses of ropivacaine corresponding to 50, 100 and 200 mg base were given as 20-ml gel enemas. Eight of these subjects also received an i.v. infusion corresponding to 20 mg ( 2 H 3 )ropivacaine base given with the last rectal dose. In study phase 2 ( n = 16, singleblind, crossover) the same rectal doses were given but formulated in 20, 40 and 80 ml gel, respectively. Peripheral venous plasma samples and urine were collected over 12 h after dosing and analysed for ropivacaine base by gas chromatography and ( 2 H 3 )ropivacaine by gas chromatography-mass spectrometry. Ropivacaine and metabolites were analysed in urine by reversed phase liquid chromatography.Results AUC was proportional to the dose with a point estimate [95% confidence interval (CI)] for the increase, after doubling the dose, of 1.91 (1.66-2.20) and 1.95 (1.78-2.13) in study phases 1 and 2, respectively. The increase in C max was also proportional to the dose with corresponding results of 1.76 (1.52-2.04) and 1.84 (1.70-1.99). The volume of the rectal formulation had no influence on either the extent or the time course of absorption. The mean (s.d.) absolute bioavailability (% F ) was 56 (18)%. AUC and C max showed a two-to three-fold lower intra-than interindividual variability. Zero-order kinetics dominated the first 4 h of the absorption phase. Thereafter first-order kinetics were observed. The terminal half-lives were similar between the rectal doses and were longer than that after the i.v. administration, indicating an absorption-dependent half-life. The main urinary metabolite was 3-hydroxyropivacaine corresponding to about 23% of the dose. The subjects had no difficulties in retaining the doses and rectal administration of ropivacaine was well tolerated, both locally and systemically. Conclusions Plasma drug concentrations were proportional to the dose after rectally administered doses corresponding to 50-200 mg ropivacaine base in a gel formulation. The drug was well-tolerated. Mean bioavailability was about 60% and not influenced by variations in the enema volume. Initial absorption seemed to follow zero-order kinetics and then first-order kinetics after about 4 h. C max and AUC showed considerably less intra-compared with inter-individual variability, resulting in more consistent plasma concentrations within subjects.

The relative bioavailability of bacampicillin hydrochloride, a pro-drug of ampicillin, was compared after rectal and oral administration. Bacampicillin was administered rectally as a microenema. The oral formulation was an aqueous microcapsule suspension. They were given as single doses of 400 mg to 12 healthy volunteers after overnight fasting using a randomized cross-over design. Ampicillin and bacampicillin were determined in plasma and blood, respectively, using HPLC. Bacampicillin was rapidly absorbed from the rectum but to a much smaller degree compared to the oral dose. The median t-max was 0.5 and 0.75 h after the rectal and oral doses, respectively. The mean (SD) C_p-max was 1.2 (0.33) mg/l after rectal and 4.8 (0.98) mg/l after oral administration, respectively. Blood concentrations of bacampicillin were extremely low or undetectable with no indication of differences between the two modes of administration. The 95% confidence limits for the relative bioavailability of the microenema were 22.4–39.2 and 22.5–40.4% based on area under the plasma concentration time curve and urinary recovery, respectively. The rectal dose was followed by distress, diarrhea or pain, in 7 subjects. There were no adverse reactions after the oral dose. Bacampicillin was unaffected by β-lactamases produced by intestinal bacteria.